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- Preemptive analgesia effects of Ketamine in patients undergoing surgery. A meta-analysis. [JOURNAL ARTICLE]
- Acta Cir Bras 2014 Dec; 29(12):819-825.
To evaluate the preemptive analgesia effects of ketamine for postoperative pain.PubMed, EMBASE and Cochrane Library were searched to identify randomized controlled trials (RCTs) involved in ketamine for preemptive analgesic up to March 2013. The relative risk (RR) or mean difference (MD) as well as the confounding 95% confidence interval (CI) were calculated by the Revman 5.0 software.A total of five studies including 266 patients were included in this meta-analysis. Overall, ketamine could reduce the postoperative morphine consumption and significantly prolong the time to first analgesic (p < 0.00001, MD = 0.91, 95% CI: 0.56 to 1.26). However, there was no significant difference in indicators of nausea and vomiting (p = 0.87, RR = 1.04, 95% CI: 0.67 to 1.60), surgical time (p = 0.41, MD = -2.13, 95% CI: -7.21 to 2.95) and anesthetic time (p = 0.53, MD = -1.54, 95% CI: -6.34 to -3.26) between ketamine and control group.Ketamine was able to accomplish some preemptive analgesic effects of reducing postoperative morphine consumption and prolonging the time to first analgesic. Meanwhile, ketamine was as safe as physiological saline in side effects of nausea and vomiting.
- Fentanyl Transdermal Patch (Durogesic®D-TRANS) for post abdominal laparotomy analgesia: a double blind randomized study. [JOURNAL ARTICLE]
- Minerva Chir 2014 Dec 17.
The Fentanyl Transdermal Patch (Durogesic®D--TRANS) is a strong pain medication for moderate to severe chronic pain that can provide long---lasting relief for persistent pain. This study was conducted to determine the analgesia and adverse effects of the fentanyl transdermal patch (Durogesic®D-TRANS) post elective laparotomy.One--hundred twenty patients undergoing elective laparotomy were randomized into two groups of Fentanyl and placebo. In the first group, patients received two fentanyl patches with 25 and 50 μg in 10 h preoperatively. Patient's postoperative assessments included pain score, adverse effects, mean amount and interval of supplementary morphine, respiratory rate and oxygen saturation, which were recorded during 36 h.The mean pain intensity scores over 36 h in Fentanyl Transdermal Patch Durogesic (FTD) group were significantly less than placebo group (FTD, 35.28; placebo, 46.61 and P =0.01). However, the pain score at the 3rd timepoint in the placebo group was slightly less than the FTD group (39.4±2.23 vs. 39.47±4.97, respectively). The mean interval and amount of supplementary morphine were significantly better in the FTD group than the placebo group (FTD 367.7±349.7 min vs. placebo 59±13.88 min; P = 0.04 and FTD 2.10±3.46 mg vs. 29.15±3.71 mg; P < 0.001, respectively). The incidence of adverse effects including vomiting (FTD 16 vs. placebo 9; P = 0.45), nausea (FTD 22 vs. placebo 18; P = 0.33), itching (FTD 16 vs. placebo 18; P =1.00) and respiratory depression (FTD 1 vs. placebo 0; P = 1.00) were not significant between the groups, except the dizziness that had a higher incidence in the FTD group (FTD 23 vs. placebo 1; P = 0.02).It seems that the Fentanyl Transdermal Patch system is a safe and effective procedure to use in post laparotomy analgesia and its related adverse effects are not serious.
- [Wavelet packet extraction and entropy analysis of telemetry EEG from the prelimbic cortex of medial prefrontal cortex in morphine-induced CPP rats.] [JOURNAL ARTICLE]
- Sheng Li Xue Bao 2014 Dec 25; 66(6):675-682.
The purpose of the present study is to analyze the relationship between the telemetry electroencephalogram (EEG) changes of the prelimbic (PL) cortex and the drug-seeking behavior of morphine-induced conditioned place preference (CPP) rats by using the wavelet packet extraction and entropy measurement. The recording electrode was stereotactically implanted into the PL cortex of rats. The animals were then divided randomly into operation-only control and morphine-induced CPP groups, respectively. A CPP video system in combination with an EEG wireless telemetry device was used for recording EEG of PL cortex when the rats shuttled between black-white or white-black chambers. The telemetry recorded EEGs were analyzed by wavelet packet extraction, Welch power spectrum estimate, normalized amplitude and Shannon entropy algorithm. The results showed that, compared with operation-only control group, the left PL cortex's EEG of morphine-induced CPP group during black-white chamber shuttling exhibited the following changes: (1) the amplitude of average EEG for each frequency bands extracted by wavelet packet was reduced; (2) the Welch power intensity was increased significantly in 10-50 Hz EEG band (P < 0.01 or P < 0.05); (3) Shannon entropy was increased in β, γ1, and γ2 waves of the EEG (P < 0.01 or P < 0.05); and (4) the average information entropy was reduced (P < 0.01). The results suggest that above mentioned EEG changes in morphine-induced CPP group rat may be related to animals' drug-seeking motivation and behavior launching.
