[Opioid-free anesthesia : Wrong track or meaningful exit from the era of opioid-based analgesia?] / Opioidfreie Anästhesie : Irrweg oder sinnvoller Ausweg aus der Ära der opioidbasierten Analgesie?

The limitations and disadvantages of opioids in anesthesia are very well known but the advantages combined with a lack of effective alternatives even now still prevents refraining from using opioids as part of an adequate pain therapy. For decades, pain research has had the declared goal of replacing opioids with new substances which have no serious side effects; however, currently this goal seems to be a long way off. Due to the media coverage of the "opioid crisis" in North America, the use of opioids for pain management is also increasingly being questioned by the patients. Measures to contain this crisis are only slowly taking effect in view of the increasing number of deaths, which is why the triggers are still being sought. The perioperative administration of opioids is not only a possible gateway to addiction and abuse but it can also cause outcome-relevant complications, such as respiratory depression, postoperative nausea and vomiting and an increase in postoperative pain. Therefore, these considerations gave rise to the idea of an opioid-free anesthesia (OFA), i.e., opioids are not administered as part of anesthesia to carry out surgical procedures. Although this idea may make sense at first glance, a rapid introduction of this concept appears to be risky as it entails significant changes for the entire anesthesiological management. Based on relatively robust data from clinical studies, this concept can now be evaluated and discussed not only emotionally but also objectively. This review article presents arguments for or against the complete avoidance of intraoperative or even perioperative opioids. The current conditions in Germany are primarily taken into account, so that the perioperative pain therapy is transferable to the established standards. The results from current clinical studies on the implementation of an opioid-free anesthesia are summarized and discussed.

The potentiating effect of intravenous dexamethasone upon preemptive pudendal block analgesia for hypospadias surgery in children managed with Snodgrass technique: a randomized controlled study : Dexamethasone for pain management in children.

INTRODUCTION: Evidence regarding the potentiating effects of intravenous dexamethasone on peripheral regional anesthesia in children is sparse. The objective of the current study was to investigate the potentiating effect of intravenous dexamethasone upon pudendal block during surgical correction of hypospadias using Snodgrass technique. METHODS: The study consisted of a monocentric, randomized controlled, double-blinded study. Patients were randomized to receive either intravenous dexamethasone 0.15 mg.kg- 1 (D group) or a control solution (C group). Both groups received standardized anesthesia including a preemptive pudendal block performed after the induction of anesthesia. The primary outcome was the proportion of patients needing rescue analgesia. Secondary outcomes were other pain outcomes over the first 24 postoperative hours. RESULTS: Overall, 70 patients were included in the study. Age were 24 [24; 36] and 26 [24; 38] months in the D and C groups, respectively (p = 0.4). Durations of surgery were similar in both groups (60 [30; 60], p = 1). The proportion of patients requiring rescue analgesia was decreased in the D group (23% versus 49%, in D and C groups respectively, p = 0.02). The first administration of rescue analgesia was significantly delayed in the D group. Postoperative pain was improved in the D group between 6 and 24 h after surgery. Opioid requirements and the incidence of vomiting did not significantly differ between groups. CONCLUSION: Associating intravenous dexamethasone (0.15 mg.kg- 1) to pudendal block during hypospadias surgery improves pain control over the first postoperative day. Further studies are needed in order to confirm these results. GOV IDENTIFIER: NCT03902249. A. WHAT IS ALREADY KNOWN: dexamethasone has been found to potentiate analgesia obtained with regional anesthesia in children. B. WHAT THIS ARTICLE ADDS: intravenous dexamethasone was found to improve analgesia with a preemptive pudendal block during hypospadias surgery. C. IMPLICATIONS FOR TRANSLATION: results of this study indicate that intravenous dexamethasone could be used as an adjunct to pudendal block.

Size control of ropivacaine nano/micro-particles by soft-coating with peptide nanosheets for long-acting analgesia.

