Papaver somniferum in seventeenth century (Italy): archaeotoxicological study on brain and bone samples in patients from a hospital in Milan.

In this paper, we present the results of toxicological analyses of preserved brain tissue and bone samples from the remains of the seventeenth century patients of the Ospedale Maggiore, the main hospital in Milan and one of the most innovative hospitals in Europe from the Renaissance period. Beneath it, the crypt functioned as the burial place for the deceased of the hospital. In this multidisciplinary study of the remains, toxicological analyses in particular were performed with HPLC-MS/MS on different biological samples from nine individuals. Anthropological, paleopathological, histological, radiological examinations and radiocarbon dating were also carried out. As a result, archeotoxicological analyses revealed the presence of codeine, morphine, noscapine and papaverine, derived from Papaver somniferum, a plant present in the hospital pharmacopeia used as a narcotic, analgesic, astringent, coagulant, and antitussive agent. Such analyses have shed light on the pharmacological therapies administered to the patients near the time of death and have implemented our knowledge of medical treatment and drug administration in the 1600's.

Abdominal Wall Reconstruction with Retrorectus Self-Adhering Mesh: A Single-Center Long-Term Follow-Up.

BACKGROUND: Mesh repair has been demonstrated to be superior to suture alone in ventral hernia repair. In a previous short-term pilot study, the authors found lower postoperative narcotic requirements with self-adhering mesh. The aim of this study was to follow-up on that pilot study, using long-term data. METHODS: This is a retrospective review of a prospectively collected database. All patients who underwent ventral hernia repair with retrorectus mesh and who had at least a 12-month follow-up were reviewed. Comparisons were performed between patients who received self-adhering mesh and those who received transfascially sutured mesh, using matched-pair analysis, examining perioperative outcomes, surgical-site occurrences, and hernia recurrence/bulge. RESULTS: Forty-two patients were included in the study, with 21 patients undergoing repair with transfascially sutured mesh and 21 patients receiving self-adhering mesh. Average length of follow-up was 1078 days. There were no significant differences between the two groups in baseline characteristics. Patients receiving self-adhering mesh had significantly shorter surgery, and a shorter hospital length of stay. They also had a tendency toward lower narcotic requirements. There were no significant differences in the rate of surgical-site occurrences, hernia recurrences, or bulge between the two groups. CONCLUSIONS: This long-term study shows that self-adhering mesh in ventral hernia repair results in similar long-term outcomes to transfascially sutured mesh, with shorter surgery, shorter length of stay, and a tendency toward improved pain control. These findings mirror the known advantages of self-adhering mesh in inguinal hernia repair. Further research is needed to study the incidence of chronic pain and the cost-effectiveness of self-adhering mesh. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Does the American College of Surgeons New Level I Children's Surgery Center Verification Affect Treatment Efficiency and Narcotic Administration in Treating Pediatric Trauma Patients with Femur Fracture?

BACKGROUND: In 2015, the American College of Surgeons (ACS) created a new hospital improvement program to enhance the performance of pediatric care in US hospitals. The Children's Surgery Verification (CSV) Quality Improvement Program is predicated on the idea that pediatric surgical patients have improved outcomes when treated at children's hospitals with optimal resources. Achieving ACS level I CSV designation at pediatric trauma centers may lead to greater benefits for pediatric trauma patients; however, the specific benefits have yet to be identified. We hypothesize that achieving the additional designation of ACS level I CSV is associated with decreased narcotic use perioperatively and improved efficiency when managing pediatric patients with femur fractures. STUDY DESIGN: This study is a retrospective analysis of traumatic pediatric orthopaedic femur fractures treated at a verified level I pediatric trauma center before and after CSV designation (2010 to 2014 vs 2015 to 2019). Efficiency parameters, defined as time from admission to surgery, duration of surgery, and duration of hospital stay, and narcotic administration in oral morphine equivalents (OMEs) were compared. RESULTS: Of 185 traumatic femur fractures analyzed, 80 occurred before meeting ACS level I CSV criteria, and 105 occurred after. Post-CSV, there was a significant decrease in mean wait time from admission to surgery (16.64 hours pre-CSV, 12.52 hours post-CSV [p < 0.01]) and duration of hospital stay (103.49 hours pre-CSV, 71.61 hours post-CSV [p < 0.01]). Narcotic usage was significantly decreased in both the preoperative period (40.61 OMEs pre-CSV, 23.77 OMEs post-CSV [p < 0.01]) and postoperative period (126.67 OMEs pre-CSV, 45.72 OMEs post-CSV [p < 0.01]). CONCLUSIONS: Achieving ACS level I CSV designation is associated with increased efficiency and decreased preoperative and postoperative narcotic use when treating pediatric trauma patients.