- Effect of combining tramadol and morphine in adult surgical patients: a systematic review and meta-analysis of randomized trials. [JOURNAL ARTICLE]
- Br J Anaesth 2014 Dec 16.
The role for tramadol in multimodal postsurgical analgesic strategies remains unclear. We undertook a systematic review to evaluate the utility of combining tramadol with morphine after surgery. We searched the MEDLINE, EMBASE, LILAC, Cochrane, and Clinical Trial Register databases for randomized, controlled studies comparing tramadol with placebo or active control in patients undergoing surgery. Fourteen studies (713 patients) were included. There was a limited but significant postoperative morphine-sparing effect, with a weighted mean difference (WMD) of -6.9 (95% confidence interval -11.3 to -2.5) mg. This effect was not associated with a decrease in morphine-related adverse effects. No difference in the incidence of nausea, vomiting, sedation, or shivering was observed. There was no decrease in pain intensity at 24 h; the WMD was -0.9 (-7.2; 5.2) on a 100 mm visual analogue scale at 24 h. We found no significant clinical benefit from the combination of i.v. tramadol and morphine after surgery.
- Curcumin attenuates opioid tolerance and dependence by inhibiting CaMKIIα activity. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Dec 16.
Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα), a protein kinase that have been previously proposed to be critical for opioid tolerance and dependence. In this study, we have employed a state-of-art polymeric formulation technology to produce PLGA-curcumin nanoparticles (nanocurcumin), in order to overcome the drug's poor solubility and bioavailability that have made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11-33 folds. Pretreatment with PLGA-curcumin (p.o.) prevented the development of opioid tolerance and dependence in a dose dependent manner with ED50 of 3.9 mg/kg and 3.2 mg/kg, respectively. PLGA-curcumin dose-dependently attenuated already-established opioid tolerance (ED50= 12.6 mg/kg, p.o.) and dependence (ED50= 3.1 mg/kg, p.o.). Curcumin or PLGA-curcumin did not produce antinociception by itself or affect morphine (1-10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIα activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIα activity.
- Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Dec 15.
Morphine is metabolized in humans to the pharmacologically active morphine-6-glucuronide (M6G) and inactive morphine-3-glucuronide (M3G). The hepatobiliary disposition of both metabolites relies upon Mrp3 and Mrp2, located on the sinusoidal and canalicular membrane, respectively. Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease, alters xenobiotic metabolizing enzyme and transporter function. The purpose of this study was to determine whether NASH contributes to the large inter-individual variability and postoperative adverse events associated with morphine therapy. Male Sprague-Dawley rats were fed a control diet or a methionine and choline deficient diet to induce NASH. Radiolabeled morphine (2.5mg/kg, 30μCi/kg) was administered intravenously, and plasma and bile (0-150 or 0-240 min), liver and kidney, and cumulative urine were analyzed for morphine and M3G. The antinociceptive response to M6G (5mg/kg) was assessed (0-12 h) following direct intraperitoneal administration since rats do not produce M6G. NASH caused a net decrease in morphine concentrations in the bile and plasma and a net increase in the M3G/morphine plasma AUC ratio, consistent with upregulation of Ugt2b1. Despite increased systemic exposure to M3G, NASH resulted in decreased biliary excretion and hepatic accumulation of M3G. This shift towards systemic retention is consistent with the mislocalization of canalicular Mrp2 and increased expression of sinusoidal Mrp3 in NASH and may correlate to increased antinociception by M6G. Increased metabolism and altered transporter regulation in NASH provide a mechanistic basis for inter-individual variability in morphine disposition that may lead to opioid-related toxicity.
- Reversal of Opioid Overdose Syndrome in Morphine-Dependent Rats Using Buprenorphine. [JOURNAL ARTICLE]
- Toxicol Lett 2014 Dec 12.
The method of choice for reversal of opioid-toxicity is administration of naloxone. This treatment can be accompanied by complications including acute lung-injury, myocardial infarction, or withdrawal-syndrome (in dependent-patients). We aimed to evaluate the efficacy of buprenorphine in reversal of opioid-overdose syndrome in dependent-rats. A prospective case-control study was designed, in which a total of 30 rats were put on opioid-dependency protocol with 10mg/kg of intra-peritoneal morphine twice daily for 10 days. After confirmation of dependency by naloxone administration, the rats were overdosed by giving 16mg/kg of intra-peritoneal methadone. They were divided into four groups receiving naloxone(n=7; 2mg/kg) and buprenorphine(n=8, 8, and 7 with doses of 3mg/kg, 6mg/kg, and 10mg/kg), respectively. These four groups were compared regarding reversal of opioid signs/symptoms and development of withdrawal-syndrome. Rats in the first group showed signs/symptoms of opioid-withdrawal severely and with a higher frequency (P<0.001). In the groups 2-4, all doses recovered the intoxicated-rats without inducing signs/symptoms of withdrawal; however, the 3mg/kg dose reversed toxicity slower (P<0.001) and one rat in this group died later due to the re-development of signs of toxicity. Buprenorphine recovers opioid-overdose in morphine-dependent rats and bypasses the withdrawal-syndrome due to administration of naloxone.
