Home About us Contact | |||
Opioids
Kinds of Opioids Terms modified by Opioids Selected AbstractsRisk factors for drug dependence among out-patients on opioid therapy in a large US health-care systemADDICTION, Issue 10 2010Joseph A. Boscarino ABSTRACT Aims Our study sought to assess the prevalence of and risk factors for opioid drug dependence among out-patients on long-term opioid therapy in a large health-care system. Methods Using electronic health records, we identified out-patients receiving 4+ physician orders for opioid therapy in the past 12 months for non-cancer pain within a large US health-care system. We completed diagnostic interviews with 705 of these patients to identify opioid use disorders and assess risk factors. Results Preliminary analyses suggested that current opioid dependence might be as high as 26% [95% confidence interval (CI) = 22.0,29.9] among the patients studied. Logistic regressions indicated that current dependence was associated with variables often in the medical record, including age <65 [odds ratio (OR) = 2.33, P = 0.001], opioid abuse history (OR = 3.81, P < 0.001), high dependence severity (OR = 1.85, P = 0.001), major depression (OR = 1.29, P = 0.022) and psychotropic medication use (OR = 1.73, P = 0.006). Four variables combined (age, depression, psychotropic medications and pain impairment) predicted increased risk for current dependence, compared to those without these factors (OR = 8.01, P < 0.001). Knowing that the patient also had a history of severe dependence and opioid abuse increased this risk substantially (OR = 56.36, P < 0.001). Conclusion Opioid misuse and dependence among prescription opioid patients in the United States may be higher than expected. A small number of factors, many documented in the medical record, predicted opioid dependence among the out-patients studied. These preliminary findings should be useful in future research efforts. [source] Lipopolysaccharide Inhibits Luteinizing Hormone Release Through Interaction with Opioid and Excitatory Amino Acid Inputs to Gonadotropin-Releasing Hormone Neurones in Female Rats: Possible Evidence for a Common Mechanism Involved in Infection and Immobilization StressJOURNAL OF NEUROENDOCRINOLOGY, Issue 6 2003D. He Abstract Acute immobilization stress suppresses naloxone- and N -methyl- d -aspartate (NMDA)-induced, but not gonadotropin-releasing hormone (GnRH)-induced, luteinizing hormone (LH) release in ovariectomized oestrogen-primed rats. To explore whether a common mechanism may underlie inhibition of gonadotropin secretion by various stressors, we examined in the present study the effect of lipopolysaccharide (LPS) on LH release induced by progesterone, GnRH, naloxone and NMDA. The effect of LPS on Fos expression in GnRH neurones was also examined in association with its effect on steroid-induced LH release. Injection of progesterone (1 mg/rat) at noon induced an LH surge in the afternoon in ovariectomized rats pretreated with oestradiol benzoate. In these rats, the majority of hypothalamic GnRH neurones expressed Fos in the evening. Intravenous (i.v.) administration of LPS (10 µg/rat) inhibited steroid-induced LH release and also reduced the Fos expression in GnRH neurones. In separate experiments, an i.v. injection of GnRH (50 ng/kg), naloxone (10 mg/kg) or NMDA (20 mg/kg) significantly elevated serum LH concentrations within 10 min. Pretreatment with LPS, which did not affect basal LH release or GnRH-induced LH release, inhibited naloxone-induced and NMDA-induced LH release. These results show that LPS has a suprapituitary site(s) of action to suppress the activity of GnRH neurones in female rats, and suggest that LPS affects the opioid, as well as the excitatory amino acidergic regulation of GnRH neurones. The similarity of effects of LPS and immobilization stress further suggests that a common mechanism is involved in inhibition of GnRH neurones by different stressors. [source] Neural Circuits Regulating Pulsatile Luteinizing Hormone Release in the Female Guinea-Pig: Opioid, Adrenergic and Serotonergic InteractionsJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2001A. C. Gore Abstract We studied three neurotransmitters involved in the regulation of pulsatile luteinizing hormone (LH) release: opioid peptides, serotonin and norepinephrine, using the ovariectomized guinea-pig. This is an attractive animal model due to the regularity of its LH pulses, enabling any disruptions to be clearly ascertained. In all experiments, a specific agonist or antagonist was administered, either alone or serially to enable detection of interactions, and effects on mean LH concentrations, pulse amplitude and interpulse interval were determined by PULSAR analysis. In the ovariectomized guinea-pig, catecholamines are stimulatory (acting through the ,1 and ,2 but not , receptors, unlike other species), opioids inhibitory and serotonin permissively stimulatory to pulsatile LH release. Stimulatory effects of the opiate antagonist were not blocked by pretreatment with an ,1 - or ,2 -adrenergic antagonist. Similarly, pretreatment with the opiate antagonist did not prevent the suppression of LH release by ,1 and ,2 antagonists. This suggests that, in the guinea-pig, effects of opiates and catecholamines on LH release are exerted by independent pathways to luteinizing hormone releasing hormone (LHRH) neurones. For the opiate,serotonin interactions, pretreatment with the serotonergic antagonist did not block the stimulatory effect of the opiate antagonist on LH release. However, pretreatment with the opiate agonist could not be overcome by the serotonergic agonist. This suggests that the effects of the serotonin system on LHRH release may be indirectly mediated by opioid