Trajectories of pain and opioid use up to one year after surgery: analysis of a European registry.

BACKGROUND: Long-term opioid use after surgery is a crucial healthcare problem in North America. Data from European hospitals are scarce and differentiation of chronic pain has rarely been considered. METHODS: In a mixed surgical cohort of the PAIN OUT registry, opioid use and chronic pain were evaluated before surgery, and 6 and 12 months after surgery (M6/M12). Subgroups with or without opioid medication and pre-existing chronic pain were analysed. M12-chronic pain was categorised as chronic postsurgical pain (CPSP) meeting the ICD-11 definition, chronic pain related to surgery not meeting the ICD-11 definition, and chronic pain unrelated to surgery. Primary endpoint was the rate of M12 opioid users. Variables associated with M12 opioid use and patient-reported outcomes were evaluated. RESULTS: Of 2326 patients, 5.5% were preoperative opioid users; 4.4% and 3.5% took opioids at M6 and M12 (P<0.001). Chronic pain before operation and at M6/M12 was reported by 41.2%, 41.8%, and 34.7% of patients, respectively (P<0.001). The rate of M12 opioid users was highest in group unrelated (22.3%; related 8.3%, CPSP 1.5%; P<0.001). New opioid users were 1.1% (unrelated 7.1%, related 2.3%, CPSP 0.7%; P<0.001). M12 opioid users reported more pain, pain-related physical and affective interference, and needed more opioids than non-users. The predominant variable associated with M12 opioids was preoperative opioid use (estimated odds ratio [95% confidence interval]: 28.3 [14.1-56.7], P<0.001). CONCLUSIONS: Opioid use was low in patients with CPSP, and more problematic in patients with chronic pain unrelated to surgery. A detailed assessment of chronic pain unrelated or related to surgery or CPSP is necessary. CLINICAL TRIAL REGISTRATION: NCT02083835.

Perioperative pain management models in four European countries: A narrative review of differences, similarities and future directions.

There is general agreement that acute pain management is an important component of perioperative medicine. However, there is no consensus on the best model of care for perioperative pain management, mainly because evidence is missing in many aspects. Comparing the similarities and differences between countries might reveal some insights into different organisational models and how they work. Here, we performed a narrative review to describe and compare the structures, processes and outcomes of perioperative pain management in the healthcare systems of four European countries using Donabedian's framework as a guide. Our comparison revealed many similarities, differences and gaps. Different structures of acute pain services in the four countries with no common definition and standards of care were found. Protocols have been implemented in all countries and guidelines in some. If outcome is assessed, it is mainly pain intensity, and many patients experiencing more intense pain than others have common risk factors (e.g. preoperative pain, preoperative opioid intake, female sex and young age). Outcome assessment beyond pain intensity (such as pain-related physical function, which is important for early rehabilitation and recovery) is currently not well implemented. Developing common quality indicators, a European guideline for perioperative pain management (e.g. for patients at high risk for experiencing severe pain and other outcome parameters) and common criteria for acute pain services might pave the way forward for improving acute pain management in Europe. Finally, the education of general and specialist staff should be aligned in Europe, for example, by using the curricula of the European Pain Federation (EFIC).

Analgesic use and favourable patient-reported outcome measures after paediatric surgery: an analysis of registry data.

BACKGROUND: Pain after paediatric appendectomy and tonsillectomy is often undertreated. Benchmarking of hospitals could reveal which measures are associated with improved patient- or parent-reported pain-related outcomes. METHODS: A total of 898 anonymised cases from 11 European hospitals participating in PAIN OUT infant were analysed. The children completed a questionnaire on patient-reported outcomes (PROs) 24 h after surgery. According to a composite PRO measure, including pain intensity and pain-related interference, hospitals were allocated to Group I (favourable results), II (average results), and III (unfavourable results). Benchmarking of hospital groups was performed investigating process variables (dosing of non-opioid analgesics, opioids, and dexamethasone) associated with PROs, side-effects, and children's perception of care. Variables associated with PROs were analysed using multinomial regression analysis with the PRO score-related hospital group as a dependent variable (estimated odds ratios [OR], 95% confidence interval [CI]). RESULTS: During the first 24 h after surgery, 1.2 (1.1-1.3) full daily doses of non-opioid analgesics (non-steroidal anti-inflammatory drug [NSAID], paracetamol, metamizole) were administered in group I and 0.7 (0.6-0.8) in group III (P<0.001). Intraoperative dexamethasone was administered to 70.1 and 52.6% of the children in Group I and Group III, respectively (P<0.001). A lower number of full daily doses of non-opioid analgesics: 0.22 [0.15-0.31]), less dexamethasone (0.49 [0.33-0.71]), fewer non-opioid analgesics before the end of surgery (0.37 [0.22-0.62]) and higher opioid doses were associated with hospital allocation to group III vs group I (Nagelkerke's R2=0.433). CONCLUSIONS: The results indicated substantial deficits in the concept, application, and dosing of analgesics in paediatric patients after surgery. Timely administration of adequate analgesic doses can easily be introduced into daily clinical practice. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT02083835.

