Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a mu-opioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappa-opioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or ‘serotonin syndrome’ may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden. The tandem public health crises of opioid overdose and the chronic pain have led to the current “re-imagining” of long-term analgesic therapy. Despite the fact that pain is one of the most ancient complaints in medicine, the perfect analgesic agent has yet to be developed. Opioids are effective analgesics that act as agonists of the opioid receptors, but by activating these pathways, they can cause various potentially treatment-limiting side effects, such as respiratory depression, somnolence, dizziness, opioid-induced constipation, nausea, vomiting, pruritus, opioid dependence, and opioid use disorder (OUD). The increasing prevalence of OUD has heightened scrutiny on opioid prescribing overall, leaving drug developers and healthcare professionals to search for safer analgesic therapy without sacrificing effectiveness.The recent development of atypical opioids is a partial response to that challenge . BorrowiThe aim of this narrative review is to evaluate recent studies of these agents and whether these agents may be considered safe, effective pain relievers in the population of chronic cancer and non-cancer pain patients, for whom there are often no ideal analgesic agents. The objective is to determine if they present specific advantages or disadvantages to these patients with their unique and atypical mechanisms of action.The agentsThese three atypical opioids are synthetic small molecules offering mu-opioid receptor (MOR) agonism in combination with additional synergistic effects. All are available as oral analgesics and the two commercially available products, tramadol and tapentadol, are offered in immediate-release (IR) and extended-release (ER) formulations. Cebranopadol has not yet been commercially released in the market.Tramadol, the oldest of these three agents, has become widely used in the United States for pain control, with about 36.5 million prescriptions dispensed in the United States in 2018 . The DruDeveloped in the late 1980s, tapentadol is sometimes unfairly portrayed as a newer version of tramadol . Unlike The dual mechanisms of action of cebranopadol, a first-in-class atypical analgesic, combines MOR agonism along with agnostic activity at the nociception/orphanin (NOP) FQ peptide receptors ,10. The Efficacy for chronic painTramadolTramadol may be described as a centrally acting analgesic and a weak opioid, and there is evidence in the literature that it may confers effective pain relief for some patients . TramadoThere is only limited and low-quality evidence for the use of tramadol in adult cancer pain patients . In factTapentadolFor conventional analgesics, cLBP with a neuropathic component is a prevalent condition that remains challenging to treat. In a study comparing prolonged-release (PR) tapentadol monotherapy 500 mg to a combination treatment of PR tapentadol 300 mg plus pregabalin 300 mg, 288 patients with pain ≥6 at baseline demonstrated significant improvements in neuropathic pain relief and health-related quality of life at eight weeks, but the tapentadol monotherapy group had greater pain relief . The ratLong-term pain control can be challenging to offer as pain medications can become less effective over time or tolerability issues may arise. ER tapentadol was evaluated for use of three months or more in patients with moderate to severe musculoskeletal pain in a systematic review of four studies  . ER tapeThese studies for cLBP, osteoarthritis, and musculoskeletal pain found that there was intersubject variability with respect to tapentadol response. Response stratification for any analgesic therapy is challenging but offers great potential to optimize pain control. In an open-label retrospective study of cLBP patients taking tapentadol, demographic characteristics failed to show any predictive value, but various metrics about pain intensity, pain characteristics, and the presence of neuropathic pain could be used to predict response, suggesting that response stratification algorithms might be possible .DETECT instrument to identify a neuropathic component in 196 severe cLBP patients, a 12-week open-label study was conducted using PR tapentadol, titrated to individual patients, but with a maximum daily dose of ≤500 mg with IR tapentadol 60 mg available for rescue analgesia during titration no more than twice daily [DETECT instrument allows for a possible 38 point score if pain has a neuropathic component, so reduction of three points is not considered a substantial improvement.Using the paince daily . In the ce daily . The paiChronic neck pain is a prevalent condition, but there are a paucity of studies addressing appropriate treatment. In a study of 94 adults with severe neck pain refractory to step III opioid treatment, patients were administered 100 mg/day of PR tapentadol and then doses were titrated in 50 mg increments to a maximum dose of 500 mg/day. At the end of four weeks, 70% of patients had ≥30% improvement in pain and there were significant functional improvements as well based on the Neck Disability Index . In a stPainful diabetic polyneuropathy is challenging to treat. A study of adults with moderate to severe pain associated with diabetic peripheral neuropathy allowed 318 patients to enter a three-week titration period when they received ER tapentadol 100 mg to 250 mg twice a day . Those wTapentadol has been shown in some studies to be an effective analgesic for cancer pain, but prospective studies to date have been small . In a syCebranopadolCebranopadol is the newest of these agents and has not yet been cleared for market release. In a placebo-controlled study of patients with moderate to severe cLBP, cebranopadol was administered at doses of 200, 400, and 600 mcg with PR tapentadol 200 mg twice daily as comparator . At 12 wIn a non-randomized open-label single-arm study, cancer patients with moderate to severe pain who had previously been treated in a double-blind clinical trial comparing PR morphine to cebranopadol entered a 26-week phase and were treated with cebranopadol at doses ranging from 200 to 1000 mcg per day . CebranoSafetyTramadolTolerance may develop with tramadol and its analgesic effect is limited as it is a weak opioid . A retroIn an overview of Cochrane reviews about safety and tolerability of opioids (including but not limited to tramadol) for treating chronic non-cancer pain in adults, the absolute rate of any adverse event in placebo-controlled studies was 78% with an absolute event rate of 7.5% for a serious adverse event . TramadoIn a study of 21 healthy adult subjects taking both pregabalin and tramadol concurrently, no clinically relevant drug-drug interactions were reported and both drugs were well tolerated . PatientTramadol has been associated with seizures but usually at supratherapeutic dose ranges . Since cSerotonin syndrome occurs as a result of build-up of serotonin (5-hydroxytryptamine or 5-HT) at the 5-HT receptors, capable of producing changes in mental status, autonomic hyperactivity, and neuromuscular symptoms. Other serotonin syndrome symptoms may include restlessness, anxiety, disorientation, clonus, muscle rigidity, tremor, hypertension, tachycardia, hyperthermia, and shivers . RangingIn the United States, the misuse and abuse of tramadol is less than that for hydrocodone and oxycodone . TramadoTapentadolIn several comparative studies, tapentadol was found to be associated with adverse events similar to classic opioid-associated adverse events, but with a somewhat lower incidence of gastrointestinal side effects  ,66.Using controlled-release (CR) oxycodone as the comparator drug, PR tapentadol was evaluated in a placebo-controlled clinical trial with 990 knee osteoarthritis patients . After aIn a study of 63 knee osteoarthritis patients with severe chronic pain administered PR tapentadol 50 mg to 250 mg twice daily over a five-week titration period followed by a seven-week maintenance period and using IR tapentadol as rescue analgesia, the response rate was 94.3% and pain decreased significantly from baseline to 12 weeks . AdverseIn a post-hoc pooled analysis of three randomized controlled trials of ER tapentadol (100 mg/day to 250 mg/day) for control of chronic knee pain associated with osteoarthritis, those patients with diagnosed hypertension prior to treatment  did not have clinically important changes in heart rate or blood pressure while taking ER tapentadol .Tapentadol is not associated with serotonin syndrome but serotonin syndrome may occur when it is taken with other drugs that may lead to serotonin toxicity . In factTapentadol has a lower affinity for the MOR than other opioid analgesics, which suggests it has less abuse potential than typical opioids, such as morphine, hydromorphone, oxycodone, and others. In a retrospective study, it was found that the odds of abuse with tapentadol were 65% lower than those of oxycodone .CebranopadolIn the first human study of analgesic efficacy of cebranopadol, 641 cLBP patients were treated for 14 weeks with 200, 400, or 600 mcg of cebranopadol daily; tapentadol 200 mg twice daily; or placebo . TreatmeIn a preclinical murine study, it was reported that the so-called “therapeutic window” between pain relief and respiratory depression was longer for cebranopadol than fentanyl, and this has been attributed to the NOP/FQ receptor activity of cebranopadol . It has In a non-randomized, open-label, 26-week clinical trial using oral cebranopadol to treat cancer pain, 84% of patients had at least one treatment-emergent adverse event and the most frequently observed were asthenia, malignant neoplasm progression, and reduced appetite .Head-to-head clinical trialsTramadolAn eight-week, randomized, double-blind, double-dummy, active-controlled, non-inferiority study (n=280) compared the safety and effectiveness of transdermal buprenorphine to SR tramadol in patients with moderate to severe musculoskeletal pain . PatientER tramadol 200 mg was compared to modified-release (MR) flupirtine 400 mg and placebo in a four-week study of moderate to severe cLBP . FlupirtTapentadolCompanion placebo-controlled studies compared IR tapentadol (50 or 75 mg) to IR oxycodone hydrochloride (10 mg) for efficacy in treating acute and chronic pain as well as tolerability . PatientWhen compared to CR oxycodone, PR tapentadol over one year showed both agents provided adequate analgesia for moderate to severe knee or hip pain associated with osteoarthritis with similar rates of treatment-emergent adverse events (85.7% for tapentadol and 90.6% for oxycodone patients) . More CRIn a comparative trial of ER tapentadol (100 to 500 mg/day) or SR morphine (20 to 140 mg/day), cancer pain patients were all converted to ER tapentadol and 84.0% of patients maintained or had improved pain control in the first week of conversion . FurtherIn a study of cancer pain, 496 patients were randomized and then titrated to their optimal dose of PR tapentadol (100 to 250 mg twice daily) or CR morphine sulfate (40 to 100 mg twice daily) with rescue medication available in the form of IR morphine 10 mg (no maximum dose) . Of the Cancer patients treated for pain (n=343) compared ER tapentadol to CR oxycodone and reported that tapentadol analgesia was non-inferior to that of oxycodone and the rate of adverse events  were statistically similar . HoweverCebranopadolIn a study of multiple doses of cebranopadol and PR morphine in 126 cancer patients, cebranopadol was noninferior to PR morphine for pain control and treatment-emergent adverse events were similar (83.1% for cebranopadol versus 82.0% for PR morphine) . The dosConversion of these three agentsIn some situations, clinicians may wish to rotate patients from one of these single-entity molecules to another or from one formulation to another. The potential of converting IR tapentadol to ER tapentadol and vice versa was evaluated in a multicenter study of 88 patients with moderate to severe cLBP . PatientConversion from tramadol to tapentadol was reported in cancer patients who were transitioned directly to PR tapentadol from tramadol with ~70% achieving improved analgesic benefit with similar tolerability . In a muIn an open-label study of PR tapentadol (50 to 250 mg twice daily) for treatment of severe cLBP, patients were switched from previous typical opioid analgesic regimens to tapentadol, titrated over a period of five weeks, and then maintained for seven weeks . Rescue Tramadol, tapentadol, and cebranopadol may be considered atypical opioids in which dual mechanisms of action are present in a single molecule. These agents combine the analgesic efficacy of typical opioids with the promise of lesser abuse potential and greater tolerability. Their role in chronic pain control appears to be promising as they are effective pain relievers and appear to be at least as safe and tolerable as typical opioids. Tramadol is often used as first-line treatment of musculoskeletal pain while tapentadol is used for cancer pain, osteoarthritis, and other chronic pain conditions. Cebranopadol, which is not yet market released, is a first-in-class atypical opioid that has been effective in treating moderate to severe cLBP as well as cancer pain. These are important new agents in the analgesic armamentarium.