neurones. Taken together, these studies demonstrate that the three neurotransmitter systems studied are critically involved in normal pulsatile LH release in the female guinea-pig, and demonstrate novel functional relationships between the opioid and the adrenergic and serotonergic systems. [source] Opioid-Based Multimodal Care of Patients with Chronic Pain: Improving Effectiveness and Mitigating RisksPAIN MEDICINE, Issue S2 2009Scott Fishman MD First page of article [source] Synergistic Interactions Between a KCNQ Channel Opener and an Opioid: Flupirtine and Morphine in Rat Pain Models Including Neuropathic PainPAIN MEDICINE, Issue 7 2007C Goodchild Purpose of the study:, Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ 2,3 potassium channel opener. These experiments were performed to see if this property could be useful in treating more severe pain states characterised by central sensitisation with the drug either given alone or in combination with morphine. Methods:, Experiments were performed in rats in an observer blinded fashion with vehicle controls. Non sedating doses of flupirtine, morphine and combinations containing both drugs were defined using the rotarod technique. Dose response relationships were determined for non sedating doses of both drugs given alone and together in combination in causing antinociception in three nociception paradigms: electrical pain; carrageenan paw inflammation; streptozotocin-induced diabetic neuropathy. Results:, Flupirtine and morphine when given alone caused slight to moderate antinociception in all three paradigms. Flupirtine also caused significant increases in morphine antinociception in all three models. In carrageenan paw inflammation complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model (see figure) morphine 3.2 mg/kg given alone caused significant antinociception but the size of that response was significantly less than that caused by a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg (p < 0.001; one way ANOVA). Conclusions:, Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with severe pain states involving central sensitization. [source] (635) The Advantages and Adverse Effects of Long-Term Intrathecal Delivery of Opioid and Clonidine HCL AdmixturePAIN MEDICINE, Issue 2 2000Article first published online: 25 DEC 200 Introduction: Intrathecal clonidine may be effective in neuropathic pain situations where large doses of opioids and local anesthetics or baclofen result in side effects and inadequate pain control. Addition of clonidine activates K (ATP) channels via a-2 receptors. Clonidine administered intrathecally provides fourfold better pain control with lower side effects than systemic clonidine. Because clonidine does not interact with opioid receptors, it fails to cause opioid-like side effects. Clonidine and opioids may have a synergistic efficacy. Materials & Methods: We performed a retrospective analysis of 23 patients, 10 male and 13 female, with a mean age of 55.4 years. Seventeen patients had neuropathic pain and 6 patients had mixed (neuropathic-nociceptive) nonmalignant pain. They had failed to achieve satisfactory analgesia despite preclinical infusion of high dose morphine sulfate, hydromorphone HCL, or combinations of bupivacaine HCL/opioid or baclofen. The range of initiating daily dose of clonidine was 25 ,g to 50 ,g, to a maximum of 900 ,g/day. The clonidine doses were titrated upwards to the end point of either efficacy or adverse effects. Clinical parameters studied were patient vital signs, pain intensity, pain relief, quality of sleep, drug intake, and side effects. Results: The preclonidine VAPS scores were on average 7.67 and the postclonidine VAPS scores were 5.82. Sleep improved for 50% of patients having poor to fair sleep. Length of therapy ranges from 1 month to 35 months with an average of 14.7 months of therapy. Of the 23 patients studied, 8 patients have been satisfied, coping with any side effects, and are still receiving mixed clonidine/opioid therapy. The side effects noted were nausea (9), sleepiness (8), dry mouth (7), dizziness (7), orthostatic hypotension (2), short term memory loss (2), headache (2), edema (2), depression (2), tinnitus (1), lethargy (1), nausea with vomiting (1), decreased energy (1), decreased libido (1), impotence (1), fine tremor (1), and anxiety (1). Conclusions: Intraspinal infusion of clonidine plus opioid may provide safer and better synergistic control of intractable neuropathic or mixed nonmalignant pain than pure intraspinal infusions of u-opioid with local anesthetic. [source] Effects of a distance learning program on physicians' opioid- and benzodiazepine-prescribing skillsTHE JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS, Issue 4 2006Deana Midmer BScN Abstract Introduction: Opioid misuse is common among patients with chronic nonmalignant pain. There is a pressing need for physicians to increase their confidence and competence in managing these patients. Methods: A randomized controlled trial of family physicians (N = 88) attending 1 of 4 continuing medical education events helped to determine the effectiveness of e-mail case discussions in changing physician behavior. Before random assignment, participants completed a pretest and attended a 3-hour didactic session on prescribing opioids and benzodiazepines. The intervention group participated in 10 weeks of e-mail case discussions, with designated participants responding to questions on cases. An addictions physician facilitated the discussion. Several months after the e-mail discussion, participants took part in a mock telephone consultation; a blinded researcher posing as a medical colleague asked for advice about 2 cases involving opioid and benzodiazepine