'Desire for more analgesic treatment': pain and patient-reported outcome after paediatric tonsillectomy and appendectomy.

BACKGROUND: Insufficiently treated pain after paediatric appendectomy and tonsillectomy is frequent. We aimed to identify variables associated with poor patient-reported outcomes. METHODS: This analysis derives from the European PAIN OUT infant registry providing information on perioperative pharmacological data and patient-reported outcomes 24 h after surgery. Variables associated with the endpoint 'desire for more pain treatment' were evaluated by elastic net regularisation (odds ratio [95% confidence interval]). RESULTS: Data from children undergoing appendectomy (n=472) and tonsillectomy (n=466) between 2015 and 2019 were analysed. Some 24.8% (appendectomy) and 20.2% (tonsillectomy) wished they had received more pain treatment in the 24 h after surgery. They reported higher composite pain scores (5.2 [4.8-5.5] vs 3.6 [3.5-3.8]), more pain-related interference, and more adverse events than children not desiring more pain treatment, and they received more opioids after surgery (morphine equivalents (81 [60-102] vs 50 [43-56] µg kg-1). Regression analysis revealed that pain-related sleep disturbance (appendectomy odds ratio: 2.8 [1.7-4.6], tonsillectomy 3.7 [2.1-6.5]; P<0.001) and higher pain intensities (1.5-fold increase) increased the probability of desiring more pain treatment. There was an inverse association between the number of different classes of non-opioids administered preventively, and the desire for more analgesics postoperatively. Children not receiving any non-opioid analgesics before the end of a tonsillectomy had a 3.5-fold (2.1-6.5-fold) increase in the probability of desiring more pain treatment, compared with children receiving at least two classes of different non-opioid analgesics. CONCLUSIONS: Preventive administration of at least two classes of non-opioid analgesics is a simple strategy and may improve patient-reported outcomes.

[Perioperative analgesia with nonopioid analgesics : Joint interdisciplinary consensus-based recommendations of the German Pain Society, the German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Surgery]. / Perioperative Schmerztherapie mit Nichtopioidanalgetika : Gemeinsame interdisziplinäre Empfehlung der Deutschen Schmerzgesellschaft, der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Deutschen Gesellschaft für Chirurgie.

BACKGROUND: Nonopioid analgesics are frequently used for perioperative analgesia; however, insufficient research is available on several practical issues. Often hospitals have no strategy for how to proceed, e.g., for informing patients or for the timing of perioperative administration of nonopioid analgesics. METHODS: An expert panel representing the German national societies of pain, anaesthesiology and intensive care medicine and surgery developed recommendations for the perioperative use of nonopioid analgesics within a formal, structured consensus process. RESULTS: The panel agreed that nonopioid analgesics shall be part of a multimodal analgesia concept and that patients have to be informed preoperatively about possible complications and alternative treatment options. Patients' history of pain and analgesic intake shall be evaluated. Patients at risk of severe postoperative pain and possible chronification of postsurgical pain shall be identified. Depending on the duration of surgery, nonopioid analgesics can already be administered preoperatively or intraoperatively so that plasma concentrations are sufficient after emergence from anesthesia. Nonopioid analgesics or combinations of analgesics shall be administered for a limited time only. An interdisciplinary written standard of care, comprising the nonopioid analgesic of choice, possible alternatives, adequate dosing and timing of administration as well as surgery-specific policies, have to be agreed upon by all departments involved. At discharge, the patient's physician shall be informed of analgesics given and those necessary after discharge. Patients shall be informed of possible side effects and symptoms and timely discontinuation of analgesic drugs. CONCLUSION: The use of nonopioid analgesics as part of a perioperative multimodal concept should be approved and established as an interdisciplinary and interprofessional concept for the adequate treatment of postoperative pain.

