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Naloxone
Kinds of Naloxone Terms modified by Naloxone Selected AbstractsAbuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusersADDICTION, Issue 4 2010Sandra D. Comer ABSTRACT Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8,9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ,drug liking' and ,desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment. [source] [Commentary] CASE FOR PEER NALOXONE FURTHER STRENGTHENEDADDICTION, Issue 10 2008SIMON LENTON No abstract is available for this article. [source] Leaving Against Medical Advice after Out-of-hospital Naloxone: A Closer Look is NeededACADEMIC EMERGENCY MEDICINE, Issue 3 2004Alberto Perez MD No abstract is available for this article. [source] Overdose training and take-home naloxone for opiate users: prospective cohort study of impact on knowledge and attitudes and subsequent management of overdosesADDICTION, Issue 10 2008John Strang ABSTRACT Aim To examine the impact of training in overdose management and naloxone provision on the knowledge and confidence of current opiate users; and to record subsequent management of overdoses that occur during a 3-month follow-up period. Design Repeated-measures design to examine changes in knowledge and confidence immediately after overdose management training; retention of knowledge and confidence at 3 months; and prospective cohort study design to document actual interventions applied at post-training overdose situations. Method A total of 239 opiate users in treatment completed a pre-training questionnaire on overdose management and naloxone administration and were re-assessed immediately post-training, at which point they were provided with the take-home emergency supply of naloxone. Three months later they were re-interviewed. Results Significant improvements were seen in knowledge of risks of overdose, characteristics of overdose and appropriate actions to be taken; and in confidence in the administration of naloxone. A 78% follow-up rate was achieved (186 of 239) among whom knowledge of both the risks and physical/behavioural characteristics of overdose and also of recommended management actions was well retained. Eighteen overdoses (either experienced or witnessed) had occurred during the 3 months between the training and the follow-up. Naloxone was used on 12 occasions (a trained client's own supply on 10 occasions). One death occurred in one of the six overdoses where naloxone was not used. Where naloxone was used, all 12 resulted in successful reversal. Conclusions With overdose management training, opiate users can be trained to execute appropriate actions to assist the successful reversal of potentially fatal overdose. Wider provision may reduce drug-related deaths further. Future studies should examine whether public policy of wider overdose management training and naloxone provision could reduce the extent of opiate overdose fatalities, particularly at times of recognized increased risk. [source] Protective effects of naloxone in two-hit seizure modelEPILEPSIA, Issue 3 2010Lu Yang Summary Purpose:, Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA),induced two-hit seizure model. Methods:, After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1, [IL-1,], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays. Results:, Naloxone reduced IL-1, synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. Conclusions:, Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood. [source] Phosphodiesterase inhibition by naloxone augments the inotropic actions of ,-adrenergic stimulationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2009W. K. PARK Background: In a shock state, naloxone generates the cardiovascular pressor effect by displacing the endogenous opiate-like peptide ,-endorphin, resulting in restoration of the normal response to catecholamines. In addition to this opioid antagonistic effect, the non-opiate receptor-mediated effect has also been proposed. The aim of this study was to define the mechanism of non-opiate receptor-mediated action of naloxone. Methods: In guinea-pig ventricular tissues, cumulative concentration,response curves for isoproterenol as well as for forskolin and 3-isobutylmethylxanthine (IBMX) were obtained by increasing the concentration stepwise. To assess the effect on the phosphodiesterase (PDE), the effects of naloxone on contractile forces induced by isoproterenol (0.05 ,M) in the presence of IBMX, cilostamide (a PDE III inhibitor), or rolipram (a PDE IV inhibitor) were observed. Naloxone-induced changes in cAMP production by isoproterenol both in the absence and in the presence of IBMX were measured. Naloxone-induced changes in cAMP production by forskolin in the presence of IBMX were also measured. Results: Naloxone (30 ,M) produced a leftward shift of the isoproterenol concentration,response curve (0.01,2 ,M) without changing the maximal response. Forskolin (0.5,10 ,M) produced a concentration-dependent increase in contractile forces. Naloxone increased the maximal inotropic response of forskolin. Naloxone showed no effect on the IBMX concentration,response curve. In the presence of IBMX (200 ,M), naloxone did not alter the contractions evoked by isoproterenol or forskolin. Whereas naloxone increased contractile forces significantly (approximately 25%) more than that of isoproterenol in the presence of rolipram, no alteration of contractile forces in the cilostamide-incubated muscles was observed. Naloxone caused a concentration-related increase of cAMP in the absence of IBMX, but caused no change in its presence. Conclusions: The enhancement of myocardial contractility by naloxone in the presence of stimulation of adenylyl cyclase activity appears to be mediated by inhibition of PDE, specifically PDE III. [source] Effect of Naloxone on Appetitive and Consummatory Phases of