Modeling spontaneous opioid withdrawal in male and female outbred mice using traditional endpoints and hyperalgesia.

Opioid withdrawal significantly impacts drug dependence cycles as hyperalgesia associated with withdrawal is often a reason for continued drug use. Animal models of addiction are important tools for studying how drug dependence and withdrawal impact not only normal neurocircuitry but also the effectiveness of potential treatments for dependence and withdrawal. We conducted a study of the time course of spontaneous morphine withdrawal in outbred male and female mice that can be used to examine sex differences in male and female mice using both traditional somatic endpoints and mechanical hyperalgesia as an endpoint of withdrawal. Male and female national institute of health (NIH) Swiss mice were made dependent upon morphine using an escalating dosing schedule. Injections were stopped after 5 days. Withdrawal behavior was assessed at time intervals up to 106 h after the final injection. Numbers of forepaw tremors, wet-dog shakes, jumps and other behaviors were scored to create a global score. Paw pressure readings were then also taken to track changes in sensitivity to a painful stimulus over time. Male and female mice had approximately similar withdrawal severity peaking at 24 h after the final injection as measured by composite global scores. Females did exhibit an earlier and greater frequency of tremors than males. Although males and females showed similar hyperalgesia during withdrawal, females recovered faster. Spontaneous opioid withdrawal peaking at 24 h was demonstrated in male and female NIH Swiss mice. We also successfully demonstrated that hyperalgesia is an endpoint that varies over the course of withdrawal.

Characterization of early versus late opioid iatrogenic withdrawal syndrome in critically ill children transitioning from fentanyl -infusions to methadone.

OBJECTIVE: Methadone is used to prevent opioid iatrogenic withdrawal syndrome (IWS) in children, but the optimal dose and overlap time with an opioid infusion have not been elucidated. The purpose was to compare clinical manifestations among patients who developed opioid IWS within 24 hours (early) versus ≥24 hours (late) of fentanyl discontinuation when enteral methadone was initiated. DESIGN: A retrospective, descriptive study. SETTING: Pediatric and cardiovascular intensive care units at a tertiary care health system. PARTICIPANTS: Sixty-seven children received fentanyl infusions for ≥3 days and initiated on methadone prior to fentanyl discontinuation. MAIN OUTCOME MEASURES: The primary objective was to compare clinical characteristics between those with early versus late opioid IWS. Opioid IWS was defined as a Withdrawal Assessment Tool-1 score ≥3 within 5 days of fentanyl discontinuation. Secondary objectives included a comparison of time to IWS, clinical characteristics, and risk factors among patients with and without IWS. RESULTS: Fifty children (74.6 percent) developed opioid IWS within a median time of 3.5 hours. No differences were noted for those with and without IWS. Thirty-seven patients (74.0 percent) with IWS developed early IWS. A higher percentage of males in the late versus early group developed IWS, 100 percent versus 51.4 percent, p = 0.002. The median overlap time with methadone and fentanyl was shorter in the early versus late IWS group without reaching statistical significance, 27.5 versus 64.0 hours, p = 0.127. CONCLUSIONS: The majority developed opioid IWS, with most developing early IWS, despite methadone initiation. Future studies should evaluate the optimal methadone dosing and overlap time to prevent opioid IWS.

