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- Neonatal Abstinence Syndrome. [REVIEW]
- Pediatrics 2014 Jul 28.
Neonatal abstinence syndrome (NAS) is a result of the sudden discontinuation of fetal exposure to substances that were used or abused by the mother during pregnancy. Withdrawal from licit or illicit substances is becoming more common among neonates in both developed and developing countries. NAS continues to be an important clinical entity throughout much of the world. NAS leads to a constellation of signs and symptoms involving multiple systems. The pathophysiology of NAS is not completely understood. Urine or meconium confirmation may assist the diagnosis and management of NAS. The Finnegan scoring system is commonly used to assess the severity of NAS; scoring can be helpful for initiating, monitoring, and terminating treatment in neonates. Nonpharmacological care is the initial treatment option, and pharmacological treatment is required if an improvement is not observed after nonpharmacological measures or if the infant develops severe withdrawal. Morphine is the most commonly used drug in the treatment of NAS secondary to opioids. An algorithmic approach to the management of infants with NAS is suggested. Breastfeeding is not contraindicated in NAS, unless the mother is taking street drugs, is involved in polydrug abuse, or is infected with HIV. Future studies are required to assess the long-term effects of NAS on children after prenatal exposure.
- [Genetic polymorphisms commonly associated with sensitivity to various addictive substances]. [English Abstract, Journal Article]
- Nihon Shinkei Seishin Yakurigaku Zasshi 2013 Nov; 33(5-6):205-9.
Opioids, such as morphine and fentanyl, are widely used as effective analgesics for the treatment of acute and chronic pain. In addition, the opioid system has a key role in the rewarding effects of morphine, ethanol, cocaine and various other drugs. The authors have focused on G-protein-activated inwardly rectifying potassium (GIRK) channel subunits, GIRK2 and GIRK3, which are important molecules in opioid transmission, and found that the SNPs within the GIRK2 and GIRK3 gene region were significantly associated with postoperative analgesic requirements, one of which was also associated with vulnerability to methamphetamine (METH) dependence. Further, by conducting a multistage genome-wide association study (GWAS) in healthy subjects, the authors found that the rs2952768 single-nucleotide polymorphism (SNP) was strongly associated with the requirements for postoperative opioid analgesics after painful cosmetic surgery and consistent results were obtained in patients who underwent abdominal surgery. In addition, the SNP also showed significant association with vulnerability to severe drug dependence in patients with METH dependence, alcohol dependence, and eating disorders and a lower 'Reward Dependence' score on a personality questionnaire in healthy subjects. These outcomes provide valuable information for the personalized treatment of pain and drug dependence.
- A Scutellaria baicalensis radix water extract inhibits morphine-induced conditioned place preference. [JOURNAL ARTICLE]
- Pharm Biol 2014 Jul 28.:1-6.
Abstract Context: Scutellaria baicalensis Georgi (Lamiaceae) has been used as a traditional herbal preparation for the treatment of neuropsychiatric disorders in Asian countries for centuries. Objective: To evaluate the effects of S. baicalensis on morphine-induced drug dependence in rats. Materials and methods: In order to evaluate the effect of S. baicalensis and baicalin on morphine-induced dependence-like behavior, a water extract of S. baicalensis [500 mg/kg, intraperitoneally (i.p.)] or baicalin (50 mg/kg, i.p., a flavonoid found in S. baicalensis) was administered prior to morphine injection [5 and 2.5 mg/kg, respectively, subcutaneously (s.c.)] to rats for 8 and 4 d, respectively. Morphine-induced conditioned place preference was assessed by measuring the time spent in a drug-paired chamber. The effect of S. baicalensis on dopamine receptor supersensitivity (locomotor activity) and dopamine agonist-induced climbing behavior due to a single apomorphine treatment (2 mg/kg, s.c.) was also measured. Results: At 50 mg/kg, a water extract of S. baicalensis decreased morphine (5 mg/kg)-induced conditioned place preference by 86% in rats. Apomorphine (2 mg/kg)-induced locomotor activity (dopamine receptor supersensitivity) in rats and climbing behavior in mice were attenuated after pretreatment with 500 mg/kg of S. baicalensis water extract by 41% and 56%, respectively. In addition, baicalin-reduced morphine-induced conditioned places preference by 86% in rats at 50 mg/kg. Discussion and conclusion: These results suggest that S. baicalensis can ameliorate drug addiction-related behavior through functional regulation of dopamine receptors.
