I.v. diclofenac and ketorolac for pain after thoracoscopic surgery.
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We studied intensity of pain, cumulative morphine consumption, ventilatory and renal function, and haemostasis in patients undergoing video-assisted thoracoscopic surgery and receiving a 2-day i.v. infusion of diclofenac, ketorolac or saline. Plasma concentrations of the two NSAID were also measured. The study was randomized, double-blind and placebo-controlled, with 10 patients in each group. Patients experienced mainly moderate pain. Mean consumption of i.v. morphine during the first day after operation was 57 (SEM 11) mg in the placebo group. Diclofenac and ketorolac were equally effective in reducing total morphine consumption (61% and 52%, respectively). Adverse events were similar and minor. Greater variability in plasma concentrations of ketorolac were detected compared with diclofenac. (+info)
Detection of 6-acetylmorphine in vitreous humor and cerebrospinal fluid--comparison with urinary analysis for proving heroin administration in opiate fatalities.
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The concentrations of morphine and 6-acetylmorphine (6-AM) in urine, cerebrospinal fluid (CSF), and vitreous humor (VH) and the morphine concentrations in blood were determined by gas chromatography-mass spectrometry for 29 fatalities after abuse of heroin either alone or in combination with alcohol and other drugs. 6-AM was found above a quantitation limit of 1 ng/mL in urine in 89% of the cases, in CSF in 68% of the cases, and in VH in 75% of the cases. The 6-AM concentrations in CSF (mean, 10 ng/mL) and VH (mean, 17 ng/mL) were in general much smaller than in urine (mean, 170 ng/mL); therefore, the different pharmacokinetic behavior of the fluids is discussed. There is no uniformity between the three fluids with respect to the presence or absence of 6-AM. Therefore, CSF or VH may be used as complementary or alternative materials to urine in order to prove heroin uptake in opiate fatalities. (+info)
GC-MS confirmation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in urine.
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A procedure for the simultaneous confirmation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in urine specimens by gas chromatography-mass spectrometry (GC-MS) is described. After the addition of nalorphine and naltrexone as the two internal standards, the urine is hydrolyzed overnight with beta-glucuronidase from E. coli. The urine is adjusted to pH 9 and extracted with 8% trifluoroethanol in methylene dichloride. After evaporating the organic, the residue is sequentially derivatized with 2% methoxyamine in pyridine, then with propionic anhydride. The ketone groups on hydrocodone, hydromorphone, oxycodone, oxymorphone, and naltrexone are converted to their respective methoximes. Available hydroxyl groups on the O3 and O6 positions are converted to propionic esters. After a brief purification step, the extracts are analyzed by GC-MS using full scan electron impact ionization. Nalorphine is used as the internal standard for codeine, morphine, and 6-acetylmorphine; naltrexone is used as the internal standard for the 6-keto-opioids. The method is linear to 2000 ng/mL for the 6-keto-opioids and to 5000 ng/mL for the others. The limit of quantitation is 25 ng/mL in hydrolyzed urine. Day-to-day precision at 300 and 1500 ng/mL ranged between 6 and 10.9%. The coefficients of variation for 6-acetylmorphine were 12% at both 30 and 150 ng/mL. A list of 38 other basic drugs or metabolites detected by this method is tabulated. (+info)
Comparison of solid-phase extraction and supercritical fluid extraction for the analysis of morphine in whole blood.
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A comparative study of the quantitative determination of morphine in whole blood using solid-phase extraction (SPE) and supercritical fluid extraction (SFE) is described. Comparative studies were made of the two techniques for the extraction of morphine from authentic forensic blood specimens. Quantitative results indicate that morphine levels measured using SPE correspond well to morphine levels produced using SFE. The two techniques are therefore comparable, although SFE is faster and cleaner and extracts may be produced with higher analyte recoveries than with SPE. This paper presents a comparison of the two techniques and the morphine concentrations determined in blood. (+info)
Characterization of the decrease of extracellular striatal dopamine induced by intrastriatal morphine administration.
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The effect of intrastriatally-administered morphine on striatal dopamine (DA) release was studied in freely moving rats. Morphine (1, 10 or 100 microM) was given into the striatum by reversed microdialysis, and concentrations of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were simultaneously measured from the striatal dialysates. Intrastriatally-administered morphine significantly and dose-dependently decreased the extracellular concentration of DA, the concentrations of the acidic DA metabolites were only slightly decreased. The effect of morphine was antagonized by naltrexone (2.25 mg kg(-1), s.c.). Pretreatment with a preferential kappa-opioid receptor antagonist, MR2266 [(-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphane; 1 mg kg(-1), s.c.], had no effect on the decrease of extracellular DA evoked by intrastriatal morphine (100 microM). Intrastriatal administration of the selective micro-opioid receptor agonist [D-Ala2,MePhe4,Gly-ol5] enkephalin (DAMGO; 1 microM), significantly decreased the extracellular concentration of DA in the striatum. When the rats were given morphine repeatedly in increasing doses (10-25 mg kg(-1), s.c.) twice daily for 7 days and withdrawn for 48 h, the decrease of extracellular DA induced by morphine (100 microM) was significantly less than that seen in saline-treated controls. Our results show that besides the well-known stimulatory effect there is a local inhibitory component in the action of morphine on striatal DA release in the terminal regions of nigrostriatal DA neurones. Tolerance develops to this inhibitory effect during repeated morphine treatment. Furthermore, our results suggest that the effect of intrastriatally-administered morphine is mediated by the micro-opioid receptors. (+info)
N-Methyl-D-aspartate receptor antagonists and the development of tolerance to the discriminative stimulus effects of morphine in rats.