Sex-differences in anxiety, neuroinflammatory markers, and enhanced fear learning following chronic heroin withdrawal.

Post-traumatic stress disorder (PTSD) and opioid use disorder (OUD) are comorbid in clinical populations. However, both pre-clinical and clinical studies of these co-occurring disorders have disproportionately represented male subjects, limiting the applicability of these findings. Our previous work has identified chronic escalating heroin administration and withdrawal can produce enhanced fear learning. This behavior is associated with an increase in dorsal hippocampal (DH) interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and glial fibrillary acidic protein (GFAP) immunoreactivity. Further, we have shown that these increases in IL-1ß and TNF-α are mechanistically necessary for the development of enhanced fear learning. Although these are exciting findings, this paradigm has only been studied in males. The current studies aim to examine sex differences in the behavioral and neuroimmune effects of chronic heroin withdrawal and future enhanced fear learning. In turn, we determined that chronic escalating heroin administration can produce withdrawal in female rats comparable to male rats. Subsequently, we examined the consequence of heroin withdrawal on future enhanced fear learning and IL-1ß, TNF-α, and GFAP immunoreactivity. Strikingly, we identified sex differences in these neuroimmune measures, as chronic heroin administration and withdrawal does not produce enhanced fear learning or immunoreactivity changes in females. Moreover, we determined whether heroin withdrawal produces short-term and long-term anxiety behaviors in both female and males. Collectively, these novel experiments are the first to test whether heroin withdrawal can sensitize future fear learning, produce neurobiological changes, and cause short-term and long-term anxiety behaviors in female rats.

Narcotics information management system in South Korea: system development and innovation.

BACKGROUND: As the misuse and abuse of medical narcotics are increasing in South Korea, an information system for the integrated information management of medical narcotic drugs across the nation is needed. This paper presents the development process of the Narcotics Information Management System (NIMS) for the monitoring of medical narcotics usage and the results of its implementation. METHODS: As the NIMS enforces that all narcotics handlers digitally report all information on handling medical narcotic drugs, the functional requirements of the NIMS have been identified in accordance with the Narcotics Control Act. In addition to the functional requirements, the non-functional requirements of the NIMS have been elicited by major narcotics handlers and their associations. The non-functional requirements include privacy, availability, connectivity, interoperability, and data integrity. The system design with entity-relationship diagrams and its implementation processes have been presented. RESULTS: The NIMS encompasses all narcotic handlers, which comprise exporting, importing, and pharmaceutical companies; wholesalers; hospitals and clinics; and pharmacies, collecting over 120 million cases annually. It enables transparent monitoring throughout the life cycle, from manufacturing, sales, purchase, and disposal of narcotics. As a result, the number of prescriptions for medical narcotics has been reduced by 9.2%. CONCLUSIONS: To the best of our knowledge, the NIMS is the world's first system to manage all information on the total life cycle of medical narcotics, including imports, production, distribution, use, and disposal of drugs. This system has enabled the safety management and monitoring of medical narcotic drugs. Additionally, it provides consistent and transparent information to physicians and patients, leading to the autonomous safety management of narcotics. The successful development of the NIMS can provide guidelines for implementing a narcotics management system in other countries.

Endomorphin analog ZH853 shows low reward, tolerance, and affective-motivational signs of withdrawal, while inhibiting opioid withdrawal and seeking.

