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Background and AimsIntense post sternotomy pain delays mobilisation and increases peri operative opioid exposure. Ultrasound guided bilateral parasternal block provides targeted anterior chest wall analgesia; however, the dose-volume relationship of local anaesthetic for this block remains undefined. After establishing that 0.125% bupivacaine is clinically effective, we conducted a randomised controlled trial to evaluate whether varying injectate volumes at this fixed concentration modulate analgesic efficacy and opioid consumption.MethodsThis prospective, randomised, single-blind trial enrolled 44 adults for elective median sternotomy. After ethics approval (Pauls Stradiņš Clinical University Hospital, 281123–11L), patients received a bilateral parasternal block with 0.125% bupivacaine: 20 ml (n = 12), 40 ml (n = 20) or 60 ml (n = 12). Pain intensity (Numerical Rating Scale, NRS 0–10) was measured at 0, 4, 8, 12, 20 and 24 h. Secondary endpoints were 24-h opioid use and time-to-rescue analgesia.ResultsMedian NRS at 12 hours postoperatively was 1 (IQR 0–3) after 20 ml, 1 (IQR 0–3) after 40 ml and 1 (IQR 0–2) after 60 ml (p = 0.801); pain scores did not differ significantly at any measured time point (p >0.05). Time to rescue was markedly shorter with 20 ml – median 120 min (IQR 120–300)—versus 40 ml – 995 min (IQR 440–1275) and 60 ml – 420 min (IQR 218–450); Repeated rescue opioid was needed in 25% of patients who received 20 ml, whereas none required it after 40 ml or 60 ml (p = 0.012).ConclusionsInjectate volume was decisive≥ 40 ml abolished rescue-opioid use; 40 ml produced the longest opioid-free period with no safety issues, whereas 60 ml offered no added benefit. Thus, a 40 ml bilateral parasternal block with 0.125% bupivacaine is the volume-efficacy sweet spot for post-sternotomy analgesia. Larger multicentre trials should validate these findings and refine practice.

Abstract With the current opioid epidemic, greater attention has been focused on polypharmacy, in particular use of benzodiazepine (BZD). This study compared prescription of opioids or BZD, co-prescription of both, and prescription of neither at discharge with returns to the hospital within 30 days of discharge of older patients (75+ years). This is a secondary analysis of a quality improvement database developed during implementation of a care transition intervention for hospitalized patients age 75+. The database includes all non-ICU admissions over a 2-year period (24,784 admission cases). Returns to the hospital included Emergency Department visits, inpatient hospital stays, and observation admissions. Among the 24,262 discharges that had medication data, 1,594 (6.6%) were prescribed opioids only, 3,594 (15.0%) BZD only, 544 (2 %) opioids and BZD together, and 18,530 (76.4%) neither opioid or BZD. Each of the four prescription groups had a > 20% return rate within 30 days of discharge: 22.1% opioids only, 23.8% BZDs only, 23.7% opioids and BZDs, and 20.2% neither. Opioids were not associated with a significantly higher incidence of hospital returns. The data highlight the importance of educating healthcare providers about appropriate use of BZD and opioids in hospitalized and post-discharge older patients. Individualized care by interdisciplinary team members and support for family caregivers, as well as careful use of opioids for pain that cannot be managed by other modalities, may reduce hospital return rates and their associated morbidity and costs in the older population.

Abstract Background Opioids are effective for the treatment of abdominal pain but are also associated with tolerance, and increased dosing leads to severe side effects. We previously showed that prolonged exposure to high doses of opioids evoked paradoxical hyperexcitability of colonic afferent nerves that was mediated by δ-opioid receptor (DOR) signaling. Recent studies suggest that DOR-dependent analgesia is mediated not only by G proteins but also via receptor endocytosis and downstream signaling, but it is unclear what intracellular signaling mechanisms are underlying opioid-induced hyperexcitability. Aims To examine the mechanisms underlying DOR-mediated hyperexcitability of dorsal root ganglia (DRG) neurons. Methods We assessed the excitability of DRG neurons isolated from C57BL/6 mice by measuring the rheobase (minimal current to elicit an action potential, i.e. lower rheobase=increased excitability) using perforated patch-clamp recordings. Dissociated neurons were exposed to a high concentration (10 µM) of the μ-opioid receptor agonist DAMGO, the DOR agonist DADLE, or the weakly internalizing DOR agonist ARM390 overnight. To examine the role of receptor endocytosis and intracellular receptor activation underlying the excitatory effect by opioids, DRG neurons exposed to DAMGO or DADLE were preincubated with the membrane-permeable opioid receptor antagonist naloxone or the endocytosis inhibitor Pitstop2. To further understand the mechanisms involved in the hyperexcitability evoked by opioid re-exposure, following overnight incubation with high concentrations of DAMGO or DADLE, neurons were washed for 1 hr and treated either with the PKA inhibitor H89 or the PKC inhibitor GFX before re-exposure to DAMGO or DADLE at a low concentration (10 nM). Results Neurons exposed to 10 µM DAMGO or DADLE were hyperexcitable (rheobase decreased 25 % and 26 % compared to controls respectively; p≤0.05, 2-way ANOVA). Naloxone and Pitstop2 blocked the increased excitability of DRG neurons induced by overnight incubations with either DAMGO or DADLE. In contrast to the hyperexcitability induced by DAMGO and DADLE, overnight incubation with 10 µM ARM390 decreased excitability (rheobase increased 31%, p≤0.05, unpaired t-test). The hyperexcitability induced by DAMGO and DADLE was reversed after a 1 hr washout but acute reapplication of a low concentration of DAMGO or DADLE (10nM) now evoked hyperexcitability (rheobase decreased 34 and 35 % respectively, p≤0.05, 2-way ANOVA). This effect was prevented by inhibiting PKC but not PKA. Conclusions Our data suggest that the DOR-dependent hyperexcitability evoked by prolonged exposure to high concentrations of opioids is dependent on receptor endocytosis and downstream PKC signaling. Targeting these pathways could mitigate the hyperexcitability of pain signaling neurons caused by high doses of opioids. Funding Agencies CCC

In this trial comparing methadone with buprenorphine in opioid-dependent pregnant women, neonates exposed to buprenorphine required less morphine to treat neonatal abstinence syndrome (NAS) and had a significantly shorter duration of hospitalization and of treatment for NAS. Opioid dependence during pregnancy is compounded by multiple risk factors contributing to adverse maternal, neonatal, and long-term developmental consequences. 1 – 6 Improved treatment options should reduce the public health and medical costs associated with the treatment of neonates exposed to opioids, which in 2009 was estimated at $70.6 million to $112.6 million in the United States alone. 7 Just as the use of methadone in nonpregnant patients with opioid dependence improves patient outcomes, 8 its use as part of a comprehensive approach to the care of pregnant women improves maternal and neonatal outcomes, as compared with no treatment and with medication-assisted withdrawal. 4 , . . .