Estimates suggest that 10-40% of lumbar spine surgery patients experience persistent post-surgical pain (PPSP). PPSP is associated with 50% greater healthcare costs, along with risks of emotional distress and impaired quality of life. In 2019, U.S. Health and Human Services identified brief and digital behavioral treatments as important for pain management after surgery. Indeed, brief behavioral pain treatments delivered in the perioperative period may offer patients a low burden opportunity to acquire essential pain coping strategies for enhanced surgical recovery. Additionally, the COVID-19 pandemic has diminished in-person pain treatment access during extended perioperative time frames, thus underscoring the need for on-line options and home based care. This report describes the integration of an online, live-instructor delivered single-session pain self-management intervention (Empowered Relief) into the standard of care for lumbar spine surgery. Here, we apply the RE-AIM framework; describe systems implementation of the Empowered Relief intervention in a large, academic medical center during the COVID-19 pandemic; describe operational challenges and financial considerations; and present patient engagement data. Finally, we discuss the scalable potential of Empowered Relief and other single-session interventions in surgical populations, their importance during extended perioperative periods, practical and scientific limitations, and new directions for future research on this topic. Global estimates suggest that close to 313 million surgeries are performed annually . Up to 8The COVID-19 pandemic has created major symptom challenges for patients seeking pain care and spine surgery, including exacerbated pain, increased distress, and decreased health promoting behaviors, such as physical activity . ProlongFew studies have examined the efficacy of behavioral pain treatments in the perioperative period, and even fewer have examined brief and online treatment delivery. Behavioral or “psychological” treatments for pain typically include pain education, strategies to reduce unhelpful ways of interpreting pain, and modification of disabling behaviors. Behavioral therapies for pain consistently demonstrate improvements in pain and distress compared to those that receive standard health education or exercise programs . A recenEmpowered Relief is a single-session 2-h pain relief skills class for acute/surgical and chronic pain that was developed by Beth Darnall at Stanford University. Multiple randomized trials provide efficacy evidence for Empowered Relief delivered across different patient populations and delivery formats. Results for a 3-arm randomized controlled trial conducted in 263 adults with chronic low back pain revealed that in-person delivered Empowered Relief was non-inferior to 16-h of CBT for reducing pain catastrophizing, pain intensity, pain interference, and multiple secondary outcomes at 3 months post-treatment . A seconTwo randomized controlled trials of MSS provide efficacy evidence in breast cancer surgery and orthopedic trauma surgery patients. Results for the first trial in breast cancer surgery revealed that compared to an automated, online health education intervention, within a 14-day window of post-surgical observation of opioid use, MSS reduced time to opioid cessation by 6.5 days n = 21) completed a post-class acceptability and satisfaction survey. Data exist only for the patients who engaged in the treatment and completed a post treatment survey. As such a major selection bias should be considered when interpreting the ratings. Among the surveys collected acceptability was high with 95% of participants rating the treatment as understandable, 85% rated it useful and relevant for the future, and the overall treatment satisfaction rating was 90%.The two trials of automated Empowered Relief provide promising early evidence for improving outcomes in different surgical populations. Based upon these findings, in 2019-2020 we implemented at Cleveland Clinic Spine Surgery an uncontrolled feasibility implementation project of automated Empowered Relief in spine surgery patients . The Cleveland Clinic Institutional Review Board assigned the project exempt status; data included patient engagement rates and frequencies related to a treatment satisfaction survey. All spine surgery patients were invited to receive the online treatment and neither compensation nor incentives were provided for treatment engagement or survey completion. Of the 158 patients who expressed interest in receiving the online treatment during an 8-week perioperative window, 58 completed the online treatment (37% treatment engagement rate which was notably lower than for the breast cancer and orthopedic trauma studies). Additionally, 36%  to an online, live clinician-delivered 2 h Empowered Relief class that was tailored to the spine surgery patient. The primary aim of this report is to describe the pathway that was built to operationalize online Empowered Relief as standard intervention in spine surgery patient care. We present patient engagement rates that support the feasibility of online live-instructor delivered Empowered Relief in spine surgery. Of note, we found no published trials that have investigated either efficacy, feasibility, or clinical implementation of an online, live instructor-delivered pain relief skills intervention in spine surgery.The Cleveland Clinic is a large multi-specialty academic medical center serving patients locally, across the nation and internationally. The Cleveland Clinic Center for Spine Health serves thousands of patients each year, treating the most complex spine issues. The center's team is comprised of specialists including neurosurgery, orthopedics, medical spine, chronic pain and pain psychology. The Center for Spine Health performs ~2,000 spine surgeries each year.p = 0.0007), although did not meet the threshold for minimally important difference . Among patients who canceled or were no-shows, none of the within-group changes were statistically significant . There were no statistically significant between-group differences in change score, which was attributed to small sample sizes of PROS completion between 1 and 90 days of the class . Further analyses revealed that individuals in the no show/cancel group were also less likely to follow up with other behavioral appointments, thus further limiting their ability to complete PROs , specifically pain interference and pain catastrophizing, compared to patients who canceled/no showed. The Cleveland Clinic IRB assigned this project exempt status. Analysis of a 12-month period from January 2021-December 2021 demonstrated a 72% engagement rate in the online class. For the patients who completed Empowered Relief, within-group pre-post changes were statistically significant for the Pain Interference T-score  education of providers and patients, 2) efficient and low burden clinical implementation, and 3) continuous improvement of the intervention's integration into standard of care. See The RE-AIM framework,  one of tThe RE-AIM model defines reach as the number of individuals in the targeted intervention that are willing to engage in the program. Education of patients and providers was essential to enhance class engagement and project success. The messaging of Empowered Relief for spine surgery as “best practice and standard of care,” in our health system is supported by the previously noted HHS recommendations and designed to enhance receptivity to surgical patients. Additionally, the brief and online format of the class specifically was designed to improve overall access to the intervention.Effectiveness refers to the impact of Empowered Relief class on key outcomes. In the early phases of the project, our team's focus was on feasibility, engagement and acceptability of the intervention. Continued data collection from this project will allow our team to assess class effectiveness on sub-acute pain (3 months post-surgery) and CPSP (6+ months post-surgery), disability and pain catastrophizing, compared to individuals who do not attend/engage in Empowered Relief.From a systems standpoint, the RE-AIM dimension of adoption centers upon the enhancement of organizational support . Thus, iOur team supported several clinicians certification as Empowered Relief instructors . The training for Empowered Relief spans over two full days and includes expert led didactic content, a demonstration patient class, interaction with peers and faculty, and small group skills practice.The Center for Spine Health received education about the class during monthly staff meetings. In-services were offered with nursing to support roll-out of the project and to enhance stakeholder buy-in. The clinical champions in nursing, surgery and psychology elicited feedback from their team each week on 1) efficiency of the referral process, 2) patient engagement and 3) barriers to implementation. Findings in these three key areas were communicated back to the core workgroup each week.An important factor to facilitate adoption of Empowered Relief as part of standard of care for spine surgery was creation of a workflow that was efficient and low burden.A physician and a nurse champion were identified to educate clinicians in their areas about the class, to enhance clinician engagement, to serve as key stakeholders to identify systems problems.An order for the electronic medical record was developed for the class that allowed real-time scheduling and provider tracking of referral and patient participation.Educational materials were created and distributed to patients at point of scheduling to provide a brief overview of the class and to remind providers to market the program.Additional educational materials were deployed to patients electronically including information on: utilizing the virtual technology, billing/insurance, and a frequently asked questions sheet; this communication helped decrease staff burden in responding to patient inquiries.The RE-AIM framework refers to implementation as patients' engagement and utilization of the intervention  and the fidelity of the intervention and adaptations made (systems level).All male and female patients aged > 18 years undergoing thoracic or lumbar laminectomies with or without fusion were referred to Empowered Relief prior to surgery. The Institutional Review Board at the Cleveland Clinic assigned this clinical improvement project exempt status. The first Empowered Relief class for the surgical cohort was offered July 1, 2021. Data on participation rates were gathered from July 1, 2021 to March 2, 2022.The Empowered Relief class recruitment occurred at the time in which spine surgery was recommended by the surgeon. Empowered Relief classes were offered 1-2 times per week to provide flexibility and accommodate patients' schedules with other perioperative appointments. For insurance billing, Health and Behavior Assessment and Intervention Services were used. These codes are designed to address psychological, behavioral, emotional, cognitive and interpersonal factors impacting the treatment of an individual with a diagnosed physical health problem. These codes may also be used to provide tele-therapy services .Online Empowered Relief is delivered by a certified instructor. Our perioperative program limited the size each class cohort to 12 patients. Classes occur through a secure online platform that is integrated with patients' electronic medical record. Family members are also encouraged to participate.t-tests for continuous variables and Fisher's exact test for categorical variables.Patient characteristics