Ethanol Self-AdministrationALCOHOLISM, Issue 7 2001Amanda L. Sharpe Background : The opioid system has been implicated in ethanol self-administration. Morphine, an opiate agonist, can sometimes increase the amount of ethanol consumed, and opiate antagonists such as naloxone and naltrexone decrease the amount of ethanol consumed in both animals and humans. The objective of this study was to examine the effect of naloxone on appetitive (or seeking) and consummatory behaviors by using an operant model developed to separate these two phases of self-administration. Methods: Intraperitoneal injections of naloxone (0.3,10 mg/kg) or vehicle were given before operant self-administration sessions to assess the effect on lever pressing (appetitive behavior) and subsequent consumption. Effects were measured in two groups of rats: one self-administered a 3% sucrose solution and the other a 10% ethanol solution. Results: Naloxone dose-dependently decreased ethanol and sucrose consumption by an earlier cessation of drinking in the session compared with vehicle injection days. There were some effects on appetitive responding after treatment with naloxone, but none was statistically significant. Conclusions: Naloxone may decrease ethanol self-administration by decreasing the postingestive or pharmacological effects of alcohol. This model provides a new method for examining the effects of potential pharmacotherapeutics on alcohol self-administration behavior. [source] Naloxone scavenges reactive oxygen speciesACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2006K. Mikawa No abstract is available for this article. [source] Expression and localization of the µ-opioid receptor (MOR) in the equine cumulus,oocyte complex and its involvement in the seasonal regulation of oocyte meiotic competence,MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 8 2008Maria Elena Dell'Aquila Abstract The µ-opioid receptor (MOR) was identified in equine oocytes, cumulus and granulosa cells. By RT-PCR, a 441bp fragment was observed. By immunoblotting, a 65 kDa band was detected in samples of winter anestrous whereas in cells recovered in breeding season, two bands, 65 and 50 kDa, were found. The 65 kDa band was significantly more intense in winter anestrous specimens. In samples recovered in the breeding season, this band significantly decreased with the raise of follicle size and was heavier in compact oocytes and cumulus cells. The protein was localized on the oolemma and within the cytoplasm of oocytes and cumulus cells. In vitro oocyte maturation rate (MR), analyzed by confocal microscopy for nuclear chromatin, microfilaments and microtubules, was reduced after the addition of 3,×,10,8 M ,-endorphin in medium without additional hormones. Inhibitory effects of 10,3 M Naloxone in oocytes collected in anestrous and spring transition were observed, both in presence and absence of hormones added to culture medium. Increased MRs were observed in oocytes collected in anestrous and cultured in presence of 10,8 M Naloxone. The exposure to 10,3 M Naloxone induced significant intracellular calcium increases in cumulus cells recovered all over the year. ,-Endorphin 3,×,10,8 M induced significant calcium increases only in cumulus cells recovered in fall transition and anestrous. Naloxone 10,8 M did not induce intracellular calcium modifications. We conclude that the MOR is differentially expressed in equine cumulus,oocyte complexes in the different seasons of the year and plays a role in the seasonal regulation of meiotic competence of equine oocytes. Mol. Reprod. Dev. 75: 1229,1246, 2008. © 2008 Wiley-Liss, Inc. [source] Effect of crocus sativus L. (saffron) stigma and its constituents, crocin and safranal, on morphine withdrawal syndrome in micePHYTOTHERAPY RESEARCH, Issue 5 2010Hossein Hosseinzadeh Abstract Crocus sativus L. has been shown to interact with the opioid system. Thus, the effects of aqueous and ethanolic extracts of stigma and its constituents were evaluated on morphine-withdrawal syndrome in mice. Dependence was induced using subcutaneous (s.c.) injections of morphine for 3 days. On day 4, morphine was injected 0.5,h prior the interaperitoneal (i.p.) injections of the extracts, crocin, safranal, clonidine (0.3,mg/kg) or normal saline. Naloxone was injected (5,mg/kg i.p.) 2,h after the final dose of morphine and the number of episodes of jumping during 30,mm was considered as the intensity of the withdrawal syndrome. Clonidine, the aqueous and ethanolic extracts of saffron reduced the jumping activity. Safranal was injected (s.c.) 30,mm prior and 1 and 2,h after the injection of morphine. It potentiated some signs of withdrawal syndrome. The aqueous extract decreased the movement in all of the doses (80, 160, 320,mg/kg) and the ethanolic extract decreased it in the dose of 800,mg/kg in open field test. But crocin and the dose of 400,mg/kg ethanolic extract showed no effect on activity in this test. It is concluded that the extracts and crocin may have interaction with the opioid system to reduce withdrawal syndrome. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effect of crocin on the morphine-induced antinociception in the formalin test in ratsPHYTOTHERAPY RESEARCH, Issue 3 2010Esmaeal Tamaddonfard Abstract In this study, the effects of intraperitoneal (i.p.) injection of crocin in the absence and presence of subcutaneous (s.c.) injections of morphine and naloxone were investigated on the formalin test in rats. The formalin test was induced by intra-plantar (i.pl.) injection of formalin (50,,L, 1%), and the time spent licking and biting of the injected paw was measured for 1,h. Formalin induced a marked biphasic (first phase: 0,5,min and second phase: 15,45,min) pain response. Morphine (1,mg/kg, s.c.) significantly (p < 0.05) suppressed both phases of pain. Naloxone (2,mg/kg, s.c.) alone did not change the intensity of pain, but pretreatment with naloxone (2,mg/kg) significantly (p < 0.05) prevented morphine (1,mg/kg)-induced antinociception. Crocin at doses of 50, 100 and 200,mg/kg significantly (p < 0.05) attenuated pain. Crocin (100,mg/kg, i.p.) significantly (p < 0.05) increased the morphine (1,mg/kg, s.c.)