- Glasgow Coma Scale scores, early opioids, and 4-year psychological outcomes among combat amputees. [Journal Article, Research Support, U.S. Gov't, Non-P.H.S.]
- J Rehabil Res Dev 2014; 51(5):697-710.
Morphine and fentanyl are frequently used for analgesia after trauma, but there is debate over the advantages and disadvantages of these opioids. Among combat amputees, intravenous (IV) morphine (vs IV fentanyl) after injury was associated with reduced likelihood of posttraumatic stress disorder (PTSD). The previous results were based on military health diagnoses over 2 yr postinjury. The present study followed psychological diagnoses of patients with amputation for 4 yr using military and Department of Veterans Affairs health data. In-theater combat casualty records (n = 145) documented Glasgow Coma Scale (GCS) scores and/or morphine, fentanyl, or no opioid treatment within hours of injury. We found that (1) GCS scores were not significantly associated with PTSD; (2) longitudinal modeling using four (yearly) time points showed significantly reduced odds of PTSD for patients treated with morphine (vs fentanyl) across years (adjusted odds ratio = 0.40; 95% confidence interval = 0.17–0.94); (3) reduced PTSD prevalence for morphine (vs IV fentanyl; morphine = 25%, fentanyl = 59%, p < 0.05) was significant, specifically among patients with traumatic brain injury during the first 2 yr postinjury; and (4) PTSD prevalence, but not other disorders (e.g., mood), increased between year 1 (PTSD = 18%) and years 2 through 4 postinjury (PTSD range = 30%–32%).
- Electrochemical simulation of cocaine metabolism-a step toward predictive toxicology for drugs of abuse. [Journal Article, Research Support, Non-U.S. Gov't]
- Eur J Mass Spectrom (Chichester, Eng) 2014; 20(4):279-85.
Knowledge of the metabolic pathways and biotransformation of the most popular drugs, such as cocaine, amphetamine, morphine and others, is crucial for the elucidation of their possible toxicity and mechanism of action in the human body. In vitro studies on metabolism are mainly based on the incubation of drugs with liver celL homogenate and utilizing Living animals. These methods need to be followed by isolation and detection of metabolic products, which makes these techniques time-consuming and technically demanding. We show here that the oxidative metabolism that occurs in the liver cells and is mainly caused by cytochrome P450 can be successfully mimicked with the electrochemical system [EC] connected on-line with electrospray ionization mass spectrometry. Cocaine was chosen as a model drug for these studies and was analyzed with a previously described system under various conditions using the boron-doped diamond working electrode. The results were compared with the number of metabolites generated by a standard procedure based on the reaction with the rat Liver microsomes. Two electrochemical products of cocaine oxidation were created, of which one was a natural metabolite of cocaine in the human body-norcocaine. The EC provides a promising platform for the screening of the addictive drug phase I metabolism. The metabolites can be directly analyzed by mass spectrometry or collected and separated by Liquid chromatog- raphy. No Liver cell homogenate or microsome is necessary to generate these metabolites, which simplifies separation of the mixtures and reduces time and costs of all experiments.
- Detection of morphine-3-sulfate and morphine-6-sulfate in human urine and plasma, and formation in liver cytosol. [Journal Article]
- Pharmacol Res Perspect 2014 Dec; 2(6):e00071.
Morphine is still the mainstay in treatment of severe pain and is metabolized in the liver mainly by glucuronidation, partly to the pharmacologically active morphine-6-glucuronide (M6G). The sulfation pathway has attracted much less attention but may also form active metabolites. The aim of the present study was to study two sulfate metabolites of morphine in humans. Urine and plasma from newborns, adult heroin addicts, and terminal cancer patients was analyzed for the presence of morphine-3-sulfate (M3S) and morphine-6-sulfate (M6S) by a new liquid chromatography - tandem mass spectrometry (LC-MS/MS) method. In addition, morphine sulfation was studied in vitro in human liver cytosol preparations. M3S was present in urine and plasma from all study groups although at lower concentrations than morphine-3-glucuronide (M3G). The plasma M3S/M3G ratio was 30 times higher in newborns than in adults indicating that the relative sulfation is more important at early stage of life. M6S was measurable in only one plasma sample from a newborn patient, and in one of the urine sample from the drug testing group. The incubation of morphine with liver cytosol extracts resulted in approximately equal rate of formation of both M3S and M6S. In conclusion, sulfation of morphine is catalyzed in human liver but this minor metabolic pathway probably lacks clinical significance. The M6S metabolite is formed at a low rate, making it undetectable in most individuals.