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Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Frequent hand hygiene by anesthesia personnel may be an important factor in reducing contamination of IV lines and medication access ports and may reduce hospital-acquired infections. Measurement of hand hygiene frequency at the individual clinician level by direct observation or electronic devices is cumbersome and expensive. We developed and validated a simple method for estimating hand hygiene frequency by individual anesthesia providers and utilized it in a quality improvement initiative to increase hand hygiene use.Pump-style, alcohol-based hand hygiene container weight at the anesthesia work station was measured before and after each surgical operation and converted to estimated number of accesses (pumps) per hour. Video observation was used to validate the estimated hand hygiene use. A quality improvement initiative utilized periodic measurement of hand hygiene frequency via the validated method, and incorporated individual provider feedback, email reminders, monthly departmental performance reports, and reminders in the electronic anesthesia record. Segmented linear regression was used to evaluate the effect of the intervention on hand hygiene use.Delivered product per pump was consistent for containers at least half-full and averaged (mean ± SD) 0.92 ± 0.13 g per pump. Video observation in 26 cases showed a strong correlation between observed hand hygiene episodes and estimated hand hygiene use frequency based on weight change of the container (linear regression, R = 0.97, P.0001). Median hand hygiene frequency was near 0 at baseline but increased progressively throughout the intervention period (segmented linear regression, overall R = 0.76, P.0001; change of intercept or mean hand hygiene after initiation of intervention [parameter estimate ± SE] [0.970 ± 0.29], P = .0008).A low-cost, simple method for measuring individual anesthesia clinician use of hand hygiene intraoperatively based on container weight change is feasible and sufficiently accurate to support a quality improvement initiative to increase its use.

PurposeIntranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity.MethodsDouble-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 μg) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects.ResultsUFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements.No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 hours, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 hours.ConclusionsUFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 hours after dosing.

Background & Objective: Regional anesthesia (RA) blocks are most commonly performed in large academic hospitals and has been shown to reduce postoperative pain. The lack of RA blocks in rural hospitals leaves a large subset of the population without availability of this service. In North Carolina, there is an increased need for these services in small community hospitals. This study examined RA nerve block success rates for total knee, hip, and shoulder arthroplasty procedures. We hypothesized that through proper mentorship, general anesthesiologists could provide safe and efficacious RA blocks at a small, community hospital.Methodology: An Institutional Review Board (IRB) approved retrospective study was performed at Lexington Medical Center (LMC), in Lexington, North Carolina part of Wake Forest Baptist Health. We analyzed 307 patients who underwent total joint arthroplasty (195 knee, 69 hip and 43 shoulder replacements) at LMC. Demographics, type of blocks, block success, and intraoperative analgesics used were also recorded. VAS was used to assess postoperative pain.Results: We found an overall success rate of 96.3% for all joints; 95.2%-femoral or 98.9%-adductor canal, 90.4%-lumbar plexus, 100%-interscalene block for knee, hip and shoulder arthroplasties respectively. 283/307 (92.2%) patients reported a verbal pain score between 0-2 in the PACU. There was a significantly higher mean fentanyl dose/h in patients that did not receive a lumbar plexus block for hip procedures.Conclusion: The results of our study support that general anesthesiologists can provide rural communities with quality, specialized regional anesthesia care safely, and at an equivalent level to that of anesthesiologists specialized in RA blocks at large academic institutions.Citation: VanEenenaam DP, Johnson KN, Harris HM, Choi JA, Bullock MW, Forest DJ, Bryan YF. Development and implementation of a regional anesthetic service by general anesthesiologists for total joint arthroplasty patients in a small community hospital in the United States. Anaesth pain & intensive care 2019;23(3):250-255

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. In vivo studies on the lead dual kappa and mu opioid receptor agonist, compound 10, showed that it produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Analgesia is commonly mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. Recently, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that some of these compounds have dual agonism on kappa and mu opioid receptors, while some have triple agonism on kappa, mu, and delta. In vivo studies on the lead dual kappa and mu opioid receptor agonist, compound 10, showed that it produced analgesic activity while avoiding anxiogenic effects in murine models, thus providing further strong evidence for the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

Simple endoscopies such as esophagogastroduodenoscopy (EGD) and colonoscopies are common procedures that require the use of sedation or general anesthesia. The risk of airway complications for these procedures depends on the type of medications administered. Wide variation exists in reported rates of airway complications for endoscopic procedures.