-induced antinociception. Naloxone (2,mg/kg) did not reverse the suppressive effect of crocin (100,mg/kg) on pain. Crocin at a dose of 400,mg/kg significantly (p < 0.05) suppressed locomotor activities. These findings indicate that morphine through a naloxone-sensitive mechanism produced analgesia. Crocin produced a dose-dependent antinociceptive effect. In addition, crocin increased morphine-induced antinociception, but naloxone did not change the antinociceptive effect of crocin. Copyright © 2009 John Wiley & Sons, Ltd. [source] Black cumin seed essential oil, as a potent analgesic and antiin,ammatory drugPHYTOTHERAPY RESEARCH, Issue 3 2004Valiollah Hajhashemi Abstract The steam-distilled essential oil of Iranian black cumin seed (Nigella sativa L.) was investigated for its composition and analgesic and antiin,ammatory properties. After oil analysis by GC/MS, 20 compounds were identi,ed in the oil, obtained in 0.4% (v/w) yield. Among them, para -cymene (37.3%) and thymoquinone (13.7%) were the major components. Acetic acid-induced writhing, formalin and light tail ,ick tests were used for assessment of analgesic activity. Antiin,ammatory activity was evaluated using carrageenan-induced paw oedema in rats and croton oil-induced ear oedema in mice. Black cumin seed essential oil (BCSEO) was found to produce a signi,cant analgesic effect in acetic acid-induced writhing, formalin and light tail ,ick tests. Naloxone, an opioid antagonist, could not reverse the analgesic effect observed in the formalin test. Although oral administration of BCSEO at doses of 100, 200 and 400 µL/kg did not exert a signi,cant antiin,ammatory effect in the carrageenan test, i.p. injection of the same doses signi,cantly (p < 0.001) inhibited carrageenan-induced paw oedema. BCSEO at doses of 10 and 20 µL/ear could also reduce croton oil-induced oedema. It seems that mechanism(s) other than opioid receptors is (are) involved in the analgesic effect of BCSEO since naloxone could not reverse this effect. Both systemic and local administration of BCSEO showed antiin,ammatory activity. Thymoquinone, as one of the major components of BCSEO, probably has an important role in these pharmacological effects. Copyright © 2004 John Wiley & Sons, Ltd. [source] Control of non-adrenergic non-cholinergic reflex motor responses in circular muscle of guinea-pig small intestine by Met-enkephalinAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2002Chr. Ivancheva Summary 1 A triple organ bath method allowing the synchronous recording of the motor activity of the circular muscle layer belonging to the oral and anal segments of guinea-pig small intestine adjacent to an electrically stimulated middle segment was developed to study the ascending and descending reflex motor responses. 2 Electrical field stimulation (0.8 ms, 40 V, 5 Hz, 10 s) applied to the middle part of the segments elicited tetrodotoxin (1 ,m)-sensitive ascending and descending contractile responses of the nonstimulated parts, oral and anal, respectively. The ascending contraction was more pronounced as compared with the descending contraction. 3 In the presence of phentolamine (5 ,m), propranolol (5 ,m) and atropine (3 ,m) a significant decrease in the amplitude of the ascending contraction was seen and a descending relaxation, instead of a contraction was observed. 4 Met-enkephalin applied at a single concentration (0.1 ,m) or cumulatively (0.001,1 ,m) inhibited both non-adrenergic non-cholinergic (NANC) descending relaxation and ascending contraction with similar efficacy but different potency, IC50 being 5.9 ± 0.3 and 39.0 ± 4 nm, respectively. Naloxone (0.5 ,m) prevented the effects of Met-enkephalin. 5 L-NNA (0.5 mm), an inhibitor of nitric oxide synthesis, increased the ascending contraction and strongly reduced but not abolished the descending relaxation. l -Arginine (0.5 mm) restored the motor responses to the initial level in l -NNA-pretreated preparations, d -Arginine (0.5 nm) had no effects. 6 Met-enkephalin (0.1 ,m) depressed the l -NNA-dependent increase of the ascending contraction and failed to change the l -NNA-resistant part of the descending relaxation. 7 Met-enkephalin did not alter spontaneous NANC mechanical activity. SNP (1 or 10 ,m), an exogenous donor of nitric oxide, caused a concentration-dependent relaxation. The effects of SNP persisted in Met-enkephalin (0.1 ,m)-pretreated preparations. 8 NANC reflex ascending contraction and descending relaxation were synchronously induced by a local nerve stimulation indicating a functional coactivation of NANC orally projected excitatory and anally directed inhibitory pathways. Acting prejunctionally, Met-enkephalin provided a negative controlling mechanism inhibiting both ascending and descending, mainly nitric oxide mediated, reflex responses. A higher sensitivity of the descending relaxation to Met-enkephalin was observed suggesting an essential role of opioid(s) in reducing the efficacy of descending motor activity. [source] Involvement of an influx transporter in the blood,brain barrier transport of naloxoneBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2010Toyofumi Suzuki Abstract Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood,brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [3H]naloxone exhibited saturability in a concentration-dependent manner (concentration range 0.5,µM to 15,mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier-mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, Kt, was 2.99±0.71,mM; the maximum uptake rate, Jmax, was 0.477±0.083,µmol/min/g brain; and