[Perioperative analgesia with nonopioid analgesics : Joint interdisciplinary consensus-based recommendations of the German Pain Society, the German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Surgery]. / Perioperative Schmerztherapie mit Nichtopioidanalgetika : Gemeinsame interdisziplinäre Empfehlung der Deutschen Schmerzgesellschaft, der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin und der Deutschen Gesellschaft für Chirurgie.

BACKGROUND: Nonopioid analgesics are frequently used for perioperative analgesia; however, insufficient research is available on several practical issues. Often hospitals have no strategy for how to proceed, e.g., for informing patients or for the timing of perioperative administration of nonopioid analgesics. METHODS: An expert panel representing the German national societies of pain, anaesthesiology and intensive care medicine and surgery developed recommendations for the perioperative use of nonopioid analgesics within a formal, structured consensus process. RESULTS: The panel agreed that nonopioid analgesics shall be part of a multimodal analgesia concept and that patients have to be informed preoperatively about possible complications and alternative treatment options. Patients' history of pain and analgesic intake shall be evaluated. Patients at risk of severe postoperative pain and possible chronification of postsurgical pain shall be identified. Depending on the duration of surgery, nonopioid analgesics can already be administered preoperatively or intraoperatively so that plasma concentrations are sufficient after emergence from anesthesia. Nonopioid analgesics or combinations of analgesics shall be administered for a limited time only. An interdisciplinary written standard of care, comprising the nonopioid analgesic of choice, possible alternatives, adequate dosing and timing of administration as well as surgery-specific policies, have to be agreed upon by all departments involved. At discharge, the patient's physician shall be informed of analgesics given and those necessary after discharge. Patients shall be informed of possible side effects and symptoms and timely discontinuation of analgesic drugs. CONCLUSION: The use of nonopioid analgesics as part of a perioperative multimodal concept should be approved and established as an interdisciplinary and interprofessional concept for the adequate treatment of postoperative pain.

Thirty-five Years of Acute Pain Services: Where Do We Go From Here?

Acute pain services (APS) have developed over the past 35 years. Originally implemented solely to care for patients with regional catheters or patient-controlled analgesia after surgery, APS have become providers of care throughout the perioperative period, with some institutions even taking the additional step toward providing outpatient services for patients with acute pain. Models vary considerably in terms of tasks and responsibilities, staffing, education, protocols, quality, and financing. Many challenges face today's APS, including the increasing number of patients with preexisting chronic pain, intake of analgesics and opioids before surgery, substance-dependent patients needing special care, shorter hospital stays, early discharge of patients in need of further analgesic treatment, prevention and treatment of chronic postsurgical pain, minimization of adverse events, and side effects of treatment. However, many APS lack a clear-cut definition of their structures, tasks, and quality. Development of APS in the future will require us to face urgent questions, such as, "What are meaningful outcome variables?" and, "How do we define high quality?" It is obvious that focusing exclusively on pain scores does not reflect the complexity of pain and recovery. A broader approach is needed-a common concept of surgical and anesthesiological services within a hospital (eg, procedure-specific patient pathways as indicated by the programs "enhanced recovery after surgery" or the "perioperative surgical home"), with patient-reported outcome measures as one central quality criterion. Pain-related functional impairment, treatment-induced side effects, speed of mobilization, as well as return to normal function and everyday activities are key.

ERK and p38 contribute to the regulation of nociceptin and the nociceptin receptor in human peripheral blood leukocytes.