Rationale: To meet the need of long-acting analgesia in postoperative pain management, slow-releasing formulations of local anesthetics (LAs) have been extensively investigated. However, challenges still remain in obtaining such formulations in a facile and cost-effective way, and a mechanism for controlling the release rate to achieve an optimal duration is still missing. Methods: In this study, nanosheets formed by a self-assembling peptide were used to encapsulate ropivacaine in a soft-coating manner. By adjusting the ratio between the peptide and ropivacaine, ropivacaine particles with different size were prepared. Releasing profile of particles with different size were studied in vitro and in vivo. The influence of particle size and ropivacaine concentration on effective duration and toxicity were evaluated in rat models. Results: Our results showed that drug release rate became slower as the particle size increased, with particles of medium size (2.96 ± 0.04 µm) exhibiting a moderate release rate and generating an optimal anesthetic duration. Based on this size, formulations at different ropivacaine concentrations generated anesthetic effect with different durations in rat sciatic nerve block model, with the 6% formulation generated anesthetic duration of over 35 h. Long-acting analgesia up to 48 h of this formulation was also confirmed in a rat total knee arthroplasty model. Conclusion: This study provided a facile strategy to prepare LA particles of different size and revealed the relationship between particle size, release rate and anesthetic duration, which provided both technical and theoretical supports for developing long-acting LA formulations with promising clinical application.

Analgesia for rib fractures: a narrative review.

PURPOSE: Rib fracture(s) is a common and painful injury often associated with significant morbidity (e.g., respiratory complications) and high mortality rates, especially in the elderly. Risk stratification and prompt implementation of analgesic pathways using a multimodal analgesia approach comprise a primary endpoint of care to reduce morbidity and mortality associated with rib fractures. This narrative review aims to describe the most recent evidence and care pathways currently available, including risk stratification tools and pharmacologic and regional analgesic blocks frequently used as part of the broadly recommended multimodal analgesic approach. SOURCE: Available literature was searched using PubMed and Embase databases for each topic addressed herein and reviewed by content experts. PRINCIPAL FINDINGS: Four risk stratification tools were identified, with the Study of the Management of Blunt Chest Wall Trauma score as most predictive. Current evidence on pharmacologic (i.e., acetaminophen, nonsteroidal anti-inflammatory drugs, gabapentinoids, ketamine, lidocaine, and dexmedetomidine) and regional analgesia (i.e., thoracic epidural analgesia, thoracic paravertebral block, erector spinae plane block, and serratus anterior plane block) techniques was reviewed, as was the pathophysiology of rib fracture(s) and its associated complications, including the development of chronic pain and disabilities. CONCLUSION: Rib fracture(s) continues to be a serious diagnosis, with high rates of mortality, development of chronic pain, and disability. A multidisciplinary approach to management, combined with appropriate analgesia and adherence to care bundles/protocols, has been shown to decrease morbidity and mortality. Most of the risk-stratifying care pathways identified perform poorly in predicting mortality and complications after rib fracture(s).

RéSUMé: OBJECTIF: Les fractures des côtes sont des blessures courantes et douloureuses souvent associées à une morbidité importante (p. ex., complications respiratoires) et à des taux de mortalité élevés, surtout chez les personnes âgées. La stratification des risques et la mise en œuvre rapide de voies analgésiques à l'aide d'une approche d'analgésie multimodale constituent un critère d'évaluation principal des soins visant à réduire la morbidité et la mortalité associées aux fractures des côtes. Ce compte rendu narratif a pour objectif de décrire les données probantes les plus récentes et les parcours de soins actuellement disponibles, y compris les outils de stratification des risques et les blocs analgésiques pharmacologiques et régionaux fréquemment utilisés dans le cadre de l'approche analgésique multimodale largement recommandée. SOURCES: La littérature disponible a été recherchée à l'aide des bases de données PubMed et Embase pour chaque sujet abordé dans le présent compte rendu et examinée par des expert·es en contenu. CONSTATATIONS PRINCIPALES: Quatre outils de stratification des risques ont été identifiés, le score de l'Étude de la prise en charge des traumatismes contondants de la paroi thoracique (Study of the Management of Blunt Chest Wall Trauma) étant le plus prédictif. Les données probantes actuelles sur les techniques d'analgésie pharmacologiques (c.-à-d. acétaminophène, anti-inflammatoires non stéroïdiens, gabapentinoïdes, kétamine, lidocaïne et dexmédétomidine) et d'analgésie régionale (c.-à-d. analgésie péridurale thoracique, bloc paravertébral thoracique, bloc du plan des muscles érecteurs du rachis et bloc du plan du muscle grand dentelé) ont été examinées, de même que la physiopathologie de la ou des fractures des côtes et de leurs complications associées, y compris l'apparition de douleurs chroniques et d'incapacités. CONCLUSION: Les fractures des côtes continuent d'être un diagnostic grave, avec des taux élevés de mortalité, de développement de douleurs chroniques et d'invalidité. Il a été démontré qu'une approche multidisciplinaire de la prise en charge, combinée à une analgésie appropriée et à l'adhésion aux ensembles et protocoles de soins, réduit la morbidité et la mortalité. La plupart des parcours de soins de stratification des risques identifiés sont peu performants pour prédire la mortalité et les complications après une ou plusieurs fractures de côtes.