prescribing. Using a checklist, the researcher recorded the questions asked and advice given by the physician. Results: On post-testing, both groups expressed greater optimism about treatment outcomes and were more likely to report using a treatment contract and providing advice about sleep hygiene. There were no significant differences between pretesting and post-testing between the groups on the survey. During the telephone consultation, the intervention group asked significantly more questions and offered more advice than the control group (odds ratio for question items, 1.27 [p = .03]; advice items, 1.33 [p = .01). Discussion: Facilitated by electronic mail and a medical expert, case discussion is an effective means of improving physician performance. Telephone consultation holds promise as a method for evaluating physicians' assessment and management skills. [source] Opioid switching from transdermal fentanyl to oral methadone in patients with cancer painCANCER, Issue 12 2004Miguel Angel Benítez-Rosario M.D., Ph.D. Abstract BACKGROUND Patients with cancer often are rotated from other opioids to methadone to improve the balance between analgesia and side effects. To the authors' knowledge, no clear guidelines currently exist for the safe and effective rotation from transdermal fentanyl to methadone. METHODS The authors evaluated a protocol for switching opioid from transdermal fentanyl to oral methadone in 17 patients with cancer. Reasons for switching were uncontrolled pain (41.1% of patients) and neurotoxic side effects (58.9% of patients). Methadone was initiated 8,24 hours after fentanyl withdrawal, depending on the patient's previous opioid doses (from < 100 ,g per hour to > 300 ,g per hour). The starting methadone dose was calculated according to a 2-step conversion between transdermal fentanyl:oral morphine (1:100 ratio) and oral morphine:oral methadone (5:1 ratio or 10:1 ratio). The correlation between previous fentanyl dose and the final methadone dose or the fentanyl:methadone dose ratio was assessed by means of Pearson and Spearman correlation coefficients (r), respectively. A Friedman test was used to compare pain intensity before and after the switch and the use of daily rescue doses. RESULTS Opioid rotation was fully or partially effective in 80% and 20%, respectively, of patients with somatic pain. Neuropathic pain was not affected by opioid switching. Delirium and myoclonus were reverted in 80% and 100% of patients, respectively, after opioid switching. A positive linear correlation was obtained between the fentanyl and methadone doses (Pearson r, 0.851). Previous fentanyl doses were not correlated with the final fentanyl:methadone dose ratios (Spearman r, , 0.327). CONCLUSIONS The protocol studied provided a safe approach for switching from transdermal fentanyl to oral methadone, improving the balance between analgesia and side effects in patients with cancer. Cancer 2004. © 2004 American Cancer Society. [source] Classical conditioning in the rat fetus: Involvement of mu and kappa opioid systems in the conditioned responseDEVELOPMENTAL PSYCHOBIOLOGY, Issue 2 2002William P. Smotherman Abstract When the Embryonic Day 20 (E20) rat fetus is given a conditioning trial involving a paired presentation of an artificial nipple (the conditioned stimulus; CS) with an intraoral infusion of milk (the unconditioned stimulus; US), it shows evidence of classical conditioning when again exposed to the CS during a test trial. Specifically, the fetus shows fewer oral grasp responses (the conditioned response; CR) when continuously presented with the artificial nipple. The present study further investigated this classically conditioned reduction in oral grasping. Separate experiments (a) examined the time course of the reduction in oral grasping (Experiment 1), (b) characterized the time course of mu opioid (Experiment 2) and kappa opioid (Experiment 3) involvement in the CR, and (c) described changes in fetal behavior (Experiment 4) associated with mu and kappa opioid effects on responding to the artificial nipple. The results are discussed in terms of opioid involvement in establishing and maintaining early suckling behavior. © 2002 Wiley Periodicals, Inc. Dev Psychobiol 40: 104,115, 2002. DOI 10.1002/dev.10016 [source] Post-traumatic stress disorder: a review of psychobiology and pharmacotherapyACTA PSYCHIATRICA SCANDINAVICA, Issue 6 2001I. Hageman Objective: To review the literature on the psychobiology and pharmacotherapy of PTSD. Method: Relevant studies were identified by literature searches (Pub-med, web of science) and through reference lists. The search was ended by May 2001. Results: There is evidence of involvement of opioid, glutamatergic, GABAergic, noradrenergic, serotonergic and neuroendocrine pathways in the pathophysiology of PTSD. Medications shown to be effective in double-blind placebo-controlled trials includes selective serotonin reuptake inhibitors, reversible and irreversible MAO-inhibitors, tricyclic antidepressants and the anticonvulsant lamotrigine. Still more agents appear promising in open-label trials. Conclusion: The complexity of the psychobiology is reflected by the difficulties in treating the disorder. According to the present knowledge, suggestions for drug treatment of PTSD are made. [source] Patterns and correlates of substance use amongst juvenile detainees in New South Wales 1989,99DRUG AND ALCOHOL REVIEW, Issue 1 2003JAN COPELAND Abstract In the decade 1989,99 there have been significant changes in the patterns of substance use in the Australian community. Juvenile offenders have been a sentinel population of these emerging trends. The social and personal costs associated with adolescent substance use, especially where it