Little is known about the mechanisms involved in the regulation of nociceptin and its receptor (nociceptin opioid peptide receptor, NOP) in response to inflammation and pain in humans. In this study, specific signaling pathways contributing to the regulation of nociceptin and NOP in human peripheral blood leukocytes were investigated. After approval by the ethics committee, peripheral blood obtained from healthy donors was cultured with or without phorbol-12-myristate-13-acetate (PMA). Prepronociceptin (ppNOC) and NOP mRNA were analyzed by real-time quantitative polymerase chain reaction, and nociceptin concentrations in culture supernatants by fluorescent enzyme immunoassay. Nociceptin and NOP protein levels in blood leukocyte subsets were determined using flow cytometry. To examine the contribution of signaling pathways to ppNOC and NOP regulation, blood was pre-treated with kinase inhibitors specific for ERK, JNK, p38, and NFκB pathways prior to culturing with or without PMA. PMA dose-dependently upregulated ppNOC mRNA but downregulated NOP mRNA in human peripheral blood leukocytes. PMA 10 ng/ml increased ppNOC after 6 h and suppressed NOP after 3 h compared to controls (both P <0.005). Nociceptin concentrations were increased in supernatants of PMA-induced blood samples after 24 h ( P <0.005), whereas expression of cell-membrane NOP was decreased by PMA in blood leukocyte subsets (all P <0.05). Blockade of ERK or p38 pathways partially prevented PMA effects on ppNOC and NOP mRNA (all P <0.05). The combination of ERK and p38 inhibitors completely reversed the effects of PMA ( P <0.05). ERK and p38 are two major signaling pathways regulating nociceptin and its receptor in human peripheral blood leukocytes under inflammatory conditions.

A serotonin transporter polymorphism is associated with postoperative nausea and vomiting: An observational study in two different patient cohorts.

BACKGROUND: Clinical risk factors for postoperative nausea and vomiting (PONV) are well described, whereas genetic findings are conflicting. OBJECTIVE: The aim of this study was to investigate a possible association of genetic variants and nongenetic variables with the incidence and severity of PONV. DESIGN: A prospective observational study in two independent and different patient cohorts. SETTING: Two independent patient cohorts differing in surgical procedures were enrolled in two tertiary care hospitals between 2008 and 2016. PATIENTS: Consecutive patients of European origin undergoing elective surgery in two university hospitals. Clinical data were collected up to 24 h after surgery, and blood was drawn for genotyping. Of 2773 patients enrolled, 918 (Cohort A) and 1663 (Cohort B) with complete data sets were analysed. MAIN OUTCOME MEASURE: Patients were allocated to one of three groups (No PONV, Intermediate PONV or Severe PONV) depending on the frequency of vomiting, the severity of nausea and the need for antiemetics. Clinical variables and 13 genetic variants of seven candidate genes were evaluated for association with these three phenotypes. The cohorts were analysed separately by ordinal logistic regression analysis, treating PONV as a dependent ordinal three-stage variable. Odds ratios (ORs) with 95% confidence intervals were calculated. RESULTS: In Cohort A, the main predictors for PONV were female sex [OR (95% CI): 3.6 (2.7 to 4.8), P < 0.0001], nonsmoking status 1.8 (1.3 to 2.5), P < 0.001, the SS genotype (5-HTTLPR, rs4795541) of the promoter polymorphism in the serotonin transporter 1.5 (1.1 to 2.1), P = 0.019, and patient age 0.99 (0.98 to 0.99), P = 0.013. Analysis of Cohort B was consistent with these findings [5-HTTLPR: 1.8 (1.4 to 2.3), P < 0.00001]. Sex-specific regression models confirmed this 5-HTTLPR association in women and men. CONCLUSION: In two independent cohorts, in addition to the well known clinical factors, a polymorphism of 5-HTTLPR in the serotonin transporter was independently associated with PONV. A possible evaluation of this biomarker to improve risk prediction within the scope of precision medicine should be considered. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT03490175.

Metamizole/dipyrone for the relief of cancer pain: A systematic review and evidence-based recommendations for clinical practice.

BACKGROUND: Dipyrone (metamizole) is one of the most widely used non-opioid analgesics for the treatment of cancer pain. AIM: Because evidence-based recommendations are not yet available, a systematic review was conducted for the German Guideline Program in Oncology to provide recommendations for the use of dipyrone in cancer pain. DESIGN: First, a systematic review for clinical trials assessing dipyrone in adult patients with cancer pain was conducted. Endpoints were pain intensity, opioid-sparing effects, safety, and quality of life. DATA SOURCES: The search was performed in MedLine, Embase (via Ovid), and the Cochrane Library (1948-2013) and additional hand search was conducted. Finally, recommendations were developed and agreed in a formal structured consensus process by 53 representatives of scientific medical societies and 49 experts. RESULTS: Of 177 retrieved studies, 4 could be included (3 randomized controlled trials and 1 cohort study, n = 252 patients): dipyrone significantly decreased pain intensity compared to placebo, even if low doses (1.5-2 g/day) were used. Higher doses (3 × 2 g/day) were more effective than low doses (3 × 1 g/day), but equally effective as 60 mg oral morphine/day. Pain reduction of dipyrone and non-steroidal anti-inflammatory drugs did not differ significantly. Compared to placebo, non-steroidal anti-inflammatory drugs, and morphine, the incidence of adverse effects was not increased. CONCLUSION: Dipyrone can be recommended for the treatment of cancer pain as an alternative to other non-opioids either alone or in combination with opioids. It can be preferred over non-steroidal anti-inflammatory drugs due to the presumably favorable side effect profile in long-term use, but comparative studies are not available for long-term use.