were summarized using mean and standard deviation for continuous variables and counts and percentages for categorical variables in the full patient sample and stratified by completion of session vs. cancel/no-show. Comparisons were made using two-sample Immediately after the class, participants received an e-survey to assess their perceptions about the class, including satisfaction, perceived usefulness of information, and likelihood to use the skills learned; all items use an 10-point scale, where 1 is the lowest rating and 10 is the highest possible rating. This survey has been used in prior work . ParticiOf the 78 patients who were scheduled for Empowered Relief from July 2022 through March 2022, 48 attended the class (61.5% engagement rate). Class participant mean age was 62.9 (SD = 12.4) with 45.8% female and 87.5% white. Patients who completed the class were less likely to be female than patients who canceled or no-showed . Fifteen patients completed the post-class survey (31.3%), which was launched mid-way through the project (November 2021), thus likely also contributing to small sample size. With the consideration of the small sample size and selection bias, those that did complete the post-class survey reported high satisfaction with the class, with the highest percentage of patients (46.7%) answering a 10/10  to the question, “How likely are you to use the skills and information you learned?” See The RE-AIM maintenance dimension refers to 1) durability of the intervention on an individual level and 2) the larger systems and organizational level buy in to sustain continuation of the project. Important challenges were identified during clinical implementation. These valuable learning points were used to continually improve the process for our team and our patients targeting both the systems and individual level.The pre-operative period is a busy and stressful period for the surgical candidate. Integration of the class into the other pre-operative requirements posed a challenge; to enhance patient engagement the class was strongly encouraged by all clinicians, but not mandated for surgery. Our administrative staff pro-actively scheduled the patient into the class to decrease burden on the patient or nursing staff. The nursing team expressed concerns upon the project launch for the potential to increase burden on their workload. Steps were taken to minimize additional work for the nursing team and to monitor this possibility on an ongoing basis. Our team met with the nursing team to further understand the workload and perioperative tasks each nurse is responsible for completing. We learned that patients often rely heavily on nurses to ask additional questions and concerns, which are typically made through electronic messages and/or phone calls. Our scheduling process was designed to divert these messages from the nursing team to our chronic pain team. This allowed nursing to be responsible only for verbally discussing the class during the pre-operative visits with the patient and then making sure that the scheduling order was placed. Our team monitored number of patient messages and phone calls as a result of the class and will continue to gather this data to allow for adjustments to the scheduling process to be made as needed.Our system has experienced an uptick in utilization of virtual technology for healthcare in response to the COVID pandemic. We utilize secure, encrypted technology through the electronic medical record that also allows for group visits. After the initial pilot we recognized a need to provide multiple layers of education prior to and during the group visit to ensure patient engagement and to troubleshoot technology difficulties. Each class was delivered with an administrative staff present; as the instructor focused on delivering the class content, the other staff addressed participant logistic and technologic issues.via the automated scheduling process to minimize burden on nursing staff. Anecdotally, during the class patients reported increased anxiety associated with care interruption and extended surgical delays, thus underscoring the importance of the class. Observed limitations include difficulty treating patients who reside out-of-state, and, for some patients, apprehensiveness about virtual care.The COVID pandemic has created specific challenges in surgical care. In particular our workflow was impacted by 1) clinical staff shortages, 2) surgical delays leading to patient uncertainty and distress due to waiting times and 3) conversion to online/virtual delivery of care. Nursing shortages result in provider burnout and clinician overwhelm with integration of a new process or project into their already busy workday. We streamlined the workflow To our knowledge, this is the first report of pragmatic implementation of an online clinician delivered behavioral intervention targeting spine surgery candidates. We sought to address key gaps identified by the HHS by integrating online-delivered Empowered Relief as standard care for chronic pain and in spine surgery patients at an academic medical center. We described a model of clinical integration based in the RE-AIM framework that dually considered the needs of patient and clinician stakeholders. Our model underscores the importance of developing systems to enhance provider and patient engagement in augmenting standard care with stakeholder education, creation of an efficient clinician-centered workflow and continuous improvement. Our model may serve as an initial implementation blueprint for other healthcare systems wishing to initiate similar initiatives.A standard care model for behavioral pain medicine stands in stark contrast to current models of behavioral health service delivery wherein typically only patients at highest risk are selected for therapist intervention. Online options offer patients the option of home-based receipt of care with a goal of optimizing the surgical outcomes of all patients rather than treating only those at the greatest risk. Engagement rates for chronic pain (72%) and spine surgery (61%) cohorts suggest good initial feasibility for a standard care model and high rates of patient satisfaction. Further study is needed on larger sample sizes to understand patient perceptions and class utility more broadly.Previous investigations have revealed that another barrier to behavioral pain care is patient reluctance to see a psychologist . Our mesThis report also highlights the unique challenges that exist within the context of the COVID pandemic. There is a need to maintain continuity of care and support patients who are experiencing extended delays to surgery. This is an emergent and understudied issue. A recent systematic review on the impact of the COVID pandemic on surgical practices similarly reported that there are no studies addressing the clinical impact of delaying surgical care during lockdowns . Brief, We highlight several challenges and opportunities for improvement. Our findings regarding class acceptability and efficacy were limited by low survey response rates. There are several factors to consider: (1) It is likely that patient habituation to multiple electronic messages prior to surgery contributed to low survey completion; (2) patients were not incentivized to complete the class satisfaction survey; (3) patients receive multiple other patient satisfaction surveys as part of standard of care. Implementing a system that would immediately deploy the anonymous satisfaction survey to class attendees may enhance patient survey completion. Additionally, survey completion rates may be improved with compensation or incentives.Findings from our project highlight several opportunities for future research. First, there is a need to understand the efficacy of brief, online delivered behavioral intervention in the perioperative period for spine surgery. Opportunities exist to examine the impact of single-session perioperative interventions on surgical outcomes such as pain, pain related coping and opioid use. Research is needed to elucidate the unique medical and psychological challenges of the spine surgery candidate in the context of the COVID pandemic. Such information will inform improvements in processes and systems to support these patients fully and enhance continuity of care.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.This study was reviewed and approved by the Cleveland Clinic Institutional Review Board.SD, JS, AS, and BD contributed to concept and design of the study. SD and AS facilitated data gathering and analysis. SD wrote the first draft of the manuscript. BD heavily edited the manuscript. NT assisted in data analysis. All authors assisted in editing and revision of the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Percutaneous plasma disc decompression (PPDD) is a minimally invasive treatment for discogenic low back pain and herniated disc-related symptoms. However, there are no known outcome predictive variables during the procedure. The purpose of this study was to evaluate and validate epidurography as an intra-procedure outcome predictor. We retrospectively enrolled 60 consecutive patients who did not respond to conventional treatments. In the next stage of treatment, PPDD was performed, and the epidurography was conducted before and after the PPDD. We analyzed the relationship between epidurographic improvement and the success rate. The Numerical Rating Scale and the Oswestry Disability Index were used to assess pain and functional capacity, respectively, before the procedure and 1 month after the procedure. The pain reduction and the success rate in the epidurographic improvement group were significantly higher than in the epidurographic non-improvement group. Both the Numerical Rating Scale and the Oswestry Disability Index scores were significantly reduced in both groups, but there was no significant difference in Oswestry Disability Index scores. This study’s results showed that PPDD is an effective treatment method. We also suggested that epidurography may be a potential outcome predictor for ensuring successful outcomes and determining the endpoint of the procedure. Low back pain is very common and affects 80% of individuals at some point in their lives ,2. AccorManagement of chronic discogenic low back pain includes noninvasive conservative treatments, such as medications, physical therapy, behavior management, psychotherapy, and invasive surgical approaches. In a recent meta-analysis, it was argued that surgical treatment is not superior to non-surgical treatment as a treatment for chronic low back pain . In addi® technique) using bipolar radiofrequency energy to remove disc material [Percutaneous plasma disc decompression (PPDD) was approved in the USA by the Food and Drug Administration (FDA) as a minimally invasive technique for discogenic back pain in 2000 . It is pmaterial . PPDD ismaterial .To evaluate the success of the procedure, standardized pain measuring tools—e.g., a visual analog scale (VAS); numerical rating scale (NRS); and standardized assessments of functional capacity in spinal mobility deficit caused by back pain, such as the Oswestry Disability Index (ODI)—were used. In addition, several imaging modalities, such as plain radiography, computed tomography (CT), and magnetic resonance imaging (MRI), were used to evaluate the success of the procedure. However, these modalities are expensive, do not offer real-time assessment during the intra-procedure period, and may take longer to show changes in disc volume. Moreover, their results do not always coincide with the patients’ symptoms .Although there are studies