leads to increased criminal offending requires urgent attention. This study was a replication of the 1989 and 1994 surveys of young people in detention in New South Wales, Australia. The 300 voluntary participants from nine detention centres had a similar demographic profile to participants of the previous surveys. They were predominantly male (90%) with a mean age of 16.5 years and an over-representation of Aboriginal and Torres Straits Islander peoples. The patterns of lifetime alcohol and tobacco use were stable over the decade, with particular increases in amphetamine, opioid and cocaine use since 1994. The more concerning pattern of at least weekly substance use revealed significant increases in cannabis, opioid and cocaine use since 1994, but a significant decrease in the frequent use of alcohol. This study also reports on high levels of negative health and psychosocial consequences of substance use, including overdose, among this group. High levels of self-reported depression and suicidal behaviours, family and gender issues are also discussed. Encouragingly, there was a relatively high level of self-recognized treatment need for substance use and mental health problems among the sample. This highlights further the growing need for the development and dissemination of novel interventions that harness this willingness and actively engage, motivate and maintain these young people in accessible, appropriate and effective interventions. [source] Risk factors for drug dependence among out-patients on opioid therapy in a large US health-care systemADDICTION, Issue 10 2010Joseph A. Boscarino ABSTRACT Aims Our study sought to assess the prevalence of and risk factors for opioid drug dependence among out-patients on long-term opioid therapy in a large health-care system. Methods Using electronic health records, we identified out-patients receiving 4+ physician orders for opioid therapy in the past 12 months for non-cancer pain within a large US health-care system. We completed diagnostic interviews with 705 of these patients to identify opioid use disorders and assess risk factors. Results Preliminary analyses suggested that current opioid dependence might be as high as 26% [95% confidence interval (CI) = 22.0,29.9] among the patients studied. Logistic regressions indicated that current dependence was associated with variables often in the medical record, including age <65 [odds ratio (OR) = 2.33, P = 0.001], opioid abuse history (OR = 3.81, P < 0.001), high dependence severity (OR = 1.85, P = 0.001), major depression (OR = 1.29, P = 0.022) and psychotropic medication use (OR = 1.73, P = 0.006). Four variables combined (age, depression, psychotropic medications and pain impairment) predicted increased risk for current dependence, compared to those without these factors (OR = 8.01, P < 0.001). Knowing that the patient also had a history of severe dependence and opioid abuse increased this risk substantially (OR = 56.36, P < 0.001). Conclusion Opioid misuse and dependence among prescription opioid patients in the United States may be higher than expected. A small number of factors, many documented in the medical record, predicted opioid dependence among the out-patients studied. These preliminary findings should be useful in future research efforts. [source] Challenges to antagonist blockade during sustained-release naltrexone treatmentADDICTION, Issue 9 2010Nikolaj Kunøe ABSTRACT Aims Naltrexone is a competitive opioid antagonist that effectively blocks the action of heroin and other opioid agonists. Sustained-release naltrexone formulations are now available that provide long-acting opioid blockade. This study investigates the use of heroin and other opioids among opioid-dependent patients receiving treatment with long-acting naltrexone implants, their subjective experience of drug ,high' after opioid use, and factors associated with opioid use. Methods Participants (n = 60) were opioid-dependent patients receiving treatment with naltrexone implants. Outcome data on substance use, drug ,high', depression and criminal activity were collected over a 6-month period. Blood samples were taken to monitor naltrexone plasma levels, and hair samples to verify self-reported opioid use. Findings More than half [n = 34 or 56%; 95% confidence interval (CI) 44,68%)] the patients challenged the blockade with illicit opioids during the 6-month treatment period; 44% (n = 26; 95% CI 32,56%) were abstinent from opioids. Mean opioid use was reduced from 18 [standard deviation (SD)13] days during the month preceding treatment to 6 days (SD 11) after 6 months. Of the respondents questioned on opioid ,high' (n = 31), nine patients (30%; 95% CI 16,47%) reported partial drug ,high' following illicit opioid use, and three (12%; 95% CI 3,26%) reported full ,high'. Opioid use was associated with use of non-opioid drugs and criminal behaviour. Conclusions Challenging naltrexone blockade with heroin on at least one occasion is common among sustained-release naltrexone patients, but only a minority of patients use opioids regularly. Challenges represent a warning sign for poor outcomes and often occur in the context of polydrug use and social adjustment problems. [source] Retention in methadone maintenance drug treatment for prescription-type opioid primary users compared to heroin usersADDICTION, Issue 5 2009Caleb J. Banta-Green ABSTRACT Aims To assess retention in methadone maintenance treatment for prescription-type opioid primary (PTOP) users compared to heroin users. Design and participants A retrospective cohort study was carried out to examine the association between opiate types used on 12-month retention. The study population consisted of adults admitted to one of 11 not-for-profit