Current practice of acute pain management in children-a national follow-up survey in Germany.

OBJECTIVES: This study aimed to summarize the current standard practices for acute pain management in children in Germany and the implementation of these procedures. The last survey on acute pain management in children was performed in 1999, highlighting the need for an up to date review. METHODS: A questionnaire was mailed to German departments of anesthesiology (n = 885), asking for structures and processes of acute pain management in children. Results were compared between hospitals with and without an acute pain service and with and without a pediatric department. RESULTS: Of the 407 responding hospitals (response rate of 46%), 342 treated children younger than 14 years. These were considered for analysis. Of the 342 hospitals, 42% contained either a general pediatric department or a department of pediatric surgery, and the majority of the responding hospitals had an acute pain service (83%). Pain intensities were measured at least once per shift in 40% of the institutions, and at least once or twice a day in 27%. Of the institutions, 31% did not document pain scores regularly, without any difference between hospitals with or without a pediatric department. Standard operating procedures for acute pain management existed in 68% of the hospitals, with large differences in content and length. Opioids were administered to children in 85% of the hospitals. Nonopioid analgesics were the first choice baseline analgesics in most hospitals. Peripheral regional and epidural analgesia were performed in children in 18% and 8% of the hospitals, respectively (21%/16% with a paediatric department, 16%/1% without; P < 0.001). CONCLUSION: Current practice of pediatric pain management varied widely and the recommendations of guidelines, like regular pain management, were frequently not met. However, improvements could be observed since 1999, for example, an increase in regular pain measurements (4% vs 67%). Furthermore, pain management in hospitals running a pediatric department had a higher degree of organization, and more sophisticated analgesic techniques.

Ethical procedures and patient consent differ in Europe.

BACKGROUND: Research ethics approvals, procedures and requirements for institutional research ethics committees vary considerably by country and by type of organisation. OBJECTIVE: To evaluate the requirements and procedures of research ethics committees, details of patient information and informed consent based on a multicentre European trial. DESIGN: Survey of European hospitals participating in the prospective observational study on chronic postsurgical pain (euCPSP) using electronic questionnaires. SETTING: Twenty-four hospitals in 11 European countries. PARTICIPANTS: From the 24 hospitals, 23 local investigators responded; 23 answers were analysed. OUTCOME MEASURES: Comparison of research ethics procedures and committee requirements from the perspective of clinical researchers. Comparison of the institutions' procedures regarding patient information and consent. Description of further details such as costs and the duration of the approval process. RESULTS: The approval process lasted from less than 2 weeks up to more than 2 months with financial fees varying between 0 and 575 &OV0556;. In 20 hospitals, a patient information sheet of variable length (half page up to two pages) was provided. Requirements for patients' informed consent differed. Written informed consent was mandatory at 12, oral at 10 and no form of consent at one hospital. Details such as enough time for consideration, possibility for withdrawal and risks/benefits of participation were provided in 25 to 30% of the institutions. CONCLUSION: There is a considerable variation in the administrative requirements for approval procedures by research ethics committees in Europe. This results in variation of the extent of information and consent procedures for the patients involved. TRIAL REGISTRATION: euCPSP in Clinicaltrials.gov identifier: NCT01467102; PAIN-OUT in Clinicaltrials.gov identifier: NCT02083835.

Chronic postsurgical pain in Europe: An observational study.