on variables that can predict and evaluate the success of PPDD before and after the procedure, there is no study on intra-procedure outcome predictive variables ,9. In orWhen disc protrusion occurs in the epidural space, the contrast medium does not spread well on the epidurography. Consequently, epidurography was used during percutaneous epidural neuroplasty and spinal surgery to confirm the success of the procedure ,14.We speculated that PPDD would reduce the disc volume, ensuring the epidural space and resulting in the improvement of epidurography. Thus, the purpose of this study was to evaluate and validate epidurography as an intra-procedure outcome predictor by correlating the change in epidurography with the change in the pain and functional score after PPDD.This retrospective observational study was approved by the Institutional Review Board of Ajou University Hospital of Korea (IRB No. AJIRB-MED-MDB-19-409) in November 2019. The requirement for informed consent was waived because of the retrospective case-control nature of the study.From January 2017 to December 2019, we retrospectively enrolled 60 consecutive patients with low back pain, with or without leg radicular pain (NRS ≥ 4), who did not respond to physical therapy, medications, and epidural steroid injections . As the PPDD was performed on an outpatient basis by a pain physician with more than 10 years of experience in the field. . A prophA 17-gauge spinal cannula was introduced into the disc using the Kambin’s triangle approach. The Kambin’s triangle was formed by the path of the spinal nerve, upper border of the lower vertebral body, and anterior border of the superior articular process of the low vertebra.After the cannula was positioned at the junction of the annulus and nucleus, the stylet was removed from the cannula, and the into-LB  was placed into the spinal cannula and advanced until its tip was approximately 5 mm beyond the tip of the spinal cannula. At this point, the active portion of the into-LB was situated beyond the inner layer of the annulus and within the nucleus. A total of 6 channels were created at the 2, 4, 6, 8, 10, and 12 o’clock positions. After the withdrawal of the into-LB, 2 mL of 0.3% mepivacaine was injected into the PPDD tract, but not intradiscally. The skin puncture site was then closed with a suture or Steri-Strips.Before the PPDD, a wire-type epidural catheter, ABEL catheter , was inserted via the sacral hiatus toward the anterior epidural space of the involved disc level under fluoroscopic guidance. After confirming the position of the wire-type epidural catheter, 5 cc of a nonionic contrast medium  was injected a, and thAll the patients were observed for 2–4 h postoperatively for any development of neurological deficit or other procedure-related complications. Before discharge, we provided patients with post-procedure precautions and information about rehabilitation treatment . For theEach patient’s epidurograms  were analyzed by two pain physicians, who were not involved in the procedures and were only aware of the spinal level to be investigated. The analysis of the epidurograms was categorized as “improvement” or “no improvement.” Epidurographic improvement was defined as post-PPDD contrast media extending above the involved disc level in the anteroposterior view, although it did not extend above the involved disc level in pre-PPDD contrast media a,c. EpidThe patient’s degree of pain was measured using a standardized 11-point (0–10) NRS and evaluated by a well-trained physician at baseline 1 month after PPDD. The severity of pain was scored from 0 to 10, where “0” represented no pain and “10” represented the worst pain. The patients were encouraged to express their feelings regarding the pain.The ODI was used to assess the patients’ degree of dysfunction. The ODI assessments were performed at baseline 1 month after PPDD. The ODI is a 10-item questionnaire used globally to functionally assess patients with low back pain. However, in this study, we used the 9-item Korean version of the ODI, which excludes the assessment of sexual function, for cultural reasons .A successful treatment after 1 month was defined as over a 50% reduction in the NRS score post-PPDD. Further, we analyzed the relationship between epidurographic improvement and the success rate.When estimating the sample size by the pilot study, the total sample size was 28 patients when the significance level was 0.0500 and the power was 0.8 in the Chi-square test. However, since the number of patients is small and if w (Phi) is corrected, a suitable total sample size of 60 was obtained. The patients’ demographic data were analyzed using the Student’s t-test, Chi-square test, and Mann–Whitney U test. A Wilcoxon signed-rank test was used to determine the difference in NRS and ODI scores before and after PPDD. The relationship between epidurographic improvement and the success rate was analyzed using the Chi-square test.p < 0.001).The demographic data are shown in In this study, we found that PPDD is effective in reducing pain and improving functional capacity in patients who have chronic discogenic low back pain and herniated lumbar disc-related symptoms, regardless of the groups. Our results were similar to those of previous studies . AlthougPPDD mechanisms on the intervertebral discs have been well established . PPDD shThe disc volume reduction effect of PPDD has been demonstrated in several studies ,21. ChenNumerous studies have found favorable results with PPDD in the treatment of discogenic low back pain and herniated lumbar disc, especially contained disc protrusion ,29,30,31® technology have been analyzed. PPDD achieved a volumetric reduction of the disc tissues without overt thermal or structural damage to adjacent tissues [The safety and efficacy of the PPDD procedure using Coblation tissues . Lee et  tissues  showed t tissues ,37. In a tissues .In addition to the pain and functional scores, there are various methods to verify the success of PPDD. Radiological imaging studies, including plain radiography, CT, and MRI have been used ,22, and Traditionally, epidurography during epidural steroid injections provided safe and accurate therapeutic injection ,42,43. IIn this study, we applied the advantages of epidurography to the decompression effect of a disc by PPDD. Before PPDD, we observed that the contrast media did not extend above the involved disc level. After PPDD, when the disc was decompressed, we observed that the contrast media extended above the involved disc level. Moreover, the wire-type epidural catheter, which had not been passed before, was passed in some cases. We assumed that the partial removal of the nucleus pulposus by radiofrequency energy ensured the epidural space. Similar to other studies’ results on the efficacy of epidurography mentioned above, our study showed that the high success rate of PPDD is correlated with an improvement in epidurography. Based on our results, intra-procedure epidurography may be a reliable method for ensuring adequate decompression of the disc. Therefore, it is expected that the patient’s outcomes can be improved by using intra-procedure epidurography in addition to the existing manufacturer guidelines during PPDD.Our findings need to be interpreted within the limitations of the study. First, this study was retrospective and had a relatively small sample size. Second, we could not analyze the difference in disc volume change by MRI before and after PPDD because of the cost implications. Third, the different proportions of type and severity of disc herniation between the two groups, which may affect the success rate of the procedure, were not evaluated on MRI. Fourth, epidural adhesion was not evaluated. A herniated disc may cause inflammation within the epidural space, and it can also make epidural adhesion that affects contrast media spreading. Fifth, the observation periods were relatively short. A randomized, controlled, double-blind, long-term follow-up study should be conducted to support the finding of this study.This study’s results showed that PPDD is an effective treatment method for patients with chronic discogenic low back pain and herniated lumbar disc-related symptoms. We also suggested that intra-procedure epidurography may be a potential PPDD outcome predictor for ensuring successful outcomes and determining the endpoint of the procedure.


To evaluate the effect of 4 weeks of treatment with Janus kinase inhibitors (JAKis) on central sensitization (CS) and pain catastrophizing, and to determine the pain-related variables predictive of disease activity improvement, in patients with active rheumatoid arthritis (RA).Δ values) between the final and baseline were studied with the t test, Δ values of the variables were correlated with each other using Pearson’s test, and predictor variables for improvement in SDAI were also investigated using multivariate regression analysis.Consecutive RA patients with active disease starting a JAKi have been enrolled in this prospective observational study. Patients have been assessed at baseline and after 4 weeks of treatment. The evaluation was comprehensive of disease activity [Simplified Disease Activity Index (SDAI) and ultrasonographic (US) score] and of questionnaires aimed at investigating primarily CS [Central Sensitization Inventory (CSI)] and pain catastrophizing [Pain Catastrophizing Scale (PCS)]. Differences (p < 0.0001), PCS decreased from 32.46 to 28.72 (p = 0.0001). ΔSDAI showed a significant correlation with both ΔPCS and ΔCSI . ΔPCS was the only variable predictive of an improvement in SDAI .A total of 115 patients were evaluated. Overall, all variables demonstrated significant improvement between baseline and final except the US score. In particular, CSI decreased from 36.73 to 32.57 (JAKis would appear to have a positive effect on pain-related variables, particularly CS and pain catastrophizing, for the genesis of which extra-synovial mechanisms are responsible. Persistent pain is a common problem for patients with rheumatoid arthritis (RA), despite a good control of synovitis , which are documented in approximately 20–30% of patients. CS is an abnormal spinal and supraspinal pain processing that increases nociceptive afferent input. Neuroplastic changes in sensory pathways at both the peripheral and central levels are linked to pain sensitization.It manifests in the body as a hypersensitivity to pain that extends beyond the area from which the pain itself originates Woolf . CS, on Catastrophizing, which is a strong predictor of pain, has also been linked to CS, but few studies have investigated possible interactions between catastrophizing and CS  signaling pathway has been linked to the signaling of several cytokines, such as interleukin (IL)-6, IL-12, IL-23, and interferons (IFNs) that play a role in the pathophysiology of RA. In randomized clinical trials, JAK inhibitors (JAKis) have been found to be very effective at reducing pain and other patient-reported outcomes , Italy. To be included in the study, patients had to meet the 2010 American College of Rheumatology (ACR)—European League Against Rheumatism (EULAR) classification criteria for RA and be 18 or older , aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 1.5 the upper limit of normal (ULN); recent, current, or chronic infections (including inadequately treated hepatitis B or C or Mycobacterium tuberculosis infection); or active neoplasms or lymphoproliferative disorders; coexisting diseases of the central or peripheral nervous systems ; coexisting fibromyalgia (diagnosed according to the 2016 ACR criteria) or concomitant