methadone maintenance clinics in 2004 and 2005 throughout Washington State (n = 2308). Logistic regression analyses with fixed effects for treatment agencies were conducted. Measurements Opiate use type in past 30 days: any heroin use or primary prescription opioid without heroin use. Demographics, other drugs used, self-reported medical and psychiatric concerns, social, familial and legal issues, public assistance type and housing stability were documented at intake using a comprehensive biopsychosocial instrument, the Treatment and Assessment Reports Generation Tool. Findings The odds of being retained in treatment for PTOP compared to heroin users not adjusting for other factors was 1.33 (95% confidence interval [CI], 1.03, 1.71). In the final logistic regression model the odds of retention for PTOP compared to heroin users was 1.25 (95% CI, 0.93, 1.67), indicating that there was no statistically significant difference in treatment retention by opiate type after adjusting for demographics, treatment agencies, other drug use, public assistance type, medical, psychiatric, social, legal and familial factors. Conclusion The findings of this study suggest that PTOP can be treated at methadone maintenance treatment facilities at least as effectively as heroin users in terms of treatment retention. [source] PRECLINICAL STUDY: FULL ARTICLE: Ethanol-induced activation of AKT and DARPP-32 in the mouse striatum mediated by opioid receptorsADDICTION BIOLOGY, Issue 3 2010Karl Björk ABSTRACT The reinforcing properties of ethanol are in part attributed to interactions between opioid and dopaminergic signaling pathways, but intracellular mediators of such interactions are poorly understood. Here we report that an acute ethanol challenge induces a robust phosphorylation of two key signal transduction kinases, AKT and DARPP-32, in the striatum of mice. Ethanol-induced AKT phosphorylation was blocked by the opioid receptor antagonist naltrexone but unaffected by blockade of dopamine D2 receptors via sulpiride. In contrast, DARPP-32 phosphorylation was abolished by both antagonists. These data suggest that ethanol acts via two distinct but potentially synergistic striatal signaling cascades. One of these is D2-dependent, while the other is not. These findings illustrate that pharmacology of ethanol reward is likely more complex than that for other addictive drugs. [source] CLINICAL STUDY: Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicatorsADDICTION BIOLOGY, Issue 3 2009Wendy Ooteman ABSTRACT Acamprosate and naltrexone are effective medications in the treatment of alcoholism. However, effect sizes are modest. Pharmacogenomics may improve patient-treatment-matching and effect sizes. It is hypothesized that naltrexone exerts its effect through genetic characteristics associated with the dopaminergic/opioidergic positive reinforcement system, whereas acamprosate works through the glutamatergic/GABAergic negative reinforcement system. Alcohol-dependent subjects were randomly assigned to either acamprosate or naltrexone. Subjects participated in a cue-exposure experiment at the day before and at the last day of medication. Reductions in cue-induced craving and physiological cue reactivity were measured. Differential effects of naltrexone and acamprosate on these outcomes were tested for different polymorphisms of the opioid, dopamine, glutamate and GABA-receptors. Significant matching effects were found for polymorphisms at the DRD2, GABRA6 and GABRB2 gene. In addition, a trend was found for the OPRM1 polymorphism. This provides evidence for the matching potential of genotypes. It is expected that more effective treatments can be offered when genetic information is used in patient-treatment-matching. [source] Constitutive opioid receptor activation: a prerequisite mechanism involved in acute opioid withdrawalADDICTION BIOLOGY, Issue 2 2005E Freye The opioid receptor antagonist naltrexone, which is used in detoxification and rehabilitation programmes in opioid addicts, can precipitate opioid withdrawal symptoms even in patients who have no opioid present. We tested the hypothesis that in order to precipitate withdrawal, opioids need to convert the inactive opioid receptor site via protein kinase C into a constitutively active form on which the antagonist precipitates withdrawal. Acute abstinence symptoms were induced by the potent opioid receptor agonist sufentanil (21?,g/kg), given for 6 days, which was followed by the antagonist naltrexone (20?,g/kg i.v.) in the awake trained canine (n,=,10). Abrupt displacement of opioid binding resulted in acute withdrawal symptoms: increase in blood pressure, heart rate, increase in amplitude height of somatosensory evoked potential, reduced tolerance to colon distention and a significant increase in grading of vegetative variables (restlessness, panting, thrashing of the head, whining, yawning, gnawing, salivation and/or rhinorrhoea, mydriasis, stepping of extremities and vomiting). Following a washout period of 14 days, the same animals were given the highly specific protein kinase C inhibitor H7 (250?,g/kg) prior to the same dosages of sufentanil and naltrexone. Such pretreatment was able to either attenuate or completely abolish the acute withdrawal symptoms. The data suggest that for precipitation of withdrawal, intracellular phosphorylation is a prerequisite in order to activate the opioid ,-receptor. In such a setting, naltrexone acts like an ,inverse agonist? relative to the action of the antagonist on a non-preoccupied receptor site not being exposed previously to a potent opioid agonist. [source] Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2009Victor Tortorici Abstract Opiate analgesia can be hampered by a reduction in