Predicting the optimal concentration of remifentanil for skull pin fixation with hemodynamic and analgesia nociception index monitoring.

Inadequate antinociception during skull pin fixation may cause hemodynamic instability in intracranial surgery. The optimal concentration of remifentanil to provide adequate antinociception and stable hemodynamics during skull pin fixation under analgesia nociception index monitoring is unknown. This study is to assess the 90% effective concentration of remifentanil for skull pin fixation under hemodynamic and analgesia nociception index monitoring. Twenty-six patients were enrolled for intracranial surgery, anesthesia was induced and maintained under total intravenous anesthesia using target-controlled infusion for remifentanil and propofol under analgesia nociception index and bispectral index monitoring. Skull pin fixation was performed at different effect-site concentrations of remifentanil required for Dixon's up-and-down method with a step size of 0.5 ng/ml under bispectral index 40-60. Inadequate antinociception is defined when either ANI < 30 or > 20% in hemodynamic changes from baseline (e.g. heart rate > 100 beats/min, or blood pressure > 180/100 mmHg) and the effect-site concentration of remifentanil is considered as failure. It is considered success as ANI > 30 and < 20% hemodynamic changes from baseline simultaneously. Seven pairs of failure/success were used for probit analysis. The 90% effective concentration of remifentanil for skull pin fixation with adequate antinociception and hemodynamic stability was 4.7 ng/ml.

Comparison of ultrasound-guided subtransverse process interligamentary plane block with paravertebral block for postoperative analgesia in thoracic surgery: protocol for a randomised non-inferiority trial.

INTRODUCTION: The subtransverse process interligamentary (STIL) plane block is an emerging interfascial plane block that has garnered attention for its potential to provide effective postoperative analgesia for breast and thoracic surgeries. However, a direct comparative assessment between the STIL plane block and the paravertebral block is currently lacking. Consequently, our study aims to assess the analgesic efficacy of the STIL block in comparison to paravertebral block for patients undergoing video-assisted thoracoscopic surgery (VATS). METHODS AND ANALYSIS: This study is a randomised, parallel-controlled, double-blind, non-inferiority trial, with the goal of enrolling 114 participants scheduled for uniportal VATS at Shanghai Pulmonary Hospital. Participants will be randomly assigned in a 1:1 ratio through block randomisation to receive either the STIL plane block (n=57) or the paravertebral block (n=57). The primary outcome of the study is the area under the curve of Numerical Rating Scale(NRS) scores recorded over a 48-hour period following the surgical procedure. Secondary outcomes encompass the evaluation of Quality of Recovery-40, cumulative sufentanil consumption, serum inflammatory factors, rescue medication usage, the incidence of adverse events and the patient satisfaction scores. ETHICS AND DISSEMINATION: This study has received approval from the Medical Ethics Committee of Shanghai Pulmonary Hospital (approval no. L22-329). Written informed consent will be obtained from all participants. The findings will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2200066909.

Erector Spinae Plane Block for Providing Labor Analgesia in a Rural Health Care Setting in India: A Case Series.

The practice of labor analgesia is highly variable in India. Parturients are often prescribed mild opioids (tramadol and pethidine). Erector spinae plane blocks can provide widespread analgesia covering multiple dermatomes. After a process evaluation to introduce safe and effective labor analgesia mandated due to poor efficacy of the standard care, erector spinae plane analgesia was offered to nulliparous parturients. The procedure was performed under ultrasound guidance at the lumbar L4 level in 10 patients. Outcomes included pain scores. There was a major reduction in labor pain. Erector spinae plane blocks can be part of a sustainable and effective labor analgesia service.