treatment with centrally acting pain medications .Exclusion criteria were: hemoglobin < 9.0 g/dl, hematocrit < 30%, white blood cell count < 3.0 × 10.All patients received a drug targeting the JAK/STAT signaling pathway, including tofacitinib, baricitinib, upadacitinib, and filgotinib. Tofacitinib is a pan JAKi with greater selectivity for JAK1/JAK3 and minor activity on JAK2 and TYK2. Baricitinib is a JAK1/JAK2 inhibitor with moderate activity against TYK2 and minimal activity against JAK3  and the ultrasonography (US) score were employed. The SDAI is the algebraic sum of 5 untransformed, unweighted variables, including 28 swollen joint count (SJC) and 28 tender joint count (TJC), patient global assessment (PGA) and evaluator global assessment (EGA) of disease activity on 0–10 numerical rating scales (NRS), and C-reactive protein (CRP) in mg/dl. SDAI range is from 0 to 86, and remission, low, and moderate disease activity have predefined upper limits of 3.3, 11 and 26, respectively  was used as an estimate of central sensitization of symptoms  and is composed of two parts. Part A has 25 questions concerning CS symptoms, graded on a 5-point Likert scale from 0 to 4. Higher overall scores indicate more CS symptoms. A cut-off point of 40 out of 100 indicates the presence of CSS  and the scores for temporal (− 1 to + 1) and spatial qualities (0 or + 2) yield to a score ranging from − 1 to 38. A score < 12 indicates that the pain is unlikely to be neuropathic, a score > 19 indicates that pain is likely to be neuropathic, and a score between 13 and 18 indicates a slight chance of neuropathic component  . The Kolmogorov–Smirnov test was used to determine if the distribution was normal. A paired t test was performed to study the scores changes between baseline and after 4 weeks of JAKis administration. The degree of correlation between the difference  of the variables  was measured using Pearson’s r. The correlation strength was classified as very mild (0.00–0.19), weak (0.20–0.39), moderate (0.40–0.59), strong (0.60–0.79), and very strong (0.80–1.00) for r values. To evaluate the difference in clinical outcomes among the various JAKis, a one-way analysis of variance (ANOVA) was performed distinguishing patients into seven categories, respectively, single molecule monotherapy  and their association with MTX . Finally, to determine predictors of improved disease activity, a multivariate analysis was conducted considering the reduction in SDAI as the dependent variable and the changes of pain-related indices , the changes of sonographic findings (ΔUS score), laboratory (ACPA titer), and demographic features  as independent variables.All the data were entered into a Microsoft Excel database and analyzed using MedCalcThe study was completed by 115 patients (84.3% of women), with a mean age of 58.4 years and a mean disease duration of 10.3 years. Before starting a JAKi, the 61.7% of patients was taking a non-biologic DMARD, and the 38.3% was taking a biologic DMARD. Twenty-two patients were treated with tofacitinib monotherapy (5 mg BD), 19 patients received tofacitinib and methotrexate (MTX), 19 patients received baricitinib monotherapy (4 mg OD), 14 patients received baricitinib and MTX, 17 patients received upadacitinib monotherapy (15 mg OD), 16 patients received upadacitinib and MTX, and 8 patients received filgotinib and MTX (200 mg OD).At baseline, the mean (SD) SDAI was 44.3 17.4) and CRP levels were 1.5 mg/dl. Overall, the 36.5% showed symptoms of CS (CSI ≥ 40), the 62.6% exceeded the threshold for the presence of pain catastrophizing (PCS > 30), and the 43.5% showed symptoms of neuropathic pain (PDQ ≥ 19) (Table 7.4 and Cp < 0.0001). The US score did not change significantly .After 4 weeks of treatment, 12 patients (10.5%) achieved SDAI remission, and 18 (15.6%) met the criteria for low disease activity (LDA). SDAI decreased from 44.30 to 27.83 (p < 0.0001), PCS decreased from 32.46 to 28.72 (p = 0.0001), PDQ decreased from 17.65 to 15.66 (p = 0.0005), and the PRI-SQR decreased from 17.21 to 12.52 (p < 0.0001).CSI decreased from 36.73 to 32.57 , between ΔCSI and ΔPRI-SQR , and between ΔCSI and ΔPCS  , and to a lesser extent with ΔUS score  (Table Significant relationships have been found between the 1) Table , Fig. 1.6) Table .Table 2PΔCSI (p = 0.465), ΔPCS (p = 0.165), or ΔPRI-SQR (p = 0.144).Considering the distinction of patients into the different treatment categories, the ANOVA did not document statistically significant differences among the various JAKis, whether in monotherapy or in combination with MTX, for either ΔSDAI as the dependent variable, revealed ΔPCS  as the only associated independent variable , baricitinib (JAK1/JAK2 inhibitor), upadacitinib (JAK1 inhibitor), and filgotinib (JAK1 inhibitor). Most cytokines exert their function by activating the JAK/STAT pathway after binding type I/II cytokine receptor. The three main cytokines that do not activate this mechanism are tumor necrosis factor (TNF), IL-1 and IL-17 (O'Shea et al. The main cytokine involved in the CS of pain during RA seems to be IL-6, capable of activating both JAK1 and JAK2. Its actions take place both at synovial and dorsal root ganglia level (Choy and Calabrese The JAK/STAT pathway could also modulate anti-nociceptive mechanisms since IL-10, a potent anti-inflammatory cytokine, carries out its action through the JAK/STAT pathway, activating JAK1, JAK2 and TYK2 (Baral et al. This study has some limitations. First, the decline in disease activity over the course of the study was considered to be due to the medications administered during the time period considered. However, because this was a prospective observational study rather than a randomized controlled trial, we are unable to rule out the Hawthorne effect, which is defined as the occurrence of symptom improvement as a result of having been noted (Berthelot et al. In conclusion, there is substantial evidence that CS and pain catastrophizing are prevalent in many active RA patients. Because of the influence of CS and pain catastrophizing, centrally acting immunomodulatory drugs such as JAKis could result in a rapid analgesic effect. Next to pharmacological therapy, effective non-pharmacological approaches on CS and pain catastrophizing would also be desirable to be more integrated in the therapy of patients with RA (Nijs et al.


OPRM1  and COMT  genes, were analysed. Test CNCP cases evidenced a significantly higher pain relief predictable due to pain intensity and quality of life (R2 = 0.3), in front of controls. Here, OXN achieved the greatest pain relief under a 28% higher MEDD, 8–13% higher use of pregabalin and duloxetine, and 23% more prescription change due to pain, compared to TAP. Whilst, TAP yielded a better tolerability due the lower number of 4 [0–6] AEs/patient, in front of OXN. Furthermore, OXN COMT-AA homozygotes evidenced higher rates of erythema and vomiting, especially in females. CNCP real-world patients achieved higher pain relief than other traditional opioids with a better tolerability for TAP. Further research is necessary to clarify the potential influence of COMT and sex on OXN side-effects.Tapentadol (TAP) and oxycodone/naloxone (OXN) potentially offer an improved opioid tolerability. However, real-world studies in chronic non-cancer pain (CNCP) remain scarce. Our aim was to compare effectiveness and security in daily pain practice, together with the influence of pharmacogenetic markers. An observational study was developed with ambulatory test cases under TAP (n = 194) or OXN (n = 175) prescription with controls (prescribed with other opioids (control), n = 216) CNCP patients. Pain intensity and relief, quality of life, morphine equivalent daily doses (MEDD), concomitant analgesic drugs, adverse events (AEs), hospital frequentation and genetic variants of  Since then, there has been an increase in opioid long-term use for conditions that are beyond the evidence base4. Efforts are necessary to optimize the opioid benefit/risk balance of opioid use developing best clinical practice guidelines based on researched circumstances5.In last decades, prescription opioids began to be used for chronic non-cancer pain (CNCP) outside the context of palliative medicine6. However, naloxone, a μ receptor antagonist, combined with oxycodone (OXN), a μ and k-opioid receptor agonist, may improve pain control, minimizing opioid-related bowel dysfunction adverse events (AEs)8. Another new opioid is tapentadol (TAP), that has a dual mode of action. TAP as a Tapentadol displays μ-opioid receptor agonist and noradrenaline reuptake inhibitor properties and is purported to have comparable analgesic efficacy to controlled-release oxycodone with a better opioid tolerability profile9 and fewer pharmacological interactions10 due others opioids.New, recently marketed opioid with potentially improved tolerability have opened a more optimistic door. Most clinically relevant opioid analgesics bind to μ opioid receptors in the central and peripheral nervous system in an agonist manner to elicit analgesia12. Randomized placebo-controlled studies demonstrated similar analgesic levels between the two in osteoarthritis knee pain cases13, and similar tolerability profiles following minor orthopaedic/trauma surgeries15. However, in other CNCP studies, TAP showed better gastrointestinal tolerance and quality of life improvement than OXN did16. The main question is whether this better profile is maintained or changed in real-world pain practice with polymedicated and elderly regular pain patients.There are several well-designed studies comparing both OXN’s and TAP’s analgesic effects, however some of the results seem contradictoryMu opioid receptors (OPRM) and Catechol-O-Methyltransferase (COMT) are candidate genes with a significant influence on morphine analgesic response18. There are few validated studies that ultimately call for pharmacogenetic testing to be conducted when initiating opioid therapy in pain management23. Results have indicated that many favourable analgesic effects may depend on increased OPRM density25 and on higher dopamine concentrations in the prefrontal cortex17. Moreover, the OPRMgene has been widely studied for distinct pain sensitivity phenotypes26 and it seems that OPRM A118G (rs1799971) and COMT G1947A (rs4680) heterozygous patients, need significantly less morphine as compared to A118 mutant homozygous ones27. What´s more, sex-specific effects that have been detected9 could be responsible for modulating the COMT genotype’s effects on synaptic dopaminergic concentrations and emotion modulation capabilities28. These results imply a complex nature in the genotype-phenotypes’ interactions.Given this scenario, precision medicine could provide data to understand such variability. OPRM1 and COMT genes) impact on clinical outcomes were analysed.The purpose of present study was to compare OXN and TAP analgesic effects and tolerability in real-world CNCP management. Here, genetic variants’ , followed by knee pain. Nearly half of them had mixed neuropathic-nociceptive symptoms.A summary of the characteristics of the subjects included in the study is presented in Table Most of CNCP patients were elderly females  who presented moderate chronic pain , mild relief (37 ± 29 mm) and moderate QoL (45 ± 22 mm) at the time of inclusion. A total of 3–6% of them had no pain, and 57% had severe or extremely severe pain. Controls suffered around 10% more extreme severe pain and a statistically significant lower pain relief level  as compared to OXN (40 ± 30 mm) and TAP (36 ± 28 mm) test cases (p < 0.001) without any significant differences on pain relief