Currently available µ-opioid receptor agonist pharmacotherapies for opioid use disorder possess adverse effects limiting their use and, despite treatment, rates of relapse remain high. We previously showed that endomorphin analog ZH853 had no effect in rodent models that predict abuse liability in humans. Here we extended these findings by examining dependence liability and reinforcing properties in female rats and male rats with previous opioid exposure. The potential use of ZH853 in managing opioid use disorder was evaluated by examining its effect on opioid-seeking behavior and withdrawal. We found that ZH853 did not induce locomotor activation in male and female mice and was not self-administered by female rats. Relative to morphine, ZH853 led to similar somatic signs of withdrawal, but low affective-motivational signs of withdrawal, and absent changes in ventral tegmental area K(+)-Cl(-) co-transporter expression associated with reward dysregulation. The low abuse liability of ZH853 was further supported in oxycodone self-administering male rats, where ZH853 substitution extinguished opioid-seeking behavior. ZH853 priming also did not reinstate morphine conditioned place preference. Lastly, ZH853 inhibited oxycodone-seeking behavior during relapse after forced abstinence and decreased the expression of morphine withdrawal. These findings suggest the potential use of ZH853 as a safer opioid medication for long-term treatment of pain and opioid use disorder.

Inequities in Inpatient Obstetrics Pain Management and Evaluation: Age, Race, Mental Health, and Obesity.

OBJECTIVE: To evaluate disparities of pain management among patients giving birth in inpatient Obstetrics units based on age, race, BMI, and mental health diagnoses. METHODS: A retrospective cohort study was performed and included all individuals giving birth at a tertiary-care institution in 2019. Patient-reported pain scores, and inpatient narcotic administration and dosing for pain control were collected. Models were adjusted for race, age, BMI, and diagnoses of anxiety, depression, opioid use disorder, and/or schizophrenia. RESULTS: 4788 Individuals met the inclusion criteria. A higher proportion of African American patients reported severe pain (n = 233/607, 38.4%) and received narcotics (n = 653/1141, 57.2%) compared to patients of other races. Despite controlling for several possible confounders, African American patients (OR 1.55, 95% CI 1.08-2.22), patients with increased BMI (OR 1.02, 95% CI 1.01-1.03), and patients with a mental health diagnosis (OR 2.33, 95% CI 1.32-4.12) were more likely to have worse pain at rest. Older patients were more likely to be administered narcotics (n = 447/757, 59.0%) compared to younger patients (patients aged 18-26: n = 577/1257, 52.3%; patients aged 27-35: n = 1451/2774, 52.3%; p < 0.001), despite younger patients being more likely to have severe pain (OR 1.50; 95% CI 1.20-1.86; p = 0.001). CONCLUSIONS: Patients who are Non-Hispanic African American and patients with obesity and mental health diagnoses experience inequities in postpartum pain management. Pain is complex and multifactorial and can be impacted by cultural, social, environmental factors and more. Further studies on factors that influence pain perception and management in inpatient obstetrics units are needed.

Utilization of an Enhanced Recovery After Surgery (ERAS) protocol for pediatric metabolic and bariatric surgery.

INTRODUCTION: Enhanced recovery after surgery (ERAS) protocols for pediatric metabolic and bariatric surgery are limited. In 2018, an ERAS protocol for patients undergoing robotically assisted vertical sleeve gastrectomy (r-VSG) was instituted. This study's aim was to compare outcomes before and after ERAS initiation. METHODS: A single institution retrospective review of patients undergoing r-VSG from July 2015 to July 2021 was performed. The multimodal ERAS protocol focused on limiting post-operative nausea and narcotic utilization. Subjects were categorized into non-ERAS (July 2015-July 2018) and ERAS (August 2018-July 2021) groups. In-hospital and 30-day outcomes were compared. RESULTS: 110 subjects (94 females) with a median age of 17.6 years (range 12.5-22.0 years) were included (60 non-ERAS, 50 ERAS). Demographics were similar except for a higher proportion of females in the non-ERAS group (97% vs 72%, p < 0.001). A significant decrease in narcotic use (p < 0.001) and higher utilization of acetaminophen (p < 0.001) and ketorolac (p < 0.001) was observed in the ERAS group. Additionally, median time to oral intake, a proxy for postoperative nausea and vomiting [2:00 h (1:15, 2:30) vs. 3:22 h (2:03, 6:15), p < 0.001] and hospital length of stay (LOS) [1.25 days (1.14, 1.34) vs. 2.16 days (1.48, 2.42), p < 0.001] were shorter in the ERAS group. Eleven subjects (10%; ERAS = 5, non-ERAS = 6) experienced post-discharge dehydration, prompting readmission 8 times for 7 (6%) individuals. CONCLUSION: Utilization of ERAS led to a significant decrease narcotic utilization, time to first oral intake, and hospital LOS with no change in adverse events following pediatric metabolic and bariatric surgery. Larger studies, including comparative analysis of health care utilization, should be carried out. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Treatment Study.