BACKGROUND: Chronic postsurgical pain (CPSP) is an important clinical problem. Prospective studies of the incidence, characteristics and risk factors of CPSP are needed. OBJECTIVES: The objective of this study is to evaluate the incidence and risk factors of CPSP. DESIGN: A multicentre, prospective, observational trial. SETTING: Twenty-one hospitals in 11 European countries. PATIENTS: Three thousand one hundred and twenty patients undergoing surgery and enrolled in the European registry PAIN OUT. MAIN OUTCOME MEASURES: Pain-related outcome was evaluated on the first postoperative day (D1) using a standardised pain outcome questionnaire. Review at 6 and 12 months via e-mail or telephonic interview used the Brief Pain Inventory (BPI) and the DN4 (Douleur Neuropathique four questions). Primary endpoint was the incidence of moderate to severe CPSP (numeric rating scale, NRS ≥3/10) at 12 months. RESULTS: For 1044 and 889 patients, complete data were available at 6 and 12 months. At 12 months, the incidence of moderate to severe CPSP was 11.8% (95% CI 9.7 to 13.9) and of severe pain (NRS ≥6) 2.2% (95% CI 1.2 to 3.3). Signs of neuropathic pain were recorded in 35.4% (95% CI 23.9 to 48.3) and 57.1% (95% CI 30.7 to 83.4) of patients with moderate and severe CPSP, respectively. Functional impairment (BPI) at 6 and 12 months increased with the severity of CPSP (P < 0.01) and presence of neuropathic characteristics (P < 0.001). Multivariate analysis identified orthopaedic surgery, preoperative chronic pain and percentage of time in severe pain on D1 as risk factors. A 10% increase in percentage of time in severe pain was associated with a 30% increase of CPSP incidence at 12 months. CONCLUSION: The collection of data on CPSP was feasible within the European registry PAIN OUT. The incidence of moderate to severe CPSP at 12 months was 11.8%. Functional impairment was associated with CPSP severity and neuropathic characteristics. Risk factors for CPSP in the present study were chronic preoperative pain, orthopaedic surgery and percentage of time in severe pain on D1. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01467102.

Following Evidence-Based Recommendations for Perioperative Pain Management after Cesarean Section Is Associated with Better Pain-Related Outcomes: Analysis of Registry Data.

Women who have had a Cesarean Section (CS) frequently report severe pain and pain-related interference. One reason for insufficient pain treatment might be inconsistent implementation of evidence-based guidelines. We assessed the association between implementing three elements of care recommended by guidelines for postoperative pain management and pain-related patient-reported outcomes (PROs) in women after CS. The analysis relied on an anonymized dataset of women undergoing CS, retrieved from PAIN OUT. PAIN OUT, an international perioperative pain registry, provides clinicians with treatment assessment methodology and tools for patients to assess multi-dimensional pain-related PROs on the first postoperative day. We examined whether the care included [i] regional anesthesia with a neuraxial opioid OR general anesthesia with wound infiltration or a Transvesus Abdominis Plane block; [ii] at least one non-opioid analgesic at the full daily dose; and [iii] pain assessment and recording. Credit for care was given only if all three elements were administered (= "full"); otherwise, it was "incomplete". A "Pain Composite Score-total" (PCStotal), evaluating outcomes of pain intensity, pain-related interference with function, and side-effects, was the primary endpoint in the total cohort (women receiving GA and/or RA) or a sub-group of women with RA only. Data from 5182 women was analyzed. "Full" care was administered to 20% of women in the total cohort and to 21% in the RA sub-group. In both groups, the PCStotal was significantly lower compared to "incomplete" care (p < 0.001); this was a small-to-moderate effect size. Administering all three elements of care was associated with better pain-related outcomes after CS. These should be straightforward and inexpensive for integration into routine care after CS. However, even in this group, a high proportion of women reported poor outcomes, indicating that additional work needs to be carried out to close the evidence-practice gap so that women who have undergone CS can be comfortable when caring for themselves and their newborn.

Cost-effectiveness of the Perioperative Pain Management Bundle a registry-based study.