the nonsaturable first-order rate constant, Kd, was 0.160±0.044,ml/min/g brain. The uptake of [3H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H1 -antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [3H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L -carnitine or substrates for organic anion transport systems such as p -aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH-dependent and saturable influx transport system that is a selective transporter for cationic H1 -antagonists is involved in the BBB transport of naloxone in the rat. Copyright © 2010 John Wiley & Sons, Ltd. [source] Effects of endomorphin on substantia gelatinosa neurons in rat spinal cord slicesBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2003Su-Ying Wu Whole-cell patch recordings were made from substantia gelatinosa (SG) neurons in transverse lumbar spinal cord slices of 15- to 30-day-old rats. Endomorphin 1 (EM-1) or EM-2 (10 ,M) hyperpolarized or induced an outward current in 26 of the 66 SG neurons. The I,V relationship showed that the peptide activates an inwardly rectifying K+ current. EM-1 or EM-2 (0.3,10 ,M) suppressed short-latency excitatory postsynaptic currents (EPSCs) and long-latency inhibitory postsynaptic currents (IPSCs) in nearly all SG neurons tested or short-latency IPSCs in six of the 10 SG neurons. [Met5] enkephalin or [D -Ala2, N -Me-Phe4, Gly5 -ol]-enkephalin (DAMGO) (1,10 ,M) depressed EPSCs and IPSCs. EM-1 or EM-2 depressed synaptic responses without causing a significant change in holding currents or inward currents induced by glutamate. Glutamate also evoked a short-latency outward current in five SG neurons or a biphasic current in two neurons; the outward current was blocked by tetrodotoxin (TTX, 0.3 ,M) or bicuculline (10 ,M). EM-1 or DAMGO (1 or 5 ,M) attenuated the glutamate-evoked outward or biphasic currents in four of the seven SG neurons. EM-1 (1 ,M) reduced the frequency, but not the amplitude of miniature EPSCs or miniature IPSCs. Naloxone (1 ,M) or the selective , -opioid receptor antagonist , -funaltrexamine (, -FNA, 25 ,M) antagonized the action of EM; EM-induced hyperpolarizations persisted in the presence of the , -opioid receptor antagonist (nor-binaltorphimine dihydrochloride, 1 ,M) and/or , -opioid receptor antagonist (naltrindole hydrochloride, 1 ,M). It may be concluded that EM acting on , -opioid receptors hyperpolarizes a population of SG neurons by activating an inwardly rectifying K+ current, and attenuates excitatory and inhibitory synaptic currents evoked in a population of SG neurons, probably by a presynaptic site of action. British Journal of Pharmacology (2003) 140, 1088,1096. doi:10.1038/sj.bjp.0705534 [source] Spinal administration of lipoxygenase inhibitors suppresses behavioural and neurochemical manifestations of naloxone-precipitated opioid withdrawalBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003Tuan Trang This study investigated the role of spinal lipoxygenase (LOX) products in the induction and expression of opioid physical dependence using behavioural assessment of withdrawal and immunostaining for CGRP and Fos protein expression in the spinal cord. Administration of escalating doses (5,50 mg kg,1; i.p.) of morphine for 5 days markedly elevated CGRP-like immunoreactivity in the dorsal horn of the rat spinal cord. Naloxone (2 mg kg,1; i.p.) challenge precipitated a robust withdrawal syndrome that depleted CGRP-like immunoreactivity and increased the number of Fos-like immunoreactive neurons in the dorsal horn. Intrathecal administration of NDGA (10, 20 ,g), a nonselective LOX inhibitor, AA-861 (1.5, 3 ,g), a 5-LOX selective inhibitor, or baicalein (1.4, 2.8 ,g), a 12-LOX selective inhibitor, concurrently with systemic morphine for 5 days or as a single injection immediately preceding naloxone challenge, blocked the depletion of CGRP-like immunoreactivity, prevented increase in the number of Fos-like immunoreactive neurons in the dorsal horn, and significantly attenuated the morphine withdrawal syndrome. The results of this study suggest that activity of LOX products, at the spinal level, contributes to the expression of opioid physical dependence, and that this activity may be expressed through increased sensory neuropeptide release. British Journal of Pharmacology (2003) 140, 295,304. doi:10.1038/sj.bjp.0705440 [source] Safe reduction in administration of naloxone to newborn infants: An observational studyACTA PAEDIATRICA, Issue 9 2006Deborah Box Abstract Background: Naloxone, a specific opiate antagonist, is widely used during neonatal resuscitation to reverse possible opiate-induced respiratory depression. Aim: To determine the frequency with which naloxone is administered when resuscitation guidelines are conscientiously followed and to document any effect on respiratory morbidity. Methods: Perinatal data including naloxone administration and respiratory morbidity were collected retrospectively, and compared with prospectively collected data following the introduction of "Good Practice" guidelines. Results: There were 500 deliveries in the retrospective arm of the study and 1000 deliveries in the prospective arm. Although a similar proportion of women received opiates in labour in the two periods of study, there was a marked reduction in the use of naloxone when the guidelines were introduced (11% of opiate-exposed deliveries compared to 0.2%). There was no significant effect on respiratory morbidity with the change in practice. Conclusion: Naloxone is rarely needed to reverse the effects of opiates in newborn infants, and its use can be curtailed by following current resuscitation guidelines without increasing respiratory morbidity. [source] Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusersADDICTION, Issue 4 2010Sandra D. Comer ABSTRACT Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8,9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ,drug