between test cases groups. On the other hand, any significant clinical difference was found between naïve or opioid switchers (Supplementary Table 2 = 0.3). Pain relief was negatively affected by age in control´s relief and positively by anxiolytics in OXN group, while sex, number of AEs, MEDD, neuromodulators, and analgesics showed no impact , as can be seen in Table A summary of the prescribed analgesic drugs is presented in Table OXN showed the highest MEDD requirements (124 ± 109 mg/day), which were 28% higher than TAP’s  and 11% higher than controls . Here, TAP showed the lowest MEDD, even significantly lower than controls. In contrast, the controls required higher tramadol use than cases.On the other hand, the rates of coadjuvant medication use differed between groups. OXN patients reported a significant 15% higher use of pregabalin p = 0.002) and 8% higher duloxetine use (p = 0.040), than TAP, as seen at Table  and 8% hThe percentage of patients showing some AE is displayed in Fig. In total, 3131 AEs (incidence rate of 5 AEs/patient) were logged through questionnaires, with most being mild and having disappeared with the withdrawal of the drug. Nearly all patients (94%) reported at least one AE with a median of 6 AEs (IQR 3.5–9) per patient. Most prevalent were dry mouth (65%), nervousness (54%) and constipation (46%). According to MEDRA, the most frequents disorders were: 22% (n = 657) psychiatric , 21% (n = 611) nervous  and 16% gastrointestinal .TAP group referred the lowest number of AEs (4 [0–6] AEs/patient) compared with OXN and control groups. In this context, OXN patients reported more 13–17% frequent constipation , as well as 12% and 11% higher incidence of erythema than both TAP and control patients .What´s more, controls showed a significant 7% and 20% higher frequency of nervousness vs. TAP and OXN, respectively . Control also developed a higher frequency of edema at 11% and 14% compared to TAP and OXN, respectively . However, TAP patients showed 14% more frequent weight change compared to the control group and 3% compared to OXN .In total, 192 commonly occurring ADRs were noted (ratio of 16 AEs: 1ADR). Mainly systems affected were 25% nervous, 17% psychiatric disorders, and 12% gastrointestinal systems without notable differences between test cases and controls (data not shown).OPRM1  genotypes were 59% for A/A, 38% for A/G and 2% for G/G (Hardy–Weinberg equilibrium (HWE) p = 0.067). On the other hand, the frequency of the COMT  G/G genotype was 26%, G/A 46% and A/A 28% (HWE p = 0.219).The frequencies of occurrence in the study population of the OPRM1 and COMT genetic variants over clinical and pharmacological variables in TAP and OXN groups was analysed. In this case, no statistically significant influence was found over these variables.The influence of the OPRM1 A/A 31%, A/G 15% and G/G 0%, p = 0.037, medium effect size = 0.202), vomiting  and erythema  in OXN patients as can be seen in Fig. COMT G/G reporting 11%, G/A 8%, and A/A 26% . Incidence of erythema due a higher frequency of flushing was also found to be genotype-dependent in females . Any genetic variant analysed influence on incidence of AEs in cases.These variants’ significant impacts on frequency of occurrence of erythema , drug change requirements due to pain or hospital frequentations due to other causes. What’s more discuss the significant differences concerning coadjuvant medication in OXN and TAP groups, could contribute to the differences observed in analgesic tolerability that should be confirmed in further studies. Our results suggest that TAP could provide better clinical outcomes at lower costs due the lower opioid requirements and incidence of AEs34. It is possible that TAP’s opioid-saving effect due its mechanism of action29 could serve to optimize opioid rotation practices37. Here, the TAP more frequent weight change compared to other groups should be deeper analysed. Prior studies have identified an association between obesity and prescription opioid use in the US. However, the pain conditions that are factors in this association remain unestablished38 and this. Unfortunately, the term recorded in our study as “weight change” AE did not specify if was an increase or a loss of weight. Additional larger studies are needed to evaluate these results and, also, whether genotyping COMT, alone or in combination with OPRM1, could be potentially translated to pain practice36.These results provide clear directions in terms of clinical practice. Firstly, as expected, control group reported a higher frequency of severe painCOMT genetic influence on some side-effects, such as erythema and vomiting, especially in females. Previous studies have indicated OPRM1 and COMT genotypes’ significant influence on prevalence of erythema and nausea/vomiting39 such as for acute post-operative pain, CNCP and cancer-related pain40. This can be mediated by dopamine, which is an important neurotransmitter in the postrema area and vomiting centre, when it is used together with catecholamines that can modulate inflammatory processes41. In addition, the remarkably female predominance in this data merits further attention. Mostly of our patients were elderly women, as was previously highlighted in our pain population42. Literature data strongly suggest that men and women differ in their pain responses, potentially due to differences in modulation of the endogenous opioid system43 and sex hormones44, which could, in turn, have differential pharmacogenetic impacts46. Awareness about this sex influence should be emphasized in order to improve pain management.Our data showed a mild 47. Second, a convenience sample was assessed based on patients attending the PU. This can affect the population representativeness, especially in genotype variables, and in this way to find significant differences. Thirdly, patients in all groups were able to take multiple opioids, and thus a host of adjuvants from various opioid combinations (such as tramadol with tapentadol) and/or from other non-analgesic prescriptions might have played a role, which was not recorded in the present study. What’s more, patients could receive other concomitant prescriptions due to their comorbidities, they might have independently contributed to the observed side-effects. Thus, AEs could not be always directly attributed to the opioid with the highest prescribed dose. This may limit conclusions related to effectiveness or side-effects. Finally, while a combination of Oxycodone with naloxone may have benefits related to gastrointestinal side effects, potential interactions between these drugs have not been contemplated in this study. All these aspects should be addressed in future studies.Our data present some limitations. First, the lack of randomization is problematic and raises questions about bias. As noted above, important factors such as duration of pain, type of pain/diagnosis, and psychosocial factors were not controlled. This should be addressed in future studies. What’s more, the diagnoses associated with CNCP were done following clinical routines, but not with other objective measurements. This potentially clouds an understanding of what types of non-opioid analgesics as duloxetine or pregabalin could be appropriate for use. This could have introduced a bias influenced by several other variables, such as sociodemographics, that might be more relevant than pain statusCOMT genotypes were associated with higher incidence of some opioid side-effects, especially in females. Hence, further studies are warranted to confirm and refine these results on a wider population and finally ascertain the role that pharmacogenetic in terms of improve analgesic tolerability.Taken together the findings presented here suggest that opioids of the new generation, OXN and TAP, can control pain intensity than traditional opioids used in pain treatment routines. However, OXN showed a worse tolerability and a higher health resource as compared to TAP. Additionally, A real-world observational and cross-sectional study was conducted from November 2014 to November 2017, using CNCP outpatients who required either OXN or TAP prescriptions. CNCP patients were recruited following their routine clinical visits for standard treatment at the Pain Unit . At the time of the enrolment, all participants received information on the design and purpose of the study and provided their written informed consent, allowing their genetic samples and electronic health records (EHRs) to be used for the research. All the methods were carried out in accordance with the ethical guidelines established in the Declaration of Helsinki. The Research Ethics Committee of the Alicante-General Hospital approved the protocol , after being classify by Spanish Agency for Medicines and Health Products, which complies with the applicable STROBE guidelines.48.A total of 600 patients were pre-screened, with 7% of patients excluded . Although patients under 18 years old, pregnant women, oncologic pain or any psychiatric disorders that could interfere with the proper development of the study were excluded. Furthermore, other chronic pain syndromes of unclear pathophysiology, such as fibromyalgia, and neuropathic pain, such as painful polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain, were not includedFinally, 585 CNCP patients  were included, as displayed in Fig. Subjects were divided in two groups, cases  and controls . Cases could be previously naïve to opioids (n = 223) or who switched from another opioid (n = 146).12 .First, the researchers reviewed the schedule of PU consultations by patients weekly. Then they pre-screened patients with active OXN or TAP prescriptions and prepared the questionnaires and informed consent forms. In the case that a new patient began an OXN or TAP prescription on the day of the researchers’ visit, PU healthcare notified the researchers for their potential inclusion. For every two cases, one control was included from a concomitant observarional studyThe population selected as controls included a total of 1339 clinical records of 753 patients who routinely attend to PU for treat their CNCP. From this group, a subpopulation of 216 patients was extracted who were being treated with a main opioid  being main analgesic drug adjuvants prescription rate , similar to those of the test cases studied.The lack of randomization led to the patients’ being either: 1. under OXN or TAP prescription (the test group previously naïve to opioids), 2. switched to OXN or TAP from a different opioid (minimum a month before), or 3. under another combination of opioids , either due to the former’s use as a rescue medication or to aid the switching process. In any case, control group must not under treatment neither with OXN nor TAP and the opioid with the highest MEDD was designated as the main treatment.A consecutive sampling method was used in ambulatory patients. When a patient met the inclusion criteria, he/she was informed about the purpose of the study by the PU healthcare staff. Then, interested individuals were attended to by the research staff for signing of the informed consent paperwork and collection of a saliva sample for the pharmacogenetic analysis.49. Outcomes were assessments at a single time point where pain (intensity or relief) and QoL was asked at the present time whilst the cumulative AEs reported since last month.Demographic data, pain history, drug use and medical history were recorded from EHRs. Clinical data was reported through validated scales and questionnaires completed as part of a standard clinical routine for assessing pain intensity, pain relief, QoL, and most