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- Development of application protocols of the Emit(®) II Plus 6-Acetylmorphine Assay on the ADVIA(®) 1800 and 2400 Chemistry Systems. [JOURNAL ARTICLE]
- Forensic Sci Int 2014 Aug 26.:122-127.
New application protocols for the Emit(®) II Plus 6-Acetylmorphine Assay for human urine screening have been developed on the ADVIA(®) 1800 and 2400 Chemistry Systems. Precision was evaluated at the cutoff and ±25% controls. Recovery and linearity were studied by spiking 6-acetylmorphine (6-AM) into human urine pools. Method comparison was evaluated using urine specimens and the results were compared to those obtained from the predicate Analyzer (V-Twin(®)). Cross-reactivity with structurally related drugs was assessed at high cross-reactant concentrations. Potential interferences were assessed in the presence of 7.5 and 12.5ng/mL of 6-AM. The qualitative repeatability coefficients of variation (CV's) ranged from 0.40 to 0.90% and the within-lab CV's ranged from 1.3 to 3.5%. In analyte units (ng/mL), the repeatability CV's ranged from 1.9 to 4.3% and the within-lab CV's ranged from 3.7 to 6.1%. The limit of detection of the assay was found to be 2.5ng/mL on both instruments. Recovery was within 20% of expected value. Linearity was 2.5-20ng/mL. Method comparison showed 100% agreement with the predicate analyzer. The assay had minimal cross-reactivity to structurally related opioids including with morphine, morphine-3-glucuronide, morphine-6-glucuronide. No interference was observed with endogenous interferences.
- Interactive HIV-1 Tat and Morphine-Induced Synaptodendritic Injury Is Triggered through Focal Disruptions in Na+ Influx, Mitochondrial Instability, and Ca2+ Overload. [Journal Article]
- J Neurosci 2014 Sep 17; 34(38):12850-64.
Synaptodendritic injury is thought to underlie HIV-associated neurocognitive disorders and contributes to exaggerated inflammation and cognitive impairment seen in opioid abusers with HIV-1. To examine events triggering combined transactivator of transcription (Tat)- and morphine-induced synaptodendritic injury systematically, striatal neuron imaging studies were conducted in vitro. These studies demonstrated nearly identical pathologic increases in dendritic varicosities as seen in Tat transgenic mice in vivo. Tat caused significant focal increases in intracellular sodium ([Na(+)]i) and calcium ([Ca(2+)]i) in dendrites that were accompanied by the emergence of dendritic varicosities. These effects were largely, but not entirely, attenuated by the NMDA and AMPA receptor antagonists MK-801 and CNQX, respectively. Concurrent morphine treatment accelerated Tat-induced focal varicosities, which were accompanied by localized increases in [Ca(2+)]i and exaggerated instability in mitochondrial inner membrane potential. Importantly, morphine's effects were prevented by the μ-opioid receptor antagonist CTAP and were not observed in neurons cultured from μ-opioid receptor knock-out mice. Combined Tat- and morphine-induced initial losses in ion homeostasis and increases in [Ca(2+)]i were attenuated by the ryanodine receptor inhibitor ryanodine, as well as pyruvate. In summary, Tat induced increases in [Na(+)]i, mitochondrial instability, excessive Ca(2+) influx through glutamatergic receptors, and swelling along dendrites. Morphine, acting via μ-opioid receptors, exacerbates these excitotoxic Tat effects at the same subcellular locations by mobilizing additional [Ca(2+)]i and by further disrupting [Ca(2+)]i homeostasis. We hypothesize that the spatiotemporal relationship of μ-opioid and aberrant AMPA/NMDA glutamate receptor signaling is critical in defining the location and degree to which opiates exacerbate the synaptodendritic injury commonly observed in neuroAIDS.
- Expression and localization of cannabinoid receptor 1 in rats' brain treated with acute and repeated morphine. [Journal Article]
- Acta Neurobiol Exp (Wars) 2014; 74(3):288-97.