liking' and ,desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment. [source] Latest news and product developmentsPRESCRIBER, Issue 7 2007Article first published online: 11 JUL 200 Poor asthma control with off-licence prescribing Children who are prescribed off-licence medications are more likely to have poor asthma control, according to an analysis from Dundee (Br J Gen Practice 2007;57:220-2). The review of 17 163 consultations identified 1050 (6.1 per cent) who received a prescription for an unlicensed use (defined as not licensed for children or the particular age group, or dose not licensed). High doses (4.5 per cent) were more frequent than unlicensed indications (1.9 per cent). Children who received off-label prescriptions reported statistically significantly more symptoms in the day or night, symptoms during activity, and increased use of daily short-acting beta2-agonists. The authors note that off-label prescribing appears to be increasing. Atkins diet most effective over one year? The ultra low-carbohydrate, high-protein Atkins diet achieved greater weight loss than other popular diets in overweight women over one year, say US investigators (J Am Med Assoc 2007;297:969-77). The study compared the Atkins diet with three diets designed as low- or very high-carbohydrate, or based on USA nutritional guidance, in 311 women with body mass index 27-40. After one year, mean weight loss was 4.7kg with the Atkins diet , significantly greater than with the low- carbohydrate diet (1.6kg) but not compared with very high-carbohydrate (2.2kg) or the nutrition-based diet (2.6kg). Metabolic endpoints were comparable or more favourable in women using the Atkins diet. Androgen therapy linked to gum disease The majority of men treated with androgen deprivation therapy for prostate cancer are more likely to have periodontal disease (J Urol 2007;177:921-4). After controlling for risk factors, the prevalence of periodontal disease was 80.5 per cent among treated men compared with 3.7 per cent in matched controls not receiving treatment. There was no difference in bone mineral density between the groups but plaque scores were significantly higher among treated men. Food Commission rebuts MHRA on additives An independent watchdog has not accepted the MHRA's justification for including certain additives in medicines for children. The Food Commission (www.foodcomm.org.uk) found that most medicines for children contained additives, some of which , including azo dyes and benzoates , are not permitted in food. The Commission called on the pharmaceutical industry to stop using ,questionable additives'. The MHRA stated that the licensing process takes into account the likely exposure to excipients that are considered essential to make medicines palatable to children. Colouring helps children to identify the correct medicine, and preservatives ensure a reasonable shelf-life. A list of additives is included in the product's summary of product characteristics and patient information leaflet. In response, the Commission states: , , it is quite possible to flavour medicines with natural oils or extracts, and natural colourings such as beetroot and beta-carotene can be used instead of azo dyes. If parents were advised to give these medicinal products at mealtimes the manufacturers could also add a little sugar to sweeten their products, rather than relying on artificial sweeteners.' All triptans the same? There is no economic case for choosing one triptan over another and no evidence for preferring a particular triptan for adults, a systematic review has concluded. The Canadian Agency for Drugs and Technologies in Health (www.cadth.ca) found that published trials had compared most triptans with sumatriptan but not with one another, and most economic evaluations were flawed. New drug for HIV Janssen-Cilag has introduced darunavir (Prezista), a new protease inhibitor for the treatment of HIV infection. Licensed for highly pre- treated patients in whom more than one other pro- tease inhibitor regimen has failed, darunavir must be co-administered with ritonavir (Norvir). A month's treatment at the recommended dose of 600mg twice daily costs £446.70. Variation in liquid captopril for children The NHS uses a wide range of liquid formulations of captopril to treat children with heart failure , with no assurance of their bioequivalence (Arch Dis Child 2007; published online 15 March. doi: 10.1136/adc.2006.109389). Specialists in Leicester surveyed 13 tertiary paediatric cardiac centres and 13 hospitals that referred patients to them. Only three tertiary centres supplied the same liquid for-mulation of captopril as their referring hospitals. Four hospitals supplied tablets for crushing and dissolving in water; the other hospitals and centres used a total of nine different formulations. The authors say the formulations had widely varying shelf-lives, determined empirically in all but one case, and were used interchangeably despite a lack of quality control data to establish their bioequivalence. QOF CVD targets not good enough for GPs Two-thirds of GPs want Quality Outcome Framework (QOF) targets for cardiovascular disease brought into line with those of the Joint British Societies latest guidance (JBS2), according to a survey by doctor.net.uk. The survey of 1000 GPs showed that 88 per cent were aware of the JBS2 guidelines and most were already implementing the targets for lipids, blood pressure and blood glucose in some form; however, only 55 per cent were implementing the JBS2 obesity target and 14 per cent were implementing screening for the over-40s. The JBS2 target for lipids in at-risk patients is <4mmol per litre total cholesterol and <2 mmol per litre LDL-cholesterol, compared with <5 and <3mmol per litre respectively in QOF and the NSF. The survey was commissioned