In-tube gel electromembrane extraction: A green strategy for the extraction of narcotic drugs from biological samples.

The development of green and miniature extraction methods is always a major and controversial challenge in the field of sample preparation. In this work, in-tube gel electromembrane extraction (IT-G-EME) was developed as a miniaturized extraction device for the extraction of six narcotic drugs (codeine, oxycodone, hydrocodone, tramadol, thebaine, and noscapine) from biological samples. A transparent capillary tube (∼6 cm) was used as a microextraction unit. The middle part of the tube was filled with a narrow plug (∼3 mm) of the agarose gel (3.0% w/v) as a membrane and the other sides were filled with aqueous extractant solution (pH 2.0, 20 µL) and sample solution (pH 5.0, 200 µL). By applying electrical potential (400 V), the target drugs with positive charge were migrated from sample solution toward the extractant solution through gel membrane during short extraction time (5 min). Then, the enriched analytes in extractant solution was analyzed by HPLC-UV. Under the optimized conditions, the calibration curves were linear within the permissible range of 10.0-1500 ng/mL (r2 ≥ 0.991). Limits of detection and extraction recoveries were in the range of 3.0-4.5 ng/mL and 61.9-86.9%, respectively. On the basis of four replications, the repeatability of the method was also evaluated in terms of intra- and inter-day RSDs (%), which did not exceed from 6.6 and 7.9%, respectively in aqueous media. The figures of merit were also assessed in biological samples. Eventually, the developed method was profitably used for simultaneous determination of narcotic drugs in the real urine and plasma samples.

Utility of Removable Rigid Dressings in Decreasing Discharge Narcotic Use and Improving Ambulation Following Below-Knee Amputation.

BACKGROUND: Lower extremity amputations are often associated with limited postoperative functionality and postoperative complications. Removable rigid dressings (RRDs) have been used following below-knee amputation (BKA) to improve limb maturation, decrease postoperative complications, reduce time to prosthesis casting, and limit conversion rates to above-knee amputation (AKA). We hypothesized that usage of RRD following BKA will correlate with decreased prescription narcotics required at discharge and improved ambulatory status at follow-up. METHODS: A retrospective chart review was conducted to identify all patients who underwent BKA performed by the vascular surgery service at a large, acute care hospital between July 2016 and July 2021. Data collected included age, sex, body mass index, conversion to AKA, narcotic prescriptions at discharge, and ambulatory status at follow-up. RESULTS: Between July 2016 and 2021, rate of conversion to AKA was significantly lower in patients who received an RRD (9.3%), as opposed to those who did not (41.5%) (P = 0.0002). Narcotic prescriptions at discharge, compared following conversion to morphine equivalents, were also significantly lower in the rigid dressing group compared to patients who did not receive the dressing (50.5 vs. 108.9 morphine eq/24 h, P = 0.0019). Furthermore, use of rigid dressing significantly improved ambulatory status at follow-up to 75.9% in RRD patients compared to 29.3% in patients with conventional dressing (P < 0.0001). This statistical significance persisted after all patients who were converted to AKA were removed from analysis (79.6% vs. 39.3% ambulatory, P = 0.000363). Multivariate analysis revealed that ambulatory status at follow-up was only associated with age more than 80 years (P = 0.042) and use of postoperative RRD (P = 0.001). CONCLUSIONS: These findings support the utility of an RRD following BKA to reduce conversion to AKA, reduce narcotic dosages required at discharge, and improve ambulatory status at follow-up.