Objective To assess if there is a difference in the repositioning rate of the EZ-Blocker versus a left-sided double-lumen endobronchial tube (DLT) in patients undergoing thoracic surgery and one-lung ventilation. Design Prospective, randomized. Setting Single center, university hospital. Participants One hundred sixty-three thoracic surgery patients. Interventions Patients were randomized to either EZ-Blocker or a DLT. Measurements and Main Results The primary outcome was positional stability of either the EZ-Blocker or a left-sided double-lumen endobronchial tube, defined as the number of repositionings per hour of surgery and one-lung ventilation. Secondary outcomes included an ordinal isolation score from 1 to 3, in which 1 was poor, up to 3, which represented excellent isolation, and a visual analog postoperative sore throat score (0-100) on postoperative days (POD) one and two. Rate of repositionings per hour during one-lung ventilation and surgical manipulation in left-sided cases was similar between the two devices: 0.08 ± 0.15 v 0.11 ± 0.3 (p = 0.72). In right-sided cases, the rate of repositioning was higher in the EZ-Blocker group compared with DLT: 0.38 ± 0.65 v 0.09 ± 0.21 (p = 0.03). Overall, mean isolation scores for the EZ-Blocker versus the DLT were 2.76 v 2.92 (p = 0.04) in left-sided cases and 2.70 v 2.83 (p = 0.22) in right-sided cases. Median sore throat scores for left sided cases were 0 v 5 (p = 0.13) POD one and 0 v 5 (p = 0.006) POD two for the EZ-Blocker and left-sided DLT, respectively. Conclusion For right-sided procedures, the positional stability of the EZ-Blocker is inferior to a DLT. In left-sided cases, the rate of repositioning for the EZ-Blocker and DLT are not statistically different.

Objective: This research examined whether a cannabidiol (CBD)-opioid pharmacotherapy could attenuate cisplatin-induced tactile allodynia. Methods: Mice (C57BL/6) were given 6 doses of 2.3 mg/kg cisplatin intraperitoneally (IP) on alternating days to induce tactile allodynia as quantified using an electric von Frey (eVF). Test groups in Experiment 1 received either vehicle, 0.1 or 2.5 mg/kg morphine, 1.0 or 2.0 CBD, or the 2 drugs in combination. Test groups in Experiment 2 received either vehicle, 0.1 or 2.5 mg/kg morphine, 1.0, 2.0, 3.0, or 4.0 mg/kg NB2111 (a long-acting CBD analogue), or the 2 drugs in combination. Drugs were administered IP 45 min before eVF assessment. Results: Cisplatin produced tactile allodynia that was attenuated by 2.5 mg/kg morphine. Both CBD and NB2111 produced dose-dependent attenuation of tactile allodynia. CBD and NB2111, given in combination with sub-analgesic doses of morphine, produced attenuation of tactile allodynia equivalent to 2.5 mg/kg morphine. Conclusions: While both CBD and NB2111, either alone or in combination with sub-analgesic doses of opioids, exhibited analgesic effects, NB2111 could be capable of superior analgesia over time by virtue of enhanced pharmacokinetics.

This study sought to determine whether the cannabis constituent cannabidiol attenuates the development of morphine reward in the conditioned place preference paradigm. Separate groups of mice received either saline or morphine in combination with one of four doses of cannabidiol using three sets of drug/no-drug conditioning trials. After drug-place conditioning, morphine mice displayed robust place preference that was attenuated by 10 mg/kg cannabidiol. Further, when administered alone, this dose of cannabidiol was void of rewarding and aversive properties. The finding that cannabidiol blocks opioid reward suggests that this compound may be useful in addiction treatment settings.