common AEs in pain management49. Specifically, QoL was evaluated through the VAS-EuroQol Scale, which consists of a vertical line from 0  to 100 mm (the best imaginable), upon which the patient indicates his/her current health status. Likert pain intensity and relief scales were also registered  in subsequent questionnaires.Validated scales and questionnaires were used to evaluate clinical outcomes and were collected every time a patient was included at a single time point. Pain intensity, relief and QoL were measured using the visual analogue scale (VAS), consecutively by clinical routine. The VAS for each indicator consists of a 100 mm horizontal line ranging from 0 (lowest) to 100 mm (highest), where the patient points on the line to the intensity of pain or relief that he/she feels, respectively50.For collection of patients’ reported AEs, a questionnaire with a list of the most frequent adverse drug reactions  and a blank field to add any other AEs was collected. These AEs consisted of: sleepiness, dizziness, nausea, vomiting, constipation, itchiness, sexual dysfunction, loss of libido, weight change, headache, erythema, dry skin, dry mouth, edema, depression, insomnia, nervousness and loss of appetite. Additionally, to the questionnaire, the listed ADRs were recorded from EHRs. Clinical data of AE/ADR reporting were coded according to the medical dictionary for regulatory activities (MedDRA) and the system organ class (SOC)51.In addition, the percentage of Emergency Department (ED) visits, hospitalizations, or any drug changes due to pain or other causes were registered when patients were included referred to the last month. Prescription changes included: (1) Change in any drug-dosage. (2) Product or generic brand switch. (3) Stopping medication or non-adherence, and (4) starting a new medication53.The comparison between test cases’ and controls’ opioid benefit/risk profiles was defined as a balance between benefits (decrease in pain intensity and/or increase in pain relief) and tolerability in terms of number of AEs or hospital frequentation54.Simple analgesics’ use  as well as prescriptions for tramadol and strong opioids like OXN, TAP or others  were registered. In cases where different opioids were combined, oral MEDD was estimated using available references55.The use of any other concomitant analgesics most widely prescribed at the PU were also registered from the institution’s EHRs: antidepressants (amitriptyline and duloxetine), anxiolytics (benzodiazepines) and gabapentinoids . For the analysis, these drugs were called “neuromodulators”, given their role as substances that alter the way nerves communicate with each other and, consequently, the overall activity level of the brainOPRM1  and COMT  gene polymorphisms. All PCR amplifications were carried out in a RT-PCR Rotor Gene Q (Qiagen), using specific TaqMan probes MGB® (Applied Biosystems). The amplification parameters were as follows: initial 10 min denaturation at 95 °C, 45 cycles for 15 s at 92 °C, 90 s at 60 °C, and 1 min final extension at 60 °C.Approximately 2 ml of saliva was collected in tubes containing 6 ml of PBS. Once the saliva sample was taken, it was stored at − 80 °C until its processing. Genomic DNA was isolated using the E.N.Z.A. Forensic DNA kit (Omega bio-tek), according to the manufacturer’s instructions. Real-time polymerase chain reaction (RT-PCR) analysis was used to genotype 56. The assumption of normality was validated with the Kolmogorov Smirnov test using the Lilliefors correction method. Quantitative parametric data is presented as mean ± standard deviation (SD) while non-parametric data and discrete variables are shown using their median values (interquartile range). Categorical data is expressed by percentages, among them the relative frequencies of genotypes and alleles.Convenience sampling was considered to be more likely to represent the target population. This entailed selecting participants on the basis of availability until the final sample size was achieved2) goodness-of-fit and Fisher’s exact test. A multiple linear regression was performed to generate a predictive risk model and to analyse the influence of the following variables over pain relief: age, gender, VAS pain intensity, EQD, MEDD, number of AEs and the use of neuromodulators, anxiolytics, and analgesics.Comparisons between any two given groups  of data exhibiting parametric distributions was conducted using the independent T-test analysis, and for analyses comparing three groups an ANOVA test was carried out. Outcomes from opioid naïve vs opioid rotation patients were done to wonder any difference. Analysis of non-parametric data was done using U Mann–Whitney and Kruskal–Wallis tests for comparison between two and three groups, respectively. Comparisons for categorical data were conducted using Chi-square (χ2) was used for ANOVA and Kruskal–Wallis analyses , while for the chi-square χ2 the effect size was determined using the Cramer’s V method  and using Odd Ratios for AEs between study groups.In addition to this, the effect sizes were calculated for all the comparisons. Eta-Squared  when frequencies of mutant alleles were low.Observed gene frequencies were compared to expected values using the chi-square p-values < 0.05 were considered statistically significant. In all cases, multiple testing was adjusted using the Bonferroni correction. Analyses were carried out using the R software package version 4.0.3 and Graph Pad Prism 5.0.Supplementary Table S1.Supplementary Table S2.Supplementary Table S3.


Non-traumatic emergency general surgery involves a heterogeneous population that may present with several underlying diseases. Timeous emergency surgical treatment should be supplemented with high-quality perioperative care, ideally performed by multidisciplinary teams trained to identify and handle complex postoperative courses. Uncontrolled or poorly controlled acute postoperative pain may result in significant complications. While pain management after elective surgery has been standardized in perioperative pathways, the traditional perioperative treatment of patients undergoing emergency surgery is often a haphazard practice. The present recommended pain management guidelines are for pain management after non-traumatic emergency surgical intervention. It is meant to provide clinicians a list of indications to prescribe the optimal analgesics even in the absence of a multidisciplinary pain team.An international expert panel discussed the different issues in subsequent rounds. Four international recognized scientific societies: World Society of Emergency Surgery (WSES), Global Alliance for Infection in Surgery (GAIS), Italian Society of Anesthesia, Analgesia Intensive Care (SIAARTI), and American Association for the Surgery of Trauma (AAST), endorsed the project and approved the final manuscript.Dealing with acute postoperative pain in the emergency abdominal surgery setting is complex, requires special attention, and should be multidisciplinary. Several tools are available, and their combination is mandatory whenever is possible. Analgesic approach to the various situations and conditions should be patient based and tailored according to procedure, pathology, age, response, and available expertise. A better understanding of the patho-mechanisms of postoperative pain for short- and long-term outcomes is necessary to improve prophylactic and treatment strategies. Non-traumatic emergency general surgery involves a heterogeneous disease spectrum and a varied that may present with several underlying diseases . In the International and national guidelines recommend in case of moderate-to-severe pain a few analgesic techniques, including intravenous (i.v.), per oral (p.o.) or subcutaneous (s.c.) routes, as well as epidural analgesia (EA), patient-controlled analgesia (PCA), and continuous peripheral nerve blocks (CPNB) . AdminisSome recent data support the use of artificial intelligence (AI) to develop better clinical decision support tools based on machine learning . Some stThe aim of the present guidelines is to suggest the appropriate pain management after non-traumatic emergency surgical intervention and to give to surgeons and physicians working in different settings a list of indications in order to prescribe the best analgesia possible in the absence of a multidisciplinary pain team. Four international recognized scientific societies: World Society of Emergency Surgery (WSES), Global Alliance for Infection in Surgery (GAIS), Italian Society of Anesthesia, Analgesia Intensive Care (SIAARTI), and American Association for the Surgery of Trauma (AAST), participated in the project and approved the final manuscript.The bibliographer conducted a computerized search in different databases . Citations were included up to June 2021 using the primary search strategy: acute postoperative pain, emergency surgery, pain assessment, acetaminophen, NSAIDs, ketamine, opioids, epidural anesthesia, peripheral nerve blocks, continuous wound infusion, local infiltration combined with AND/OR with synonyms and MeSH terms. We considered acute pain management after major abdominal pathology requiring urgent emergency laparotomy or laparoscopy, including reoperations after elective gastrointestinal surgery and reoperations after previous abdominal surgery. No language restriction was imposed. Duplicates and animal studies were removed. The dates were selected to allow comprehensive published abstracts of clinical trials, consensus conferences, comparative studies, congresses, guidelines, government publication, multicenter studies, systematic reviews, meta-analysis, large case series, original articles, and randomized controlled trials. Narrative review articles were also analyzed to identify other studies. Abstracts were screened, and irrelevant studies were removed; then, a full-text assessment of the articles was performed. Case reports were excluded. In case of disagreement between the two reviewers (FC and FCo), the consensus was reached by discussion. If there was no consensus, another two reviewers were sought (FCa and FFo). PRISMA guidelines flowchart  is reporThese guidelines present evidence-based methods for optimal management of acute postoperative pain management in emergency general surgery patients. The practice indications which were promulgated in this work do not represent a standard of practice. These are suggested plans of care based on the best available evidence and experts’ consensus, but they do not exclude other approaches as being within the standard of practice. For example, they should not be used to compel adherence to a given medical management method, which method should be finally determined by the treating health care provider after considering the conditions at the relevant medical institution  and the characteristics of the individual patient. However, the treatment results’ responsibility rests with those directly engaged and not with the consensus group.Postoperative pain must be recognized and treated as soon as possible and as best as possible in all patients .Emergency general surgery may be associated with more severe postoperative pain; specific attention should be given to this patient group  .Postoperative pain assessment, at rest and—if possible—on movement, is strongly recommended, to improve patient management after emergency surgery .Preemptive analgesia is a viable option in reducing postoperative opioid consumption  .Adequate education for the patient and, if possible, of the family about the surgical and anesthesiologic treatment, options, plan, and aims of pain management should be performed