Introduction: The Perioperative Pain Management Bundle was introduced in 10 Serbian PAIN OUT network hospitals to improve the quality of postoperative pain management. The Bundle consists of 4 elements: informing patients about postoperative pain treatment options; administering a full daily dose of 1-2 non-opioid analgesics; administering regional blocks and/or surgical wound infiltration; and assessing pain after surgery. In this study, we aimed to assess the cost-effectiveness of the Bundle during the initial 24 h after surgery. Materials and methods: The assessment of cost-effectiveness was carried out by comparing patients before and after Bundle implementation and by comparing patients who received all Bundle elements to those with no Bundle element. Costs of postoperative pain management included costs of the analgesic medications, costs of labor for administering these medications, and related disposable materials. A multidimensional Pain Composite Score (PCS), the effectiveness measurement, was obtained by averaging variables from the International Pain Outcomes questionnaire evaluating pain intensity, interference of pain with activities and emotions, and side effects of analgesic medications. The incremental cost-effectiveness ratio (ICER) was calculated as the incremental change in costs divided by the incremental change in PCS and plotted on the cost-effectiveness plane along with the economic preference analysis. Results: The ICER value calculated when comparing patients before and after Bundle implementation was 181.89 RSD (1.55 EUR) with plotted ICERs located in the northeast and southeast quadrants of the cost-effectiveness plane. However, when comparing patients with no Bundle elements and those with all four Bundle elements, the calculated ICER was -800.63 RSD (-6.82 EUR) with plotted ICERs located in the southeast quadrant of the cost-effectiveness plane. ICER values differ across surgical disciplines. Conclusion: The proposed perioperative pain management Bundle is cost-effective. The cost-effectiveness varies depending on the number of implemented Bundle elements and fluctuates across surgical disciplines.

The Perioperative Pain Management Bundle is Feasible: Findings From the PAIN OUT Registry.

OBJECTIVES: The quality of postoperative pain management is often poor. A "bundle," a small set of evidence-based interventions, is associated with improved outcomes in different settings. We assessed whether staff caring for surgical patients could implement a "Perioperative Pain Management Bundle" and whether this would be associated with improved multidimensional pain-related patient-reported outcomes (PROs). METHODS: "PAIN OUT," a perioperative pain registry, offers tools for auditing pain-related PROs and obtaining information about perioperative pain management during the first 24 hours after surgery. Staff from 10 hospitals in Serbia used this methodology to collect data at baseline. They then implemented the "Perioperative Pain Management Bundle" into the clinical routine and collected another round of data. The bundle consists of 4 treatment elements: (1) a full daily dose of 1 to 2 nonopioid analgesics (eg, paracetamol and/or nonsteroidal anti-inflammatory drugs), (2) at least 1 type of local/regional anesthesia, (3) pain assessment by staff, and (4) offering patients information about pain management. The primary endpoint was a multidimensional pain composite score (PCS), evaluating pain intensity, interference, and side effects that was compared between patients who received the full bundle versus not. RESULTS: Implementation of the complete bundle was associated with a significant reduction in the PCS ( P < 0.001, small-medium effect size [ES]). When each treatment element was evaluated independently, nonopioid analgesics were associated with a higher PCS (ie, poorer outcome, and negligible ES), and the other elements were associated with a lower PCS (all negligible small ES). Individual PROs were consistently better in patients receiving the full bundle compared with 0 to 3 elements. The PCS was not associated with the surgical discipline. DISCUSSION: We report findings from using a bundle approach for perioperative pain management in patients undergoing mixed surgical procedures. Future work will seek strategies to improve the effect.

Interactions between the Nociceptin and Toll-like Receptor Systems.

Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in inflammation and impact opioid receptors and endogenous opioids expression. In this study, interactions between the nociceptin and TLR systems were investigated. Human THP-1 cells were cultured with or without phorbol myristate acetate (PMA 5 ng/mL), agonists specific for TLR2 (lipoteichoic acid, LTA 10 µg/mL), TLR4 (lipopolysaccharide, LPS 100 ng/mL), TLR7 (imiquimod, IMQ 10 µg/mL), TLR9 (oligonucleotide (ODN) 2216 1 µM), PMA+TLR agonists, or nociceptin (0.01−100 nM). Prepronociceptin (ppNOC), NOP, and TLR mRNAs were quantified by RT-qPCR. Proteins were measured using flow cytometry. PMA upregulated ppNOC mRNA, intracellular nociceptin, and cell membrane NOP proteins (all p < 0.05). LTA and LPS prevented PMA's upregulating effects on ppNOC mRNA and nociceptin protein (both p < 0.05). IMQ and ODN 2216 attenuated PMA's effects on ppNOC mRNA. PMA, LPS, IMQ, and ODN 2216 increased NOP protein levels (all p < 0.05). PMA+TLR agonists had no effects on NOP compared to PMA controls. Nociceptin dose-dependently suppressed TLR2, TLR4, TLR7, and TLR9 proteins (all p < 0.01). Antagonistic effects observed between the nociceptin and TLR systems suggest that the nociceptin system plays an anti-inflammatory role in monocytes under inflammatory conditions.