Background Rodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance. New method Rats received 5 nitroglycerin (10 mg/kg/2 ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15 days. Behavioral endpoints were assessed 110 min post nitroglycerin administration and included time spent light/dark chambers for photophobia as well as activity, facial pain expressions, and tactile allodynia. Results Animals administered nitroglycerin displayed photophobia, decreased activity, and increased facial pain expression. Similar alterations in photophobia and activity were seen in the vehicle treated animals, but these tended to diminish by the 4th or 5th injection. The presentation of spontaneous tactile allodynia was observed in the nitroglycerin group by the 5th episode. Comparison with existing methods Most NTG migraine models entail a single NTG administration and quantification of evoked allodynia. This paradigm employs recurring NTG episodes and clinically-relevant measures of photophobia, hypoactivity and facial grimace endpoints as well as introduces a novel arena apparatus to quantify spontaneous allodynia. Conclusions This repeated NTG procedure and endpoint measures aligns with the frequency and clinical presentation of episodic migraine and its chronification, respectively. Further, propylene glycol ethanol vehicle contributes to migraine endpoints.

Introduction: Cannabis sativa has been used for centuries in treating pain. However, the analgesic role of many of its constituents including terpenes is unknown. This research examined the contributions of terpenes (volatile oil) and cannabinoids in cannabis-mediated analgesia in rats. Methods: Animals received intraperitoneal administration of either vehicle, 10.0 or 18.0 mg/kg morphine, or various doses of the extract without terpenes, isolated terpenes, Δ(9)-tetrahydrocannabinol (THC), or the full extract. Thirty minutes later animals were tested on hotplate and tail-flick tests of thermal nociception. One week later, rats received a second administration of test articles and were tested 30 min later in the abdominal writhing test of inflammatory nociception. Results: In the thermal assays, hotplate and tail-flick latencies for morphine-treated rats were dose dependent and significantly higher than vehicle-treated animals. All the cannabinoid compounds except for the isolated terpenes produced dose-dependent increases in hotplate and tail-flick latencies. In the inflammatory nociceptive assay, animals treated with vehicle and isolated terpenes demonstrated increased abdominal writhing, whereas all the cannabinoid compounds significantly decreased abdominal writhing responses. Conclusions: Overall, THC alone produced robust analgesia equivalent to the full cannabis extract, whereas terpenes alone did not produce analgesia. These data suggest the analgesic activity of cannabis is largely mediated by THC, whereas terpenes alone do not cause alterations in cannabis-mediated analgesia.

In patients who undergo surgery for oropharyngeal masses, intubation is almost always successful. However, technical aspects of airway management, including bag mask ventilation and oxygenation, may still be difficult. Although rates of airway difficulty and intubation success in these patients have been studied, these data may not reflect difficulty with individual components of the intubation process. We hypothesized that rates of complications with individual elements of the intubation process would not be reflected in the rate of eventual intubation success. To test our hypothesis, we observed the process of airway management and resulting complications with oxygenation and bag mask ventilation in patients with oropharyngeal masses undergoing otorhinolaryngology procedures under general anesthesia.Forty-four patients with oropharyngeal masses scheduled for surgery were observed during the process of airway management. Observers recorded the number of airway devices used, the overall number of intubation attempts, the number and type of manual maneuvers required during bag mask ventilation, and the incidence of oxygen desaturation. The eventual intubation success rate was also recorded.All 44 patients (100%; 95% CI, 92%-100%) were successfully intubated. Thirty-six (81.8%) of 44 patients were intubated asleep and 8 (18.2%) of 44 were intubated awake using flexible fiberoptic bronchoscopy. Thirty-one (86.1%) of 36 patients who were intubated asleep received bag mask ventilation before intubation, while the other 5 patients underwent a rapid sequence induction. Twenty-seven (61.4%) of 44 patients (95% CI, 45%-75%) had ≥1 complication during airway management. Ten (23%) of 44 patients (95% CI, 11%-37%) required ≥3 attempts to intubate, 21 (68%) of 31 patients (95% CI, 49%-83%) had difficult mask ventilation, and 15 patients (34%; 95% CI, 20%-50%) experienced desaturation (oxygen saturation measured by pulse oximetry,95%).We found that, although all patients were successfully intubated, clinicians frequently encountered complications with both intubation and mask ventilation. These complications required frequent use of additional manual maneuvers during mask ventilation and a high incidence of oxygen desaturation. The difficulty of airway management in patients with oropharyngeal masses may not be effectively assessed by success rate alone.