- Preoperative Fascia Iliaca Compartment Block for Positioning Patients With Hip Fractures for Central Nervous Blockade: A Randomized Trial. [JOURNAL ARTICLE]
- Reg Anesth Pain Med 2014 Jul 25.
Appropriate pain management may positively affect outcome following hip fractures. Positioning patients for spinal anesthesia (SA) can be extremely painful. Peripheral nerve blockades are gaining popularity in this setting. This prospective, randomized study compares the efficacy of fascia iliaca compartment block (FICB) to intravenous (IV) fentanyl for positioning hip fracture patients for SA.Forty-one patients scheduled for hip fracture surgery were randomized to receive a bolus dose of IV fentanyl (IVFE) 1.5 μg/kg (IVFE group) or an FICB using 40 mL ropivacaine 0.5% (FICB group) 5 or 20 minutes before positioning for SA, respectively. Numeric rating pain scale scores before and following the analgesic intervention, time needed and quality of patient position for SA performance, postoperative analgesia in terms of time to first IV morphine dose demand and morphine consumption during the first 24 hours, and patient satisfaction were documented.Compared with the IVFE group, the FICB group showed significantly lower numeric rating pain scale scores in all instances following the analgesic intervention (P < 0.001), shorter spinal performance time (P = 0.001), and better quality of position (P = 0.001). Postoperative morphine consumption was lower (P = 0.026), the time to first dose demand was longer (P = 0.001), and patient satisfaction rates were higher (P < 0.001) in the FICB group.Performing an FICB before positioning for SA provides superior pain management compared with IVFE administration, facilitates spinal performance, and yields satisfactory postoperative analgesia and wide patient acceptance, hence improving overall quality and efficiency of care.
- Morphine-induced conditioned place preference and effects of morphine pre-exposure in adolescent and adult male C57BL/6J mice. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2014 Jul 29.
Given the increasing abuse of prescription opioids, particularly in adolescents, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults).This study compared the conditioned rewarding effects of morphine, without (experiment 1) and with morphine pre-exposure (experiment 2), in adolescent and adult male mice.Experiment 1: On each of three consecutive days, one of the two conditioning sessions was preceded by an injection of a particular dose of morphine (0.1, 0.32, 1, 3.2, 10, 32, or 100 mg/kg, intraperitoneal) and the other by saline; place preference was tested on day 4. Experiment 2: Mice received once daily injections of saline or a particular dose of morphine (17.8 or 56 mg/kg) for 4 days, and 3 days later, place conditioning with morphine (0.32, 1, 3.2, or 10 mg/kg) began.In both experiments, morphine induced conditioned place preference along similar inverted U-shaped dose-response curves in adolescent and adult mice, with maximal effects between 0.32 and 10 mg/kg. Morphine pre-exposure did not sensitize morphine-induced conditioned place preference; instead, tolerance occurred, but only in adults. Adolescents were more sensitive than adults to morphine-induced locomotor stimulation. Response to novelty predicted the locomotor stimulating effects of morphine in adolescents, but not its rewarding effects.The rewarding effects of morphine were similar in adolescent and adult mice but showed differential tolerance after morphine pre-exposure. Adolescents were more sensitive than adults to the acute locomotor stimulating effects of morphine, consistent with dopamine systems involved in locomotor activity being overactive during adolescence.
- Oral rehydration with 10% carbohydrate drink for preventing postoperative nausea and vomiting (PONV) after low dose of spinal morphine. [Journal Article, Research Support, Non-U.S. Gov't]
- J Med Assoc Thai 2014 May; 97(5):530-5.
Preoperative oral carbohydrate (CHO) drink may improve patients' comfort. However, whether it prevents or reduces postoperative nausea and vomiting (PONV) is questionable.Evaluate the effect of oral rehydration with 10% CHO drink before anesthesia on incidence and severity of postoperative nausea and vomiting (PONV) after spinal morphine injection.One hundred patients scheduled for unilateral total knee replacement (TKR) were randomly divided into two equal groups (n = 50 each). Group I patients received 400 ml 10% CHO drink the preoperative night and 2-hour before anesthesia, whereas Group II patients served as control. Spinal anesthesia for all patients contained 0.5% bupivacaine 2.0 to 3.5 ml plus morphine 0.2 mg. Pain therapy was standardized with femoral nerve block, local infiltration, intravenous parecoxib, and oral paracetamol. Incidence and severity of PONV within 24 hours were recorded In addition, preoperative intensity of thirst and hunger, dry lips and throat, and anxiety was also recordedIncidence and severity of PONV (81.2% vs. 72.0%, p = 0.536) as well as preoperative thirst, hunger dry lips, and throat were not different between the groups.Preoperative oral rehydration with carbohydrate drinks had no positive effect on PONV nor patients' comfort.
- Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence. [JOURNAL ARTICLE]
- J Subst Abuse Treat 2014 Jun 10.
Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n=95 group A, n=103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.
- Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance and opioidergic cardioprotection. [JOURNAL ARTICLE]
- Am J Physiol Heart Circ Physiol 2014 Jul 25.
Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function, and protective stress-signaling. However, the importance of membrane cholesterol content to cardiovascular function, and myocardial responses to ischemia-reperfusion (IR) and cardioprotective stimuli are unclear. We assessed effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD), and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3), on cardiac function, IR tolerance and opioid receptor (OR) mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02-1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25 min ischemia/45 min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically (sustained ligand-activated preconditioning - SLP) assessed. MβCD concentration-dependently reduced normoxic contractile function and post-ischemic outcomes in association with graded (10-30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust, only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced (while Cav-3 OE improved) myocardial IR tolerance. Protection via SLP remained equally effective in Cav-3 KO mice, and was additive with innate protection arising with Cav-3 OE. These data reveal membrane cholesterol-dependence of normoxic myocardial and coronary function, IR tolerance and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3 , while cardiac IR tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression.
- Sedation Management during Therapeutic Hypothermia for Neonatal Encephalopathy: Atropine Premedication for Endotracheal Intubation Causes a Prolonged Increase in Heart Rate. [JOURNAL ARTICLE]
- Resuscitation 2014 Jul 22.
Heart rate (HR) plays an important role in the assessment of stress during Therapeutic Hypothermia (TH) for Neonatal Encephalopathy; we aimed to quantify the effect on HR of endotracheal (ET) intubation and drugs given to facilitate it. If atropine premedication independently increased HR, the main indicator of effective sedation, we hypothesised that increased sedation would have been given.Thirty two, term, neonates recruited into a randomised pilot study comparing TH and TH combined with 50% Xenon inhalation were studied. Indications for ET intubation included: resuscitation at delivery, clinical need and elective re-intubation with a cuffed ET tube if randomised to Xenon. Standard intubation drugs comprised one or more of intravenous morphine, atropine, and suxamethonium. Local cooling guidelines were followed including morphine infusion for sedation.At postnatal hours five to eight atropine increased HR in a linear regression model (p<0.01). All other independent variables were excluded. Where more than one dose of atropine was given total morphine sedation given up to 8hours into the treatment period was significantly higher (p<0.01).We have shown that atropine premedication for ET intubation significantly increased HR, the main indicator of effective sedation and total morphine dose for sedation during early TH was increased where more than one dose of atropine was given. Bradycardia was not reported in any neonate, even without atropine premedication. We suggest that the use of atropine as part of standard premedication for ET intubation of term neonates undergoing TH should be reconsidered.
- Deficits in neuronal cytochrome P450 activity attenuate, Opioid Analgesia but not Opioid Side Effects. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Jul 22.
Morphine-like analgesics act on µ opioid receptors in the CNS to produce highly effective pain relief, but the same class of receptors also mediates non-therapeutic side effects. The analgesic properties of morphine were recently shown to require the activity of a brain neuronal cytochrome P450 epoxygenase, but the significance of this pathway for opioid side effects is unknown. Here we show that brain P450 activity is not required for three of morphine's major side effects (respiratory depression, constipation, and locomotor stimulation). Following systemic or intracerebroventricular administration of morphine, transgenic mice with brain neuron-specific reductions in P450 activity showed highly attenuated analgesic responses as compared with wild-type (control) mice. However, brain P450-deficient mice showed normal morphine-induced side effects (respiratory depression, locomotor stimulation, and inhibition of intestinal motility). Pretreatment of control mice with the P450 inhibitor CC12 similarly reduced the analgesia, but not these side effects of morphine. Because activation of brain µ opioid receptors produces both opioid analgesia and opioid side effects, dissociation of the mechanisms for the therapeutic and therapy-limiting effects of opioids has important consequences for the development of analgesics with reduced side effects and/or limited addiction liability.