by Merck Sharp & Dohme and Schering- Plough. Fracture warning Following warnings in the US that rosiglitazone (Avandia) is associated with an increased risk of fractures in women, Takeda has advised prescribers that pioglitazone (Actos) carries a similar risk. An analysis of the company's clinical trials database has revealed an excess risk of fractures of bones below the elbow and knee. The incidence was similar to the excess risk associated with rosiglitazone and also confined to women. Scottish approvals The Scottish Medicines Consortium (www.scottish medicines.org.uk) has approved for use within NHS Scotland the sublingual tablet formulation buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. It has also approved the combined formulation of valsartan and amlodipine (Exforge) and the restricted use of the If inhibitor ivabradine (Procoralan). [source] The Effectiveness of Combined Naloxone/Lofexidine in Opiate Detoxification: Results from a Double-blind Randomized and Placebo-controlled TrialTHE AMERICAN JOURNAL ON ADDICTIONS, Issue 4 2003Tracy Beswick BSc. The efficacy of lofexidine/naloxone was compared with lofexidine/placebo in a double-blind, randomized, placebo-controlled trial in 89 opiate-dependent patients. There were no significant differences between the two groups in the proportion of patients completing detoxification or in the length of stay. Patients in the active naloxone group demonstrated gradual reductions in levels of withdrawal and craving over the detoxification period. At completion of detoxification, patients who received naloxone maintained a level of withdrawal consistently lower than that in the placebo group; however, naloxone did not substantially accelerate the resolution of the withdrawal syndrome. Implications for future research are discussed. [source] G,, that interacts with adenylyl cyclase in opioid tolerance originates from a Gs proteinDEVELOPMENTAL NEUROBIOLOGY, Issue 12 2006Hoau-Yan Wang Abstract We previously demonstrated that chronic morphine induces a change in G protein coupling by the mu opioid receptor (MOR) from Gi/o to Gs, concurrent with the instatement of an interaction between G,, and adenylyl cyclase types II and IV. These two signaling changes confer excitatory effects on the cell in place of the typical inhibition by opioids and are associated with morphine tolerance and dependence. Both signaling changes and these behavioral manifestations of chronic morphine are attenuated by cotreatment with ultra-low-dose naloxone. In the present work, using striatum from chronic morphine-treated rats, we isotyped the G, within Gs and Go heterotrimers that coupled to MOR and compared these to the G, isotype of the G,, that interacted with adenylyl cyclase II or IV after chronic morphine treatment. Isotyping results show that chronic morphine causes a Gs heterotrimer associated with MOR to release its G,, to interact with adenylyl cyclase. These data suggest that the switch to Gs coupling by MOR in response to chronic morphine, which is attenuated by ultra-low-dose opioid antagonist cotreatment, leads to a two-pronged stimulation of adenylyl cyclase utilizing both G, and G,, subunits of the Gs protein novel to this receptor. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Cost-effectiveness of extended buprenorphine,naloxone treatment for opioid-dependent youth: data from a randomized trialADDICTION, Issue 9 2010Daniel Polsky ABSTRACT Aims The objective is to estimate cost, net social cost and cost-effectiveness in a clinical trial of extended buprenorphine,naloxone (BUP) treatment versus brief detoxification treatment in opioid-dependent youth. Design Economic evaluation of a clinical trial conducted at six community out-patient treatment programs from July 2003 to December 2006, who were randomized to 12 weeks of BUP or a 14-day taper (DETOX). BUP patients were prescribed up to 24 mg per day for 9 weeks and then tapered to zero at the end of week 12. DETOX patients were prescribed up to 14 mg per day and then tapered to zero on day 14. All were offered twice-weekly drug counseling. Participants 152 patients aged 15,21 years. Measurements Data were collected prospectively during the 12-week treatment and at follow-up interviews at months 6, 9 and 12. Findings The 12-week out-patient study treatment cost was $1514 (P < 0.001) higher for BUP relative to DETOX. One-year total direct medical cost was only $83 higher for BUP (P = 0.97). The cost-effectiveness ratio of BUP relative to DETOX was $1376 in terms of 1-year direct medical cost per quality-adjusted life year (QALY) and $25 049 in terms of out-patient treatment program cost per QALY. The acceptability curve suggests that the cost-effectiveness ratio of BUP relative to DETOX has an 86% chance of being accepted as cost-effective for a threshold of $100 000 per QALY. Conclusions Extended BUP treatment relative to brief detoxification is cost effective in the US health-care system for the outpatient treatment of opioid-dependent youth. [source] Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusersADDICTION, Issue 4 2010Sandra D. Comer ABSTRACT Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8,9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ,drug liking' and ,desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment. [source] Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdoseADDICTION, Issue 12 2009Debra Kerr ABSTRACT Aims Traditionally, the opiate antagonist naloxone has been administered parenterally; however, intranasal (i.n.) administration has the potential to reduce the risk of needlestick injury. This is important when working with populations known to have a high prevalence of blood-borne viruses. Preliminary research suggests that i.n. administration might be effective, but suboptimal naloxone solutions were used. This study compared the effectiveness of