pharmacological effectiveness (tolerance), and this crucially depends on the periaqueductal gray matter (PAG). Non-opioids like metamizol (dipyrone) or aspirin also induce PAG-dependent analgesia and tolerance, but the neuronal bases of this tolerance are unknown. Metamizol is a pyrazolon derivative and cyclooxygenase inhibitor with widespread use as an analgesic in Europe and Latin America. Metamizol was microinjected into the PAG of awake male rats, and antinociception was assessed by the tail flick (TF) and hot plate (HP) tests. Microinjection twice daily for 2.5 days caused tolerance to metamizol. The rats were then anesthetized and recordings from pain-facilitating on-cells and pain-inhibiting off-cells of the rostral ventromedial medulla (RVM) were performed. PAG microinjection of morphine or metamizol depresses on-cells, activates off-cells and thus inhibits nociception, including TF and HP. In metamizol-tolerant rats, however, PAG microinjection of metamizol failed to affect on- or off-cells, and this is interpreted as the reason for tolerance. In metamizol-tolerant rats morphine microinjection into PAG also failed to affect RVM neurons or nociception (cross-tolerance). In naïve, non-tolerant rats the antinociceptive effect of PAG-microinjected metamizol or morphine was blocked when CTOP, a ,-opioid antagonist, was previously microinjected into the same PAG site. These results emphasize a close relationship between opioid and non-opioid analgesic mechanisms in the PAG and show that, like morphine, tolerance to metamizol involves a failure of on- and off-cells to, respectively, disfacilitate and inhibit nociception. Cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting. [source] The 14-Alkyl- and 14-Alkenyl-5, -methylindolomorphinan Series Provide , -Selective Partial Opioid AgonistsHELVETICA CHIMICA ACTA, Issue 3 2003Peter Grundt A series of 14, -alkyl- and 14, -alkenyl-5, -methylindolomorphinans was synthesized and evaluated in opioid binding and functional assays. While being relatively nonselective in binding assays, the 14-cinnamyl and 14-isopentyl members showed selective opioid , -receptor partial agonist activity in [35S]GTP,S assays. [source] Uremic pruritus: A reviewHEMODIALYSIS INTERNATIONAL, Issue 2 2005Jocemir R. Lugon Abstract Pruritus is a major disorder among the skin derangements in advanced renal failure. Its prevalence seems to be diminishing perhaps because of improvements in dialysis treatment. Recent information suggests that interactions between dermal mast cells and distal ends of nonmyelinated C fibers may be important in the precipitation and regulation of the sensory stimuli. The knowledge as to the control of pruritus transmission to cortex areas is still incomplete but endogenous opioid and opioid receptors may have a role in this regard. A recent classification was proposed for pruritus based on the level of its origin. Uremic pruritus, however, seems to be too complex to fit perfectly in any of the suggested modalities. Inflammation and malnutrition are recognized risk factors for cardiovascular death in end-stage renal disease patients, which may be related to the genesis of pruritus. Consistent with this concept, lower serum levels of albumin and higher serum levels of ferritin were found in pruritic patients when compared to nonpruritic ones. Newer treatments for this difficult clinical problem are being developed and tested. [source] Remote pharmacological post-conditioning by intrathecal morphine: cardiac protection from spinal opioid receptor activationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2010J. LING LING Background: Intrathecal morphine pre-conditioning attenuates cardiac ischemia,reperfusion injury via activation of central opioid receptors. We hypothesized that intrathecal morphine also post-conditions the myocardium in the rat. Methods: Intrathecal morphine at 0.3 ,g/kg (LMPC), 3 ,g/kg (MMPC) or 30 ,g/kg (HMPC) was administered for 5 min before 120-min reperfusion following 30-min ischemia. Infarct size as a percentage of area at risk (IS/AAR) was determined using triphenyltetrazolium staining. MMPC was repeated following the intrathecal administration of nor BNI, NTD, CTOP, or naloxone methiodide (NM), kappa, delta, mu and non-specific opioid receptor antagonists, respectively. The role of peripheral opioid, adenosine and calcitonin gene-related peptide (CGRP) receptors was examined by the intravenous administration of NM, 8-,-sulfophenyl theophylline (8-SPT) and human CGRP fragment (CGRP8,37), respectively. Results: Morphine post-conditioning at all three doses was cardioprotective (IS/AAR of LMPC=37±4%, MMPC=35±5%, HMPC=32±4%, control=50±5%, P<0.01). The prior administration of opioid receptor antagonists intrathecally, as well as intravenous 8-SPT and CGRP8,37 receptor antagonists, abolished this effect (nor BNI+MMPC=47±7%, NTD+MMPC=49±7%, CTOP+MMPC=45±9%, NM+MMPC=47±6% 8-SPT+MPC=46±5% & CGRP8,37+MPC=53±6%, P=0.63). However, the intravenous administration of NM did not prevent the protective effect (34±4%, P<0.01). Conclusions: Intrathecal morphine administration can induce pharmacological cardiac post-conditioning as it involves opioid receptor centrally but non-opioid receptors peripherally. [source] The role of methadone in cancer pain treatment , a reviewINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 7 2009W. Leppert Summary Background:, Methadone is an opioid analgesic of step 3 of the World Health Organization (WHO) analgesic ladder. Aim and Methods:, To outline pharmacodynamics, pharmacokinetics, drug interactions, equianalgesic dose ratio with other opioids, dosing rules, adverse effects and methadone clinical studies in patients with cancer pain. A review of relevant literature