Safety of blood reinfusion drains after local infiltration analgesia in total joint replacement.

BACKGROUND: Local infiltration analgesia (LIA) is frequently administered to patient undergoing joint replacement surgical procedures. The aim of the present research was to verify the safety of collected shed blood to be reinfused postoperatively, by measuring levobupivacaine levels in drainage blood in patients undergoing LIA during knee replacement surgery. PATIENTS AND METHODS: 24 patients who underwent total knee arthroplasty (TKA) and 12 scheduled for total hip arthroplasty (THA) who received intraoperative LIA were considered. Blood samples were collected from shed blood which was present in drainage 2 and 5 hours after surgery and serum was analysed by liquid chromatography-tandem mass spectrometry. RESULTS: At 2 hours postoperatively, the median levobupivacaine serum concentration in the collected shed blood was 1.2 mg/L (SD: 4.2) for TKA and 17.13 mg/L (SD: 24.4) for THA. At 5 hours, levobupivacaine concentration was 1.84 mg/L (SD: 2.2) for TKA and 17.5 mg/L (SD: 25.2) for THA. Higher values of average serum levobupivacaine concentration were reported in drains collected from patients who had undergone THA compared to TKA (p<0.001). BMI significantly influenced levels of serum drug, that resulted to be higher in patients with BMI<25 (p= 0.01). CONCLUSION: Levobupivacaine from collected shed blood that would have been returned to the patient, was below toxicity level at 2 and 5 hours after LIA during total joint replacement. The average serum levobupivacaine concentration was found to be higher in drains taken from THA patients than TKA patients. Patients with lower BMI demonstrated the highest levels of levobupivacaine in shed blood and a lower blood volume needed for central nervous system toxicity. Therefore, in patients with a lower BMI undergoing THA, anaesthetic dosage should be reduced or autotransfusion should be avoided to prevent potential risks of toxicity.

Let Kids Play: Using Virtual Reality as a Substitute for General Anesthesia for Minor Procedures in Pediatric Population.

BACKGROUND: In the pediatric population, virtual reality (VR) has been used as an adjunct to augment analgesia and reduce the need for opioids. In this study, we review our experience using VR in lieu of anesthesia or sedation to enable minor procedures in children. METHODS: A retrospective chart review study was performed on patients who presented to our institution from 2019 to 2022 for hormone implant placement, exchange, or removal with VR distraction. Demographic and procedure information was recorded. The primary outcome was successful procedure completion without requiring pharmacologic sedation or analgesia. RESULTS: A total of 111 patients underwent the following minor procedures with VR and without anesthesia or sedation. Fourteen patients had multiple encounters resulting in a total of 126 encounters. The median age was 11 [6] years. 43 patients were female, 23 were female to male, 6 were non-binary, 7 were male, and 32 were male to female. 58 % had private insurance. Most common diagnosis was precocious puberty (54 %) followed by gender dysphoria (46 %). Most common procedure was implant placement (72 %). 69 % of procedures were performed in the clinic and 31 % in the OR. All procedures were completed without requiring the administration of additional sedation or anesthesia. None of the patients required intravenous catheter placement for the procedure. No intra-procedural complications were recorded. CONCLUSION: VR is a feasible option that can spare children from sedation or general anesthesia for minor procedures. VR may enable minor procedures in children to be successfully performed in clinic setting.

Regional anaesthesia for postoperative pain management following laparoscopic, visceral, non-oncological surgery a systematic review and meta-analysis.