concentrated (2 mg/ml) i.n. naloxone to intramuscular (i.m.) naloxone for suspected opiate overdose. Methods This randomized controlled trial included patients treated for suspected opiate overdose in the pre-hospital setting. Patients received 2 mg of either i.n. or i.m. naloxone. The primary outcome was the proportion of patients who responded within 10 minutes of naloxone treatment. Secondary outcomes included time to adequate response and requirement for supplementary naloxone. Data were analysed using multivariate statistical techniques. Results A total of 172 patients were enrolled into the study. Median age was 29 years and 74% were male. Rates of response within 10 minutes were similar: i.n. naloxone (60/83, 72.3%) compared with i.m. naloxone (69/89, 77.5%) [difference: ,5.2%, 95% confidence interval (CI) ,18.2 to 7.7]. No difference was observed in mean response time (i.n.: 8.0, i.m.: 7.9 minutes; difference 0.1, 95% CI ,1.3 to 1.5). Supplementary naloxone was administered to fewer patients who received i.m. naloxone (i.n.: 18.1%; i.m.: 4.5%) (difference: 13.6%, 95% CI 4.2,22.9). Conclusions Concentrated intranasal naloxone reversed heroin overdose successfully in 82% of patients. Time to adequate response was the same for both routes, suggesting that the i.n. route of administration is of similar effectiveness to the i.m. route as a first-line treatment for heroin overdose. [source] Doing harm reduction better: syringe exchange in the United StatesADDICTION, Issue 9 2009Don C. Des Jarlais ABSTRACT Objective To trace the growth of syringe exchange programs (SEPs) in the United States since 1994,95 and assess the current state of SEPs. Methods Annual surveys of US SEPs known to North American Syringe Exchange Network (NASEN). Surveys mailed to executive directors with follow-up interviews by telephone and/or e-mail. Response rates have varied between 70% and 88% since surveys were initiated in 1996. Results The numbers of programs known to NASEN have increased from 68 in 1994,95 to 186 in 2007. Among programs participating in the survey, numbers of syringes exchanged have increased from 8.0 million per year to 29.5 million per year, total annual budgets have increased from $6.3 to $19.6 million and public funding (from state and local governments) has increased from $3.9 to $14.4 million. In 2007, 89% of programs permitted secondary exchange and 76% encouraged it. Condoms, referrals to substance abuse treatment, human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV) counseling and testing and naloxone for overdose were among the most commonly provided services in addition to basic syringe exchange. Each of these services was provided by 40% or more of SEPs in 2007. Conclusions While syringe exchange has remained controversial in the United States, there has been very substantial growth in numbers of programs, syringes exchange and program budgets. Utilizing secondary exchange to reach large numbers of injecting drug users and utilizing SEPs as a new platform for providing health and social services beyond basic syringe exchange have been the two major organizational strategies in the growth of SEPs in the United States. [source] Overdose training and take-home naloxone for opiate users: prospective cohort study of impact on knowledge and attitudes and subsequent management of overdosesADDICTION, Issue 10 2008John Strang ABSTRACT Aim To examine the impact of training in overdose management and naloxone provision on the knowledge and confidence of current opiate users; and to record subsequent management of overdoses that occur during a 3-month follow-up period. Design Repeated-measures design to examine changes in knowledge and confidence immediately after overdose management training; retention of knowledge and confidence at 3 months; and prospective cohort study design to document actual interventions applied at post-training overdose situations. Method A total of 239 opiate users in treatment completed a pre-training questionnaire on overdose management and naloxone administration and were re-assessed immediately post-training, at which point they were provided with the take-home emergency supply of naloxone. Three months later they were re-interviewed. Results Significant improvements were seen in knowledge of risks of overdose, characteristics of overdose and appropriate actions to be taken; and in confidence in the administration of naloxone. A 78% follow-up rate was achieved (186 of 239) among whom knowledge of both the risks and physical/behavioural characteristics of overdose and also of recommended management actions was well retained. Eighteen overdoses (either experienced or witnessed) had occurred during the 3 months between the training and the follow-up. Naloxone was used on 12 occasions (a trained client's own supply on 10 occasions). One death occurred in one of the six overdoses where naloxone was not used. Where naloxone was used, all 12 resulted in successful reversal. Conclusions With overdose management training, opiate users can be trained to execute appropriate actions to assist the successful reversal of potentially fatal overdose. Wider provision may reduce drug-related deaths further. Future studies should examine whether public policy of wider overdose management training and naloxone provision could reduce the extent of opiate overdose fatalities, particularly at times of recognized increased risk. [source] Changes in Canadian heroin supply coinciding with the Australian heroin shortageADDICTION, Issue 5 2006Evan Wood ABSTRACT Aims Previous studies have largely attributed the Australian heroin shortage to increases in local law enforcement efforts. Because western Canada receives heroin from similar source nations, but has not measurably increased enforcement practices or funding levels, we sought to examine trends in Canadian heroin-related indices before