on methadone use in cancer pain was conducted. Results:, Methadone is used in opioid rotation and administered to patients with cancer pain not responsive to morphine or other strong opioids when intractable opioid adverse effects appear. Methadone is considered as the first strong opioid analgesic and in patients with renal impairment. Methadone possesses different pharmacodynamics and pharmacokinetics in comparison to other opioids. The advantages of methadone include multimode analgesic activity, high oral and rectal bioavailability, long lasting analgesia, lack of active metabolites, excretion mainly with faeces, low cost and a weak immunosuppressive effect. The disadvantages include long and changeable plasma half-life, high bound to serum proteins, metabolism through P450 system, numerous drug interactions, lack of clear equianalgesic dose ratio to other opioids, QT interval prolongation, local reactions when administered subcutaneously. Conclusions:, Methadone is an important opioid analgesic at step 3 of the WHO analgesic ladder. Future controlled studies may focus on establishment of methadone equianalgesic dose ratio with other opioids and its role as the first strong opioid in comparative studies with analgesia, adverse effects and quality of life taken into consideration. [source] Testing whether the epidural works: too time consuming?ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2010J. LARSSON Background: When using epidural anaesthesia (EDA) for pain relief after major surgery, a failure rate of 10% is common. A crucial step in improving the care of patients with EDA is to define the position of the epidural catheter. The aim of this study was to investigate how much time it takes to determine whether the block is sufficient by assessing the extent of loss of cold sensation before induction of anaesthesia. Methods: One hundred patients listed for abdominal surgery were included in the study. After an epidural catheter had been inserted and an intrathecal or an intravenous position had been made unlikely by the use of a test dose, the patient was given a bolus dose of local anaesthetic plus an opioid in the epidural catheter. The epidural block was tested every 2 min, starting at 5 min and ending at 15 min. When at least four segments were blocked bilaterally, the testing was stopped, the time was noted and the patient was anaesthetised. Results: An epidural block was demonstrated after 5,6 min in 37 patients, after 7,8 min in 43 additional patients and after 9,10 min in 15 patients. In one patient, it took 12 min and in three patients, it took 15 min. In two patients, no epidural block could be demonstrated. Conclusion: Testing an epidural anaesthetic before the induction of anaesthesia takes only 5,10 extra minutes. Knowing whether the catheter is correctly placed means better quality of care, giving the anaesthetist better prerequisites for taking care of the patient post-operatively. [source] Intrathecal sufentanil decreases the median effective dose (ED50) of intrathecal hyperbaric ropivacaine for caesarean deliveryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2010X. CHEN Background: The addition of opioid to local anaesthetics has become a well-accepted practice of spinal anaesthesia for caesarean delivery. Successful caesarean delivery anaesthesia has been reported with the use of a low dose of intrathecal hyperbaric ropivacaine coadministered with sufentanil. This prospective, double-blinded study determined the median effective dose (ED50) of intrathecal hyperbaric ropivacaine with and without sufentanil for caesarean delivery, to quantify the sparing effect of sufentanil on the ED50 of intrathecal hyperbaric ropivacaine. Methods: Sixty-four parturients undergoing elective caesarean delivery with combined spinal,epidural anaesthesia were randomized into two groups: Group R (ropivacaine) and Group RS (ropivacaine plus sufentanil 5 ,g). The initial dose of ropivacaine was 13 mg in Group R and 10 mg in Group RS. The effective dose was defined as a T6 level attained within 10 min and no supplemental epidural anaesthetic required during surgery. Effective or ineffective responses determined, respectively, a 0.3 mg decrease or increase of the dose of ropivacaine for the next patient using an up,down sequential allocation. Results: The ED50 of intrathecal ropivacaine was 11.2 mg [confidence interval (CI) 95%: 11.0,11.6] in Group R vs. 8.1 mg (CI 95%: 7.8,8.3) in Group RS. Motor block was markedly more intense in Group R than in Group RS, and the incidence of shivering was lower in Group RS than in Group R. There were no differences in the onset time of sensory block or motor block, in the incidence of hypotension, nausea and vomiting. Conclusion: Intrathecal sufentanil 5 ,g produced a 28% reduction of ED50 of intrathecal hyperbaric ropivacaine for caesarean delivery. [source] The potential for ,-opioid receptor agonists to be anti-emetic in humans: a review of clinical dataACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2010KEVIN D. JOHNSTON In animal models of vomiting, ,-opioid (MOP, OP3) receptors mediate both emesis and anti-emesis. ,-receptors within the blood,brain barrier, mediating anti-emesis, are more rapidly accessible to lipid-soluble ,-opioid receptor agonists such as fentanyl than to morphine, and fentanyl has broad-spectrum anti-emetic effects in a number of species. Whether a similar situation exists in humans is not known. A search was performed for clinical studies comparing the emetic side effects of opioids administered peri-operatively in an attempt to identify differences between morphine and more lipid-soluble ,-receptor-selective agonists such as fentanyl. Overall, the evidence appears to suggest