BACKGROUND: Postoperative pain management following laparoscopic, non-oncological visceral surgery in adults is challenging. Regional anaesthesia could be a promising component in multimodal pain management. METHODS: We performed a systematic review and meta-analysis with GRADE assessment. Primary outcomes were postoperative acute pain intensity at rest/during movement after 24 h, the number of patients with block-related adverse events and the number of patients with postoperative paralytic ileus. RESULTS: 82 trials were included. Peripheral regional anaesthesia combined with general anaesthesia versus general anaesthesia may result in a slight reduction of pain intensity at rest at 24 h (mean difference (MD) - 0.72 points; 95% confidence interval (CI) - 0.91 to - 0.54; I2 = 97%; low-certainty evidence), which was not clinically relevant. The evidence is very uncertain regarding the effect on pain intensity during activity at 24 h (MD -0.8 points; 95%CI - 1.17 to - 0.42; I2 = 99%; very low-certainty evidence) and on the incidence of block-related adverse events. In contrast, neuraxial regional analgesia combined with general anaesthesia (versus general anaesthesia) may reduce postoperative pain intensity at rest in a clinical relevant matter (MD - 1.19 points; 95%CI - 1.99 to - 0.39; I2 = 97%; low-certainty evidence), but the effect is uncertain during activity (MD - 1.13 points; 95%CI - 2.31 to 0.06; I2 = 95%; very low-certainty evidence). There is uncertain evidence, that neuraxial regional analgesia combined with general anaesthesia (versus general anaesthesia) increases the risk for block-related adverse events (relative risk (RR) 5.11; 95%CI 1.13 to 23.03; I2 = 0%; very low-certainty evidence). CONCLUSION: This meta-analysis confirms that regional anaesthesia might be an important part of multimodal postoperative analgesia in laparoscopic visceral surgery, e.g. in patients at risk for severe postoperative pain, and with large differences between surgical procedures and settings. Further research is required to evaluate the use of adjuvants and the additional benefit of regional anaesthesia in ERAS programmes. PROTOCOL REGISTRATION: PROSPERO CRD42021258281.

The analgesic effects of magnesium in veterinary patients: a qualitative evidence synthesis.

OBJECTIVE: To perform a qualitative evaluation of the analgesic effects of magnesium in domestic animals, including its anaesthetic sparing effects. STUDY DESIGN: All database searches were made using PubMed and Google Scholar. Studies published after 1990, evaluating the use of magnesium and reporting information on analgesia, in dogs, cats, horses, cows, goats and sheep were selected (last search in August 2023). A reference check in the selected papers was performed to identify any study which was omitted. The CERQual (Confidence in Evidence from Reviews of Qualitative research) approach was used to assess confidence and analyse the evidence. RESULTS: A total of 20 studies relevant to the analgesic effects of magnesium in veterinary patients and two reviews were included. All were published after 2006. Of the 20, five studies provided information about analgesia in the postoperative period in dogs with heterogenous results. Magnesium added epidurally increased the duration of the sensory block in several species. Motor block was also observed when added to spinal analgesia. Results regarding volatile agents sparing effect were conflicting. Occasional moderate adverse effects were reported in dogs, such as nausea and vomiting, when administered as a bolus in conscious animals, and hypotension when administered intraperitoneally. Collapse was reported in horses after epidural administration. CONCLUSIONS AND CLINICAL RELEVANCE: The evidence of an analgesic effect of magnesium in veterinary patients remains scarce considering the paucity and low quality of published data. Further research may be helpful to establish the efficacy and indications of magnesium in multimodal analgesia in animals.

Effect of meloxicam or robenacoxib administration timing on renal function and postoperative analgesia in cats undergoing ovariohysterectomy: A randomized, blinded, controlled clinical trial.

We evaluated the effect of administration timing of meloxicam and robenacoxib on renal function, platelet cyclo-oxygenase and perioperative analgesia in 60 cats undergoing ovariohysterectomy, in a prospective randomized blinded controlled study. Twelve cats were randomly allocated to one subcutaneous treatment group: meloxicam (0.2 mg/kg) or robenacoxib (2 mg/kg) at admission (MA, RA), at induction (MI, RI) and robenacoxib at the end of surgery (RE). All cats received the same anaesthesia protocol. Plasma renin activity (PRA), plasma creatinine, drug concentrations and serum thromboxane (TxB2) were measured sequentially. Anaesthesia significantly increased PRA, as activity at end of the surgery was higher than 2 h later (mean ± SD: 26.6 ± 2.8 versus 10.0 ± 3.9 ng/mL/h). PRA remained higher at 2 h post-surgery in admission groups compared to induction groups (p = .01). Serum TxB2 was lower with meloxicam than robenacoxib (p = .001), and was lower in the MA than each robenacoxib group at catheter placement. Admission groups (16/24 from RA and MA groups) received earlier rescue analgesia than other groups (p = .033). In conclusion, the renin-angiotensin system was activated during anaesthesia despite cyclo-oxygenase inhibition, possibly due to hypotension or surgical stimulation. There was no effect of drug or timing on the markers of renal function but one cat receiving meloxicam at induction had suspected IRIS grade II acute kidney injury.