Morphine induces adaptive changes in gene expression throughout the reward circuitry of brain. Recent research has proven the functional interactions between opioid and endogenous cannabinoid system in the central nervous system (CNS). The cannabinoid receptor 1 (CB1-R) is one of the receptors that mediate the actions of cannabinoids and endocannabinoids in the CNS. Here, we investigated the expression of CB1-R in mRNA and protein levels in the brains of rats treated with acute and repeated morphine. Three groups of rats received intraperitoneal injections (ip injections) of saline, acute morphine (10 mg/kg) and repeated morphine (10 mg/kg, twice daily for 12 consecutive days), and the mRNA levels and protein expressions of CB1-R were examined. RT-PCR and western blot analyses supported that both mRNA and protein levels of CB1-R in cortex, cerebellum and hippocampus were increased by repeated morphine treatment. However, the mRNA level in cerebellum was down-regulated only after acute morphine treatment and would returned to basal levels later. We used immunohistochemistry techniques to determine the functional expression of CB1-R in morphine treated rat's brain. Enzyme-Linked Immunosorbent Assay (ELISA) revealed the significant increase of cytokine (IL-1beta, IL-6) levels in the repeated morphine treatment rats' cortex and hippocampus regions, which are both addiction-related brain areas. In addition, the results from RT-PCR and western blot assay indicated that the expression of CB1-R was directly increased by morphine treatment in vitro. All the results indicated that the CB1-R expression could be changed by morphine exposure and it might be involved in neural immune function, which provided a potential target for neurogenic disease treatment.
- Adjuncts should always be used in pediatric regional anesthesia. [JOURNAL ARTICLE]
- Paediatr Anaesth 2014 Sep 17.
A number of different adjuncts to local anesthetics can be used to prolong and optimize postoperative pain relief following regional anesthesia in children. The present text provides a slightly opinionated but evidence-based argument in favor of this practice.
- Analgesic effects of gabapentin after scoliosis surgery in children: a randomized controlled trial. [JOURNAL ARTICLE]
- Paediatr Anaesth 2014 Sep 17.
Postoperative pain remains an important challenge after scoliosis surgery in children. Opioids are the mainstay of treatment, and adult studies demonstrate gabapentin as a useful adjunct to opioids in the management of postoperative pain.Adolescent patients undergoing idiopathic scoliosis surgery were randomized to receive a single preoperative dose of gabapentin 600 mg or placebo. The primary outcome measure was total morphine consumption in mg·kg(-1) between 0 and 24 h postoperatively. Secondary outcome measures included time to first rescue analgesia, pain intensity scores at rest and with movement, incidence of nausea, vomiting, pruritus, sedation, dizziness, presence of persisting pain symptoms, and patient satisfaction. Cumulative opioid consumption was calculated at each time point: 1, 4, 8, 12, 24, 48, and 72 h.The gabapentin group used 0.087 ± 0.06 mg·kg(-1) of morphine at 1 h, 0.24 ± 0.12 mg·kg(-1) at 4 h, 0.44 ± 0.17 mg·kg(-1) at 8 h, and 1.29 ± 0.44 mg·kg(-1) at 24 h. The placebo group used 0.121 ± 0.06 mg·kg(-1) of morphine at 1 h, 0.35 ± 0.16 mg·kg(-1) at 4 h, 0.56 ± 0.27 mg·kg(-1) at 8 h, and 1.46 ± 0.68 mg·kg(-1) at 24 h. There was no statistically significant reduction in opioid consumption in the patients receiving gabapentin. There were no significant differences in secondary outcomes.A single preoperative dose of gabapentin did not show a significant difference in opioid consumption or pain scores in adolescents undergoing idiopathic scoliosis surgery. This study is the first pediatric randomized controlled trial to assess the effectiveness of a single dose of gabapentin on morphine consumption and analgesia following major surgery.
- Oral or transdermal opioids for osteoarthritis of the knee or hip. [JOURNAL ARTICLE]
- Cochrane Database Syst Rev 2014 Sep 17.:CD003115.
Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in older people. Opioids may be a viable treatment option if people have severe pain or if other analgesics are contraindicated. However, the evidence about their effectiveness and safety is contradictory. This is an update of a Cochrane review first published in 2009.To determine the effects on pain, function, safety, and addiction of oral or transdermal opioids compared with placebo or no intervention in people with knee or hip osteoarthritis.We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL (up to 28 July 2008, with an update performed on 15 August 2012), checked conference proceedings, reference lists, and contacted authors.We included randomised or quasi-randomised controlled trials that compared oral or transdermal opioids with placebo or no treatment in people with knee or hip osteoarthritis. We excluded studies of tramadol. We applied no language restrictions.We extracted data in duplicate. We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain and function, and risk ratios for safety outcomes. We combined trials using an inverse-variance random-effects meta-analysis.We identified 12 additional trials and included 22 trials with 8275 participants in this update. Oral oxycodone was studied in 10 trials, transdermal buprenorphine and oral tapentadol in four, oral codeine in three, oral morphine and oral oxymorphone in two, and transdermal fentanyl and oral hydromorphone in one trial each. All trials were described as double-blind, but the risk of bias for other domains was unclear in several trials due to incomplete reporting. Opioids were more beneficial in pain reduction than control interventions (SMD -0.28, 95% CI -0.35 to -0.20), which corresponds to a difference in pain scores of 0.7 cm on a 10-cm visual analogue scale (VAS) between opioids and placebo. This corresponds to a difference in improvement of 12% (95% CI 9% to 15%) between opioids (41% mean improvement from baseline) and placebo (29% mean improvement from baseline), which translates into a number needed to treat (NNTB) to cause one additional treatment response on pain of 10 (95% CI 8 to 14). Improvement of function was larger in opioid-treated participants compared with control groups (SMD -0.26, 95% CI -0.35 to -0.17), which corresponds to a difference in function scores of 0.6 units between opioids and placebo on a standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10. This corresponds to a difference in improvement of 11% (95% CI 7% to 14%) between opioids (32% mean improvement from baseline) and placebo (21% mean improvement from baseline), which translates into an NNTB to cause one additional treatment response on function of 11 (95% CI 7 to 14). We did not find substantial differences in effects according to type of opioid, analgesic potency, route of administration, daily dose, methodological quality of trials, and type of funding. Trials with treatment durations of four weeks or less showed larger pain relief than trials with longer treatment duration (P value for interaction = 0.001) and there was evidence for funnel plot asymmetry (P value = 0.054 for pain and P value = 0.011 for function). Adverse events were more frequent in participants receiving opioids compared with control. The pooled risk ratio was 1.49 (95% CI 1.35 to 1.63) for any adverse event (9 trials; 22% of participants in opioid and 15% of participants in control treatment experienced side effects), 3.76 (95% CI 2.93 to 4.82) for drop-outs due to adverse events (19 trials; 6.4% of participants in opioid and 1.7% of participants in control treatment dropped out due to adverse events), and 3.35 (95% CI 0.83 to 13.56) for serious adverse events (2 trials; 1.3% of participants in opioid and 0.4% of participants in control treatment experienced serious adverse events). Withdrawal symptoms occurred more often in opioid compared with control treatment (odds ratio (OR) 2.76, 95% CI 2.02 to 3.77; 3 trials; 2.4% of participants in opioid and 0.9% of participants control treatment experienced withdrawal symptoms).The small mean benefit of non-tramadol opioids are contrasted by significant increases in the risk of adverse events. For the pain outcome in particular, observed effects were of questionable clinical relevance since the 95% CI did not include the minimal clinically important difference of 0.37 SMDs, which corresponds to 0.9 cm on a 10-cm VAS.
- A Mouse Model of Peripheral Post-Ischemic Dysesthesia: Involvement of Reperfusion-Induced Oxidative Stress and TRPA1 Channel. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Sep 16.