Clinical Outcomes of Liposomal Bupivacaine Erector Spinae Block in Minimally Invasive Transforaminal Lumbar Interbody Fusion Surgery.

BACKGROUND: Postoperative pain is a barrier to early mobility and discharge after lumbar surgery. Liposomal bupivacaine (LB) has been shown to decrease postoperative pain and narcotic consumption after transforaminal lumbar interbody fusions (TLIFs) when injected into the marginal suprafascial/subfascial plane-liposomal bupivacaine (MSSP-LB). Erector spinae plane (ESP) infiltration is a relatively new analgesic technique that may offer additional benefits when performed in addition to MSSP-LB. OBJECTIVE: To evaluate postoperative outcomes of combining ESP-LB with MSSP-LB compared with MSSP-LB alone after single-level TLIF. METHODS: A retrospective analysis was performed for patients undergoing single-level TLIFs under spinal anesthesia, 25 receiving combined ESP-LB and MSSP-LB and 25 receiving MSSP-LB alone. The primary outcome was length of hospitalization. Secondary outcomes included postoperative pain score, time to ambulation, and narcotics usage. RESULTS: Baseline demographics and length of surgery were similar between groups. Hospitalization was significantly decreased in the ESP-LB + MSSP-LB cohort (2.56 days vs 3.36 days, P = .007), as were days to ambulation (0.96 days vs 1.29 days, P = .026). Postoperative pain area under the curve was significantly decreased for ESP-LB + MSSP-LB at 12 to 24 hours (39.37 ± 21.02 vs 53.38 ± 22.11, P = .03) and total (44.46 ± 19.89 vs 50.51 ± 22.15, P = .025). Postoperative narcotic use was significantly less in the ESP-LB + MSSP-LB group at 12 to 24 hours (13.18 ± 4.65 vs 14.78 ± 4.44, P = .03) and for total hospitalization (137.3 ± 96.3 vs 194.7 ± 110.2, P = .04). CONCLUSION: Combining ESP-LB with MSSP-LB is superior to MSSP-LB alone for single-level TLIFs in decreasing length of hospital stay, time to ambulation, postoperative pain, and narcotic use.

Comparing the safety and efficacy of intravenous naloxone administration in opioid-naive and opioid-tolerant hospitalized oncology patients.

OBJECTIVE: To compare naloxone doses and clinical outcomes after emergency opioid reversal in opioid-naïve and opi-oid-tolerant inpatients. DESIGN: Cross-sectional, retrospective chart review. SETTING: Comprehensive cancer center. PATIENTS: In-patients who received ≥1 dose of intravenous naloxone for emergency opioid reversal between 2014 and 2018. METHODS: Patients were classified as opioid-tolerant based on opioid dosing history ≥60 morphine milligram equivalents/day for ≥7 consecutive days prior to naloxone administration. Response to naloxone was based on documentation of improvement in respiratory rate to >10 breaths/min or improved response to stimuli. OUTCOMES: Naloxone doses and clinical outcomes after naloxone administration. RESULTS: Ninety-three naloxone episodes (58 opioid-naive and 35 opioid-tolerant) in 80 unique patients were included. No differences between opioid-naïve and opioid-tolerant groups were found for naloxone mean starting doses (0.14 mg vs 0.19 mg, p = 0.35), total doses (0.50 mg vs 0.32 mg, p = 0.07), and response rates (74.1 percent vs 77.1 percent, p = 0.81). Naloxone adverse reactions were more frequent in the opioid-tolerant group than the opioid-naïve group (opioid withdrawal symptoms (OWSs): 14.3 percent vs 0 percent; increase in pain: 20 percent vs 8.6 percent, p = 0.002). CONCLUSIONS: In opioid-tolerant patients, naloxone total doses required and response rates were similar to opioid-naïve patients. Use of opioid dosing history to identify potentially opioid-dependent patients should be considered prior to naloxone administration to guide dosing and reduce the risk for precipitating OWSs.