Association between esketamine interventions and postpartum depression and analgesia following cesarean delivery: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to compare the efficacy and safety of the use of esketamine to reduce the risk for postpartum depression and pain after cesarean delivery. DATA SOURCES: Literature searches were conducted in PubMed, Embase, Cochrane Library, Web of Science, CNKI, and Wan fang from inception to August 2023. STUDY ELIGIBILITY CRITERIA: The eligibility criteria were all randomized controlled trials of people who underwent a cesarean delivery and who were randomized to receive esketamine interventions irrespective of age or ethnicity. The outcomes that were assessed included the incidence of postpartum depression and the Edinburgh Postnatal Depression Scale score within 7 days and at 28 to 42 days after delivery, the pain score (visual analog scale or numerical rating scale, 0-10), the consumption of opioids, and intraoperative and postoperative adverse events. METHODS: The Cochrane collaboration's tool was used for quality appraisal of the included studies. Statistical analysis of the data was performed using Review Manager 5.3 software, and the results were expressed as mean differences with 95% confidence intervals. Assessments were pooled using a random-effects or fixed-effects model. Study heterogeneity was assessed using the standard I2 statistic. RESULTS: Among the 11 included randomized controlled trials that used the Edinburgh Postnatal Depression Scale for postpartum depression assessment, patients in esketamine group had a lower risk for postpartum depression within a week of surgery (risk ratio, 0.45; 95% confidence interval, 0.33-0.62). Intraoperative use of esketamine maintained a lower Edinburgh Postnatal Depression Scale score after surgery (mean difference, -1.64; 95% confidence interval, -2.14 to -1.14). Esketamine was associated with a beneficial effect in terms of the other outcomes, including a significant decline in pain score within 48 hours (mean difference, -0.71; 95% confidence interval, -0.89 to 0.52). Esketamine increased the risk for adverse neurologic and mental events during surgery without harming health, and there was no significant difference after delivery when compared with the control group. CONCLUSION: Esketamine may reduce the risk for postpartum depression among patients who are undergoing cesarean delivery in the short term. In addition, as an adjunct to reduce analgesia, esketamine also effectively assists in pain management. Because of the lack of more high-quality evidence, we need more compelling evidence to confirm the value of esketamine in improving postpartum recovery.

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries.

BACKGROUND: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures. METHODS: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge. RESULTS: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (ß coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not. CONCLUSION: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely.

A novel investigation of placebo analgesia through social communication in mice.

BACKGROUND AND AIMS: In rodents, placebo analgesia is often investigated through direct conditioning of stimuli, but humans can experience placebo analgesia through expectation without experience. In this study, we sought to determine whether placebo analgesia could be elicited through social communication. METHODS: Male and female mice were housed in pairs (designated "Active" and "Bystander") and tested for thermal thresholds on a hot plate (53 °C). Food restriction (1 hr/day) was implemented. The Active mouse was taken to a new cage with food dusted with cocoa (COC) or cinnamon (CINN). The Bystander mice were given regular chow in the home cage. After feeding, the Active mice were given morphine (5 mg/kg, SC) or saline and tested on the hot plate. After 5 pairings of a flavor and treatment (counterbalanced), Active mice were tested following access to a flavored food. Bystander mice were given their first direct exposure to a flavored food and tested on the hot plate. The protocol was repeated with naloxone (10 mg/kg, IP) administered prior to testing. Finally, mice were tested in a two-choice test with both flavored foods available. RESULTS: Active mice showed a conditioned analgesic response to the morphine-paired flavor that was reduced by naloxone. Bystander mice showed a placebo analgesic response to their cagemate's morphine-paired flavor that was not significantly impacted by naloxone. Bystander mice spent more time in the chamber associated with their cagemate's morphine-paired flavor. CONCLUSIONS: To our knowledge, this is the first investigation of placebo analgesia without direct conditioning, instead relying on social communication between mice. The lack of effect with naloxone pretreatment suggests an opioid-independent effect in the Bystander mice. Placebo analgesia in mice may be possible without direct conditioning to better model the effect of expectation of a novel analgesic in humans.