We behaviorally examined peripheral post-ischemic dysesthesia in mice and investigated the underlying molecular mechanism with a focus on oxidative stress. Hind-paw ischemia was induced by tight compression of the ankle with a rubber band, and reperfusion was achieved by cutting the rubber tourniquet. We found that reperfusion after ischemia markedly provoked licking of the reperfused hind paw, which was significantly inhibited by systemic administration of the antioxidant N-acetyl-L-cysteine and the TRPA1 channel blocker HC-030031. Post-ischemic licking was also significantly inhibited by an intraplantar injection of another antioxidant phenyl-N-tert-butylnitrone. The TRPV1 channel blocker N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide did not inhibit post-ischemic licking. An intraplantar injection of hydrogen peroxide elicited hind-paw licking, which was inhibited by N-acetyl-L-cysteine, phenyl-N-tert-butylnitrone, and HC-030031. Post-ischemic licking was not affected by chemical depletion of sensory C-fibers, but it was inhibited by morphine, which has been shown to inhibit the C- and Aδ-fiber-evoked responses of dorsal horn neurons. Interestingly, post-ischemic licking was not inhibited by gabapentin and pregabalin, which have been shown to inhibit the C-fiber- but not Aδ-fiber-evoked response. The present results suggest that ischemia-reperfusion induces oxidative stress, which activates TRPA1 channels to provoke post-ischemic licking. This behavior is suggested to be mediated by myelinated (probably Aδ-type) afferent fibers. Oxidative stress and TRPA1 channels may be potential targets to treat peripheral ischemia-associated dysesthesia.
- Drug-poisoning Deaths Involving Opioid Analgesics: United States, 1999-2011. [Journal Article]
- NCHS Data Brief 2014 Sep; (166):1-8.
Data from the National Vital Statistics System, Mortality File. The age-adjusted rate for opioid-analgesic poisoning deaths nearly quadrupled from 1.4 per 100,000 in 1999 to 5.4 per 100,000 in 2011. Although the opioid-analgesic poisoning death rates increased each year from 1999 through 2011, the rate of increase has slowed since 2006. Natural and semisynthetic opioid analgesics, such as hydrocodone, morphine, and oxycodone, were involved in 11,693 drug-poisoning deaths in 2011, up from 2,749 deaths in 1999. Benzodiazepines were involved in 31% of the opioid-analgesic poisoning deaths in 2011, up from 13% of the opioid-analgesic poisoning deaths in 1999. During the past decade, adults aged 55-64 and non-Hispanic white persons experienced the greatest increase in the rates of opioid-analgesic poisoning deaths. Poisoning is the leading cause of injury death in the United States (1). Drugs-both illicit and pharmaceutical-are the major cause of poisoning deaths, accounting for 90% of poisoning deaths in 2011. Misuse or abuse of prescription drugs, including opioid-analgesic pain relievers, is responsible for much of the recent increase in drug-poisoning deaths (2). This report highlights trends in drug-poisoning deaths involving opioid analgesics (referred to as opioid-analgesic poisoning deaths) and updates previous Data Briefs on this topic.
- Postoperative analgesia in patients older than 75 years undergoing intervention for per-trochanteric hip fracture: a single centre retrospective cohort study. [JOURNAL ARTICLE]
- Aging Clin Exp Res 2014 Sep 17.
The aim of this study was to compare the efficacy of four analgesia techniques on postoperative pain after per-trochanteric femur fracture. A retrospective cohort study was conducted on 131 consecutive patients older than 75 years enrolled in an 18-month period and who underwent per-trochanteric fracture repair under spinal analgesia. Patients received postoperative analgesia from: G1 (n = 36), intravenous analgesia on demand only; G2 (n = 28) administration of acetaminophen at fixed hours; G3 (n = 50) continuous morphine infusion; G4 (n = 17), preoperative echo-graphic guided femoral nerve block. Continuous opioid infusion failed to prevent the onset of pain at the end of the effects of subarachnoid anesthesia (rescue dose of analgesic in 48 % of patients in G3 vs. 22 % in G2 in the first day; p < 0.05). The greater effectiveness was achieved by preventing the onset of pain with drugs administered at time intervals (rescue dose of analgesic in 48 % of patients in G3, 58 % in G1 and 48 % in G4 vs. 22 % in G2 in the first day and rescue dose of analgesic in 32 % of patients in G3, 67 % in G1 and 76 % in G4 vs. 18 % in G2 in the second day; p < 0.05). Our study does not confirm the effectiveness of a single shot femoral nerve block on postoperative pain in per-trochanteric femur fracture (PAIN VAS score > 3 at t1 in 23 % of patients in G1 and 19 % in G4 vs. 10 % in G2 and G3; p < 0.05).