and after the Australian heroin shortage, which began in approximately January 2001. Methods During periods before and after January 2001, we examined the number of fatal overdoses and ambulance responses to heroin-related overdoses that required the use of naloxone in British Columbia, Canada. As an overall marker of Canadian supply reduction, we also examined the quantity of heroin seized during this period. Lastly, we examined trends in daily heroin use among injection drug users enrolled in the Vancouver Injection Drug Users Study (VIDUS). Results There was a 35% reduction in overdose deaths, from an annual average of 297 deaths during the years 1998,2000 in comparison to an average of 192 deaths during 2001,03. Similarly, use of naloxone declined 45% in the period coinciding with the Australian heroin shortage. Interestingly, the weight of Canadian heroin seized declined 64% coinciding with the Australian heroin shortage, from an average of 184 kg during 1998,2000 to 67 kg on average during 2001,03. Among 1587 VIDUS participants, the period coinciding with the Australian heroin shortage was associated independently with reduced daily injection of heroin [adjusted odds ratio: 0.55 (95% CI: 0.50,0.61); P < 0.001]. Conclusions Massive decreases in three independent markers of heroin use have been observed in western Canada coinciding with the Australian heroin shortage, despite no increases in funding to Canadian enforcement efforts. Markedly reduced Canadian seizure activity also coincided with the Australian heroin shortage. These findings suggest that external global heroin supply forces deserve greater investigation and credence as a potential explanation for the Australian heroin shortage. [source] Protective effects of naloxone in two-hit seizure modelEPILEPSIA, Issue 3 2010Lu Yang Summary Purpose:, Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA),induced two-hit seizure model. Methods:, After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1, [IL-1,], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays. Results:, Naloxone reduced IL-1, synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. Conclusions:, Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood. [source] PRECLINICAL STUDY: Is withdrawal hyperalgesia in morphine-dependent mice a direct effect of a low concentration of the residual drug?ADDICTION BIOLOGY, Issue 4 2009Vardit Rubovitch ABSTRACT Withdrawal of opioid drugs leads to a cluster of unpleasant symptoms in dependent subjects. These symptoms are stimulatory in nature and oppose the acute, inhibitory effects of opiates. The conventional theory that explains the opioid withdrawal syndrome assumes that chronic usage of opioid drugs activates compensatory mechanisms whose stimulatory effects are revealed upon elimination of the inhibitory opioid drug from the body. Based on previous studies that show a dose-dependent dual activity of opiates, including pain perception, we present here an alternative explanation to the phenomenon of withdrawal-induced hyperalgesia. According to this explanation, the residual low concentration of the drug that remains after cessation of its administration elicits the stimulatory withdrawal hyperalgesia. The goal of the present study was to test this hypothesis. In the present study we rendered mice dependent on morphine by a daily administration of the drug. Cessation of morphine application elicited withdrawal hyperalgesia that was completely blocked by a high dose of the opiate antagonist naloxone (100 mg/kg). Similarly, naloxone (2 mg/kg)-induced withdrawal hyperalgesia was also blocked by 100 mg/kg of naloxone. The blockage of withdrawal hyperalgesia by naloxone suggested the involvement of opioid receptors in the phenomenon and indicated that withdrawal hyperalgesia is a direct effect of a residual, low concentration of morphine. Acute experiments that show morphine- and naloxone-induced hyperalgesia further verified our hypothesis. Our findings offer a novel, alternative approach to opiate detoxifications that may prevent withdrawal symptoms by a complete blockage of the opioid receptors using a high dose of the opioid antagonist. [source] A test of the opponent-process theory of motivation using lesions that selectively block morphine rewardEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Hector Vargas-Perez Abstract The opponent-process theory of motivation postulates that motivational stimuli activate a rewarding process that is followed by an opposed aversive process in a homeostatic control mechanism. Thus, an acute injection of morphine in nondependent animals should evoke an acute rewarding response, followed by a later aversive response. Indeed, the tegmental pedunculopontine nucleus (TPP) mediates the rewarding effects of opiates in previously morphine-naive animals, but not other unconditioned effects of opiates, or learning ability. The aversive opponent process for acute morphine reward was revealed using a place-conditioning paradigm. The conditioned place aversion induced by 16-h spontaneous morphine withdrawal from an acute morphine injection in nondependent rats was abolished by TPP lesions performed prior to drug experience. However, TPP-lesioned rats did show conditioned aversions for an environment paired with the acute administration of the opioid antagonist naloxone, which blocks endogenous opioids. The results show that blocking the rewarding effects of morphine with TPP lesions also blocked the opponent aversive effects of acute morphine withdrawal in nondependent animals. Thus, this spontaneous withdrawal aversion (the opponent process) is induced by the acute rewarding effects of morphine and not by other unconditioned effects of morphine, the pharmacological effects of morphine or endogenous opioids being displaced from opiate receptors. [source] | ||||||||||||||||||||||||||||||||||