Numerous studies demonstrate the promise of opioid peptides as analgesics, but poor oral bioavailability has limited their therapeutic development. This study sought to increase the oral bioavailability of opioid peptides by cyclization, using Hantzsch-based macrocyclization strategies to produce two new series of cyclized DAMGO and Leu/Met-enkephalin analogs. Opioid receptor affinity and selectivity for compounds in each series were assessed in vitro with radioligand competition binding assays. Compounds demonstrated modest affinity but high selectivity for the mu, delta, and kappa opioid receptors (MOR, DOR and KOR), while selectivity for mu opioid receptors varied by structure. Antinociceptive activity of each compound was initially screened in vivo following intracerebroventricular (i.c.v.) administration and testing in the mouse 55 °C warm-water tail-withdrawal test. The four most active compounds were then evaluated for dose- and time-dependent antinociception, and opioid receptor selectivity in vivo. Cyclic compounds 1924-10, 1936-1, 1936-7, and 1936-9 produced robust and long- lasting antinociception with ED50 values ranging from 0.32–0.75 nmol following i.c.v. administration mediated primarily by mu- and delta-opioid receptor agonism. Compounds 1924-10, 1936-1 and 1936-9 further displayed significant time-dependent antinociception after oral (10 mg kg−1, p.o.) administration. A higher oral dose (30 mg kg−1. p.o.) of all four cyclic peptides also reduced centrally-mediated respiration, suggesting successful penitration into the CNS. Overall, these data suggest cyclized opioid peptides synthesized by a Hantzsch-based macrocyclization strategy can retain opioid agonist activity to produce potent antinociception in vivo while conveying improved bioavailability following oral administration.

Background Made as a tea, the Thai traditional drug “kratom” reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects. Methods Lyophilized kratom tea (LKT) was evaluated in C57BL/6J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 °C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA. Results Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice. Conclusions The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.

Sativex, a cannabinoid extract with a 1 : 1 ratio of tetrahydocannabinol and cannabidiol, has been shown to alleviate neuropathic pain associated with chemotherapy. This research examined whether tetrahydocannabinol or cannabidiol alone could attenuate or prevent cisplatin-induced tactile allodynia. In experiment 1, mice (C57BL/6) received eight administrations of 2.3 mg/kg cisplatin or saline solution IP every other day to induce tactile allodynia. Mice were then administered vehicle, 100 mg/kg gabapentin, 2 mg/kg tetrahydocannabinol, or 2 mg/kg cannabidiol IP and tested 60 min later on an electronic Von Frey. In experiment 2, prevention studies, cannabidiol (0.0, 0.5, 1.0, and 2.0 mg/kg) or tetrahydocannabinol (0.0, 0.5, 1.0, and 2.0 mg/kg) was given IP 30 min prior to cisplatin administration (2.3 or 1.0 mg/kg) utilizing a six-dose alternate day protocol. In both studies, tactile responses to the hind paws were quantified in g of force using an electronic Von Frey prior to and after the cisplatin administration protocol. Cisplatin produced a reduction in g of force indicative of neuropathy that was attenuated by gabapentin, tetrahydocannabinol, and cannabidiol but not prevented by either cannabinoid. These data demonstrate that each of the major constituents of Sativex alone can achieve analgesic effects against cisplatin neuropathy.