Ninety-Hz Spinal Cord Stimulation-Induced Analgesia Is Dependent on Active Charge Balance and Is Nonlinearly Related to Amplitude: A Sham-Controlled Behavioral Study in a Rodent Model of Chronic Neuropathic Pain.

BACKGROUND: Ninety-Hz active-recharge spinal cord stimulation (SCS) applied at below sensory-threshold intensity, as used with fast-acting subperception therapy spinal cord stimulation, has been shown clinically to produce significant analgesia, but additional characterization is required to better understand the therapy. This preclinical study investigates the behavioral effect of multiple 90-Hz SCS variants in a rodent model of neuropathic pain, focusing on charge balance and the relationship between 90-Hz efficacy and stimulation intensity. MATERIALS AND METHODS: Rats (n = 24) received a unilateral partial sciatic nerve ligation to induce neuropathic pain and were implanted with a quadripolar lead at T13. Mechanical hypersensitivity was assessed before, during, and after 60 minutes of SCS. After a prescreen with 50-Hz SCS 67% motor threshold ([MT], the positive control), rats underwent a randomized-crossover study including sham SCS and several 90-Hz SCS paradigms (at 40% MT or 60% MT, either using active or pseudopassive recharge) (experiment 1, n = 16). A second, identical experiment (experiment 2) was performed to supplement data with 90-Hz SCS at 20% and 80% MT (experiment 2, n = 8). RESULTS: Experiment 1: At 40% MT, 90-Hz active-recharge SCS produced a significantly larger recovery to baseline than did 90-Hz pseudopassive SCS at both tested intensities and sham SCS. Experiment 2: Only the 90-Hz SCS active recharge at 40% MT and 50-Hz SCS positive control caused mean recovery to baseline that was statistically better than that of sham SCS. CONCLUSIONS: The degree to which 90-Hz SCS reduced mechanical hypersensitivity during stimulation depended on the nature of charge balance, with 90-Hz active-recharge SCS generating better responses than did 90-Hz pseudopassive recharge SCS. In addition, our findings suggest that the amplitude of 90-Hz active-recharge SCS must be carefully configured for efficacy.

Outcomes and outcome measures utilised in randomised controlled trials of postoperative caesarean delivery pain: a scoping review.

BACKGROUND: Inadequately treated postoperative pain following caesarean delivery can delay recovery and the ability to care for a newborn. Effectiveness studies of interventions to treat postoperative caesarean delivery pain measure different outcomes, limiting data pooling for meta-analysis. We performed a comprehensive review of existing outcomes with the aim of recommending core outcomes for future research. METHODS: A scoping review to identify all outcomes reported in randomised controlled trials (RCTs) and clinical trial registries of interventions to treat or prevent postoperative caesarean delivery pain, with postoperative pain as a primary outcome measure. We searched PubMed, Web of Science, CINAHL, LILACS, Embase, CDSR and CRCT for studies from May 2016 to 2021. Outcomes were extracted and frequencies tabulated. RESULTS: Ninety RCTs and 11 trial registries were included. In total, 392 outcomes (375 inpatient and 17 outpatient) were identified and categorised. The most reported outcome domain was analgesia (n = 242/375, 64.5%), reported in 96% of inpatient studies, with analgesic consumption accounting for 108/375, 28.8% of analgesia outcomes. The second most common domain was pain intensity (n = 120/375, 32%), reported in 97% of inpatient studies, using the visual analogue scale (68/120, 59%) and the numerical reporting scale (37/120, 25%). Maternal and neonatal adverse effects accounted for 65/375 (17.3%) and 19/375 (5.1%) of inpatient outcomes, respectively. CONCLUSIONS: Outcomes reported in RCTs for postoperative caesarean delivery pain vary widely. The results of this review suggest that standardisation is needed to promote research efficiency and aid future meta-analyses to identify optimal postoperative caesarean delivery pain management.