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Several reports have indicated that N-methyl-D-aspartate (NMDA) receptor antagonists prevent the development of analgesic tolerance to opiates. Some effects of opiates, such as their discriminative stimulus effects, are known to be more resistant to tolerance induction. In this study, adult male Long-Evans rats were trained to discriminate 3.2 mg/kg of s.c. morphine from water (vehicle) using a standard, two-lever fixed ratio 10 schedule of food reinforcement. Subsequently, repeated morphine treatment (20 mg/kg; 14 days b.i.d.) was administered, which induced tolerance-like rightward shifts in the dose-effect curves for both morphine's discriminative stimulus and response rate-suppressing effects. Withdrawal-induced, response rate reductions indicative of behavioral dependence appeared as well. Separate groups were then treated repeatedly with a combination of morphine or its vehicle and one of the following competitive or noncompetitive NMDA antagonists: dizocilpine (0.1 mg/kg i.p.), 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CPPene; 3 and 5.6 mg/kg i.p.), eliprodil (17.3 mg/kg i.p.), or R(+)-3-amino-1-hydroxy-2-pyrrolidone [(+)-HA-966; 10 mg/kg i.p.]. The development of tolerance to morphine's stimulus effects was attenuated by eliprodil and the higher dose of D-CPPene, but not by dizocilpine, the lower dose of D-CPPene, nor R(+)-3-amino-1-hydroxy-2-pyrrolidone. All antagonists prevented the induction of tolerance to morphine's response rate effects. Dizocilpine and D-CPPene (5.6 mg/kg) appeared to prevent the induction of behavioral dependence as well. NMDA antagonists can prevent tolerance to the discriminative stimulus effects of morphine, and perhaps to its behavioral dependence effects, but their site of action on the NMDA receptor complex confers a different ability to do so. (+info)
Topical opioids in mice: analgesia and reversal of tolerance by a topical N-methyl-D-aspartate antagonist.
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In addition to its central actions, morphine has important peripheral effects. To examine peripheral analgesic mechanisms, we developed a topical opioid paradigm in which the tail was immersed in a dimethyl sulfoxide (DMSO) solution containing various drugs. Alone, DMSO was inactive in the tail-flick assay in mice. DMSO solutions containing morphine and peptides such as [D-Ala2,MePhe4, Gly(ol)5]enkephalin (DAMGO) produced a potent, dose-dependent analgesia with the radiant heat tail-flick assay. The actions of the drugs were local. Analgesia was observed only in regions of the tail exposed to the solution and not in more proximal unexposed portions of the tail. Immersion of the tail in a solution containing either 125I-labeled morphine or 125I-labeled DAMGO revealed no detectable uptake of radioactivity into the brain, spinal cord, or blood. In the tail, radioactivity was limited only to the regions actually immersed in the solutions. The topical drugs potentiated systemic agents, similar to the previously established synergy between peripheral and central sites of action. Local tolerance was rapidly produced by repeated daily exposure of the tail to morphine. Topical morphine tolerance was effectively blocked by the N-methyl-D-aspartate (NMDA) antagonist MK801 given either systemically or topically but not intrathecally. The ability of a topical NMDA antagonist to block local morphine tolerance suggests that peripheral NMDA receptors mediate topical morphine tolerance. Morphine was cross-tolerant to DAMGO, but not to morphine-6beta-glucuronide, implying different mechanisms of action. These observations are significant in the design and use of opioids clinically. (+info)
Impact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.
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CYP2D6 is polymorphically distributed so that in poor metabolizers enzyme activity is missing. The goal of this study was to compare the pharmacokinetics and pharmacodynamics of codeine with and without quinidine between Caucasian and Chinese extensive metabolizers of debrisoquin. Nine Caucasians and eight Chinese subjects received in random, double blind fashion, on two occasions, codeine 120 mg. with placebo or with quinidine 100 mg. Pharmacodynamic effects were determined over 6 h. Codeine-apparent clearance and partial metabolic clearance by O-demethylation were significantly greater in the Caucasian than in the Chinese subjects (1939 +/- 175 ml/min versus 1301 +/- 193 ml/min, p <.03 and 162.7 +/- 36.6 ml/min versus 52.7 +/- 12.7 ml/min, p <.02, respectively). Codeine's respiratory effects (except on resting ventilation) were significantly greater in the Caucasian than in the Chinese subjects (p <.05), but no interethnic differences were noted in codeine's effect on the digit symbol substitution test and pupillary ratio. No morphine or morphine metabolites were detected in plasma when codeine was coadministered with quinidine. Codeine O-demethylation was significantly reduced after quinidine in both ethnic groups; however, the absolute decrease was greater in Caucasians (115.8 +/- 25.9 ml/min versus 46.8 +/- 10.6 ml/min, respectively, p <.03). The diminished production of morphine after quinidine was associated in the Caucasians, but not in the Chinese, with a marked reduction in codeine's effects (p <.01). In conclusion, Chinese produce less morphine from codeine, exhibit reduced sensitivity to that morphine, and therefore might experience reduced analgesic effect in response to codeine. In addition, quinidine induced inhibition of codeine O-demethylation is ethnically dependent with the reduction being greater in Caucasians. (+info)