whenever it is possible  .Perioperative pain management should be implemented considering patient history, comorbidities, ongoing chronic therapy, and potential risk for substance abuse  .Validated pain scales should be included into treatment planning, ongoing evaluation, and adjusting process  .Pain management should be adjusted to ensure the greatest effect and the lowest side effects possible  .Emergency general surgery (EGS) is related to a worse acute postoperative pain compared to elective surgery –18. PatiAn accurate evaluation including psychiatric comorbidities, namely dementia and delirium, may facilitate APP management since pain assessment techniques in these conditions may be much more time-consuming , 21, 24.All these conditions may contribute to worsening APP outcome. Coping strategies could be used specially to contrast catastrophizing thoughts.The assessment of preoperative chronic pain is necessary because it is demonstrated that previous chronic pain history since may be associated to a worse APP . MoreoveAccurate APP’s assessment, which is essential, is usually underestimated, underevaluated, and underperformed , 28–32. Consideration should be given to APP follow-up evaluation and adequate therapy during the postoperative period. In fact, pain drugs are often administered not at regular intervals , 33 nor In addition to psychiatric comorbidities, chronic pain, and patient dealing with substances of abuse, special attention should be paid to OSAS patients, since a correlation with APP is not fully understood , 37. In Preemptive and preventive NSAIDs seem to reduce both pain and morphine use. Clinically significant adverse events from nonsteroidal anti-inflammatory drugs (NSAIDs) administered before surgery are possibly under-reported; for this reason, it is impossible to define with high level of evidence the safety of either preemptive or preventive NSAIDs .Opiates usage should be reduced as much as possible in postoperative pain management strategies .Multimodal pain management should always be considered to improve analgesia while reducing individual class-related side effects; a pharmacological step-up approach including major opiates when necessary should be adopted .Whenever contraindications are absent, acetaminophen, NSAIDs , and gabapentinoids administration  are recommended in multimodal analgesia.Acetaminophen administered at the beginning of postoperative analgesia may be better and safer than other drugs .Acetaminophen used in multimodal and preemptive therapy is associated with a reduction of opiates side effects and improved postoperative outcomes .Coxib administration may be considered if there are no contraindications .Multimodal analgesia involves the use of different classes of analgesic medications  with different mechanisms of action on the peripheral and/or central nervous system.Acetaminophen (paracetamol): it is effective as an analgesic mainly if used in combination with NSAIDs or morphine. Its use reduces opioids use –41NSAIDs: are indicated for the treatment of moderate pain when used alone. Their use in multimodal analgesia reduces morphine consumption and related side effects Opiates: are the first-line therapy to treat pain in these patients. They also reduce anxiety and dyspnea , 43. PCAGabapentinoids such as gabapentin and pregabalin can be considered as a component in multimodal analgesia. They act by decreasing the release of neurotransmitters in the synapse, thus providing a nociceptive blocking activity.Alpha-2-agonists: in addition to their anti-hypertensive effect, they have been shown to have a sympatholytic effect by inhibiting norepinephrine release, thus reducing the opiates requirements.The different combinations of these drugs lead to additive or synergistic effects on pain relief and can potentially reduce the side effects of mono-modal interventions. The drugs used for this purpose include:Acetaminophen in a multimodal regimen is a valid and effective option. A study conducted in nearly 800,000 patients undergoing common major surgical elective and emergency procedures showed that this drug in a multimodal therapy regimen provides a cost-effective strategy to improve outcomes and patient satisfaction with a side-effect profile that is superior to opioids alone in moderate–severe APP , lidocaine infusions, gabapentinoids, and ketamine. Numerous studies have shown the opioid-sparing effect of this approach resulted in an accelerated GI recovery and improved outcomes. However, an optimal combination of these elements has not yet been elucidated , 99.Caffeine is widely known as a stimulant to colonic motor activity in animals and humans. Clinical trials have shown that caffeinated drinks decrease the time to flatus and first bowel movement and if given as soon as 2 h after surgery, it may accelerate GI recovery and reduce LOS , 101.Lastly, the use of regional anesthesia over general anesthesia whenever possible may help in reducing the number of drugs used and thus may reduce the likelihood of constipation after surgery.Unlike patients with treatable conditions or where active organ support is chosen for their care, there remains a group of frail patients or those for whom surgical intervention would be non-beneficial and there is a defined role for analog-sedative medications in the treatment of this cohort.Periodic assessment of pain score is mandatory using validated systems to evaluate the response to treatments and to allow adjustments .Observational pain scales are less reliable than patient reported metrics. However, in the non-communicative patient, observational pain scales should still be applied Different pain assessment tools have been validated: NRS , VAS  and VRS  or the Behavioral Pain Scale (BPS) and the Critical Care Pain Observation Tool (CCPOT) in case of critically ill patients. There is no evidence of the superiority of one specific tool, and the choice should be made according to patient status . It remains that patient self-assessment of pain is the most valuable tool. Patient’s opinion must be listened and his/her feelings trusted –104.Multimodal analgesia is suggested to treat moderate-to-severe pain in patients not amenable for surgical interventions or already operated on but not suitable for further interventions .The combination of systemic multimodal analgesia with regional analgesia is suggested in patients already operated on but not suitable for further interventions Patients not amenable for surgical interventions or already operated on but not suitable for further interventions should be considered for palliation to achieve the control of all other related symptoms such as nausea, vomiting, dyspnea, agitation, and delirium In patients not suitable for further intervention due to the clinical conditions or due to the disease itself, multimodal analgesia is effective and should be adopted in postoperative pain management. The different combinations of the known drugs with their additive or synergistic effects on pain relieve reduce the side effects of mono-modal interventions and increase the effect on pain reduction Table .Table 1INausea and vomiting should be managed with medications that target dopaminergic pathways  .Octreotide should be utilized in the treatment of nausea and vomiting due to bowel obstruction caused by cancer .We suggest adding a second agent  to control nausea and vomiting when the first-line medications are unable to control the symptoms .3 medications to be superior to older dopaminergic agents in treating nausea at the end of life [Aforementioned drugs are routinely used as therapies for nausea because of their inhibition of receptors in the brain’s chemoreceptor trigger zone. Studies have not shown newer 5-HT of life –108.All medications that may be added as second agent in treating refractory nausea are listed in Table Whenever appropriate, the evaluation of delirium should be done using standardized assessment tools validated in critically ill patients like Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) or Intensive Care Delirium Screening Checklist (ICDSC) .Possible causes of delirium, including drug-induced delirium, must be minimized, and pain control should be optimized before the pharmacological approach is implemented .The use of i.v. haloperidol or droperidol in hyperactive (RASS + 1/ + 4) or hypoactive (RASS 0/-3) delirium with or without hallucinations is recommended .Delirium is common in the last weeks/days of life, so it must be considered in every patient in palliative care showing a change in behavior. Symptoms can affect different areas of cognition  and may include hallucinations and disturbances in the sleep–wake cycle and can cause distress in both the patients experiencing it and those around them (DSM-5 ). ValidaReversible causes account for 30–50% cases of delirium, especially drugs and poorly controlled pain. Drugs potentially responsible for delirium include benzodiazepines, corticosteroids, anticholinergics, opioids, and other drugs with psychoactive properties. Other possible reversible causes are metabolic disturbances , hypoxia, anemia, sepsis .Overall, only 50% of delirium cases are reversible. The other half requires medical management which focuses on reducing agitation and perceptual abnormalities. Haloperidol is the drug of choice in the pharmacological treatment of delirium. An initial dose of 0,5-2 mg in. slow iv bolus may be used off-label. Haloperidol is associated with extrapyramidal side effects and lengthening of QT , 111.The assessment of respiratory distress should be done using a standardized assessment tool and the presence of suggestive objective signs. We recommend a stepwise approach to the treatment of dyspnea When death is not imminent, the treatment of the etiology of dyspnea is recommended .Noninvasive ventilation to control dyspnea is suggested only until a properly deep sedation is reached or when sedation is inadequate. We recommend noninvasive ventilation only in predisposed settings with trained medical staff .Opioid usage as first-line treatment for dyspnea is recommended Dyspnea is the subjective awareness of altered respiratory function which usually results in respiratory distress. Respiratory distress is the totality of behavioral modifications that can be observed and measured . Dyspnea is usually present in dying patients. When possible, being a subjective symptom, it must be assessed directly with the patient using standardized assessment tools .The use of non-medical strategies to decrease respiratory distress should be considered like optimal positioning in sitting position, increased ambient air flows, use of fans, cold air. Noninvasive ventilation techniques as oxygen therapy include high-flow nasal cannula (HFNC) and continuous positive airway pressure (CPAP) ventilation to relief or mitigating dyspnea  by reducSedation with benzodiazepines or propofol can be considered as second line if dyspnea is not resolved with adequate doses of opioids since fear and anxiety can be con causes of the dyspnea in the dying patient .Dealing with acute postoperative pain in the emergency abdominal surgery setting is complex, requires special attention, and should be multidisciplinary. Several tools are available, and their combination is mandatory whenever is possible. Analgesic approach to the various situations and conditions should be patient based and tailored according to procedure, pathology, age, response, and available expertise. A better understanding of the patho-mechanisms of postoperative pain for short- and long-term outcomes is necessary to improve prophylactic and treatment strategies.