A Survey Study of Surgeons and Anesthesiologists Regarding Perioperative Multimodal Analgesia for Opioid-Tolerant Patients.

PURPOSE: Perioperative pain management of opioid-tolerant patients can be challenging. Although regional anesthesia and multimodal analgesics may be beneficial, these modalities are often underused. It is unclear whether practice patterns for perioperative pain management are determined by the knowledge, attitudes, and beliefs of surgeons and anesthesiologists. DESIGN: Descriptive survey. METHODS: Using a Qualtrics survey, we polled a randomly selected group of 25 surgeons and 25 anesthesiologists regarding their knowledge, attitudes, beliefs, and practices for pain management in an opioid-tolerant patient. FINDINGS: Of 25, 23 anesthesiologists and 18/25 surgeons responded to the survey. Demographics were similar between the 2 groups. Most of the participant surgeons and anesthesiologists believed that pain management may be challenging in an opioid-tolerant patient. However, only 56% of surgeons would recommend a preoperative pain consultation. Most surgeons and anesthesiologists believed in the efficacy of regional anesthetics. However, 43% of surgeons would not advocate for a regional block, perhaps due to their perception of the added perioperative time. Multimodal analgesics were widely accepted by both surgeons and anesthesiologists. CONCLUSIONS: There is an urgent need to reinforce the importance of patient-centered care, with a specific focus on addressing knowledge gaps and improving perceptions for all the members of the team, including surgeons, anesthesiologists, and perioperative nursing teams, if optimal outcomes are to be achieved for our patients.

Nonsteroidal Anti-inflammatory Medications in Cranial Neurosurgery: Balancing Opioid-Sparing Analgesia with Bleeding Risk.

Postcraniotomy pain is a common problem frequently encountered by neurosurgeons. This is typically managed with opioids; however, opioids have been shown to increase intracranial pressure by way of hypercapnia and straining from the associated constipation. Additionally, opioids can confound and mask the neurologic examination of postcraniotomy patients, as well as be the nidus for a potential opioid addiction. Thus, alternative solutions for opioids have been a major topic of investigation within the neurosurgical community. Nonsteroidal anti-inflammatory drugs (NSAIDs) present as a potential solution due to their nonaddictive and analgesic properties, but utilization of NSAIDs in neurosurgical patients has been controversial given that NSAIDs alter platelet function. The degree to which NSAIDs alter platelet function and bleeding time to a clinically relevant manner has remained controversial, although several well-designed studies concluded that the utilization of NSAIDs in post-craniotomy patients does not increase the risk of postoperative bleeding. Herein, we review the pharmacology, efficacy, and safety of NSAIDs with a particular emphasis on NSAID use for postintracranial neurosurgical procedure pain management.

Does Active Inference Provide a Comprehensive Theory of Placebo Analgesia?

Placebo interventions generate mismatches between expected pain and sensory signals from which pain states are inferred. Because we lack direct access to bodily states, we can only infer whether nociceptive activity indicates tissue damage or results from noise in sensory channels. Predictive processing models propose to make optimal inferences using prior knowledge given noisy sensory data. However, these models do not provide a satisfactory explanation of how pain relief expectations are translated into physiological manifestations of placebo responses. Furthermore, they do not account for individual differences in the ability to endogenously regulate nociceptive activity in predicting placebo analgesia. The brain not only passively integrates prior pain expectations with nociceptive activity to infer pain states (perceptual inference) but also initiates various types of actions to ensure that sensory data are consistent with prior pain expectations (active inference). We argue that depending on whether the brain interprets conflicting sensory data (prediction errors) as a signal to learn from or noise to be attenuated, the brain initiates opposing types of action to facilitate learning from sensory data or, conversely, to enhance the biasing influence of prior pain expectations on pain perception. Furthermore, we discuss the role of stress, anxiety, and unpredictability of pain in influencing the weighting of prior pain expectations and sensory data and how they relate to the individual ability to regulate nociceptive activity (endogenous pain modulation). Finally, we provide suggestions for future studies to test the implications of the active inference model of placebo analgesia.