that fentanyl and other phenylpiperidines are associated with less nausea and vomiting than morphine, but not all studies support this, and fentanyl-like drugs are associated with nausea and vomiting per se. Good evidence, however, exists to show that fentanyl and alfentanil do not cause more nausea and vomiting than the ultra fast-acting remifentanil. Because remifentanil is cleared rapidly post-operatively, such trials suggest that the emetic side effects of fentanyl and alfentanil are minimal. The clinical evidence, although limited, is at least consistent with the possibility that central ,-opioid receptors may mediate anti-emesis in humans. It is possible that the role of ,-opioid agonists in anti-emesis may become clearer in the future as a result of the use of peripheral ,-opioid receptor antagonists. [source] Management of Noncancer Pain in Community-Dwelling Persons with DementiaJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 12 2006Joseph W. Shega MD OBJECTIVES: To explore the pharmacological treatment of noncancer pain in persons with dementia and identify predictors associated with insufficient analgesia. DESIGN: Cross-sectional analysis of an observational cohort study. SETTING: Academic outpatient geriatric clinic in Chicago, Illinois. PARTICIPANTS: A total of 115 dyads, mostly African American, consisting of community-dwelling persons with dementia and their caregivers. MEASUREMENTS: Patient report of demographics, noncancer pain, function, cognition, and depression. Caregiver report of patient agitation and over-the-counter and prescription medications. RESULTS: Sixty-two of 115 (54%) patients reported pain "on an average day." The caregivers of more than half of persons with dementia who reported pain "on an average day" did not report analgesic use. The majority of caregivers who reported analgesic use reported that patients took a World Health Organization Class I medication. No patients had been prescribed a Class III (strong opioid) drug. Fifty-three of 115 (46%) patients had potentially insufficient analgesia. In the logistic regression, insufficient analgesia was associated with greater age, Mini-Mental State Examination score of less than 10, and impairment in daily functioning. Insufficient analgesia was 1.07 times as likely (95% confidence interval (CI)=1.01,1.14) for each additional year of age, 3.0 times as likely (95% CI=1.05,9.10) if the subject had advanced dementia, and 2.5 times as likely (95% CI=1.01,6.25) if the patient had any impairment in activities of daily living. CONCLUSION: In this convenience sample from a geriatric clinic, many persons with dementia and noncancer pain were not receiving pharmacological treatment. Those at greatest risk for insufficient analgesia were older, had moderate to severe dementia, and experienced impairments in activities of daily living. [source] Impact of the CYP2D6 genotype on post-operative intravenous oxycodone analgesiaACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2010S. T. ZWISLER Background: Oxycodone is a semi-synthetic opioid with a ,-receptor agonist-mediated effect in several pain conditions, including post-operative pain. Oxycodone is metabolized to its active metabolite oxymorphone by O -demethylation via the polymorphic CYP2D6. The aim of this study was to investigate whether CYP2D6 poor metabolizers (PMs) yield the same analgesia post-operatively from intravenous oxycodone as extensive metabolizers (EMs). Methods: Two hundred and seventy patients undergoing primarily thyroid surgery or hysterectomy were included and followed for 24 h post-operatively. The CYP2D6 genotype was blinded until study procedures had been completed for all patients. All patients received intravenous oxycodone as pain treatment for 24 h post-operatively and morphine 5 mg was used as escape medication. A responder was characterized as a patient without the need for escape medication and a positive evaluation in a questionnaire 24 h post-operatively. Results: Twenty-four patients were PM (8.9%) and 246 were EM (91.1%). One PM (4.17%, CI=0.1,21.1) was a non-responder and 42 EM (17.07%, CI=12.6,22.4) were non-responders. The non-responder rate did not differ between the two genotypes (P=0.14). There was no difference in the total consumption of oxycodone between the two genotypes (EM=14.7 mg, CI=13.0,16.4 and PM=13.0 mg, CI=8.9,17.0, P=0.42). The mean oxymorphone/oxycodone ratios were 0.0031 and 0.00081 in the EMs and PMs, respectively (P<0.0001). Conclusion: This study showed for the first time in patients that the oxymorphone formation depends on CYP2D6, but we found no difference in the post-operative analgesic effect of intravenous oxycodone between the two CYP2D6 genotypes. [source] From neuroanatomy to gene therapy: searching for new ways to manipulate the supraspinal endogenous pain modulatory systemJOURNAL OF ANATOMY, Issue 2 2007I. Tavares Abstract The endogenous pain modulatory system is a complex network of brain areas that control nociceptive transmission at the spinal cord by inhibitory and facilitatory actions. The balance between these actions ensures effective modulation of acute pain, while during chronic pain the pronociceptive effects appear to prevail. The mechanisms underlying this imbalance were studied as to the role of two medullary components of the pain modulatory system: the dorsal reticular nucleus and the caudal ventrolateral medulla, which function primarily as pronociceptive and antinociceptive centres, respectively. Both areas are connected with the spinal dorsal horn by closed reciprocal loops. In the spino-dorsal reticular nucleus loop, the ascending branch is strongly inhibited by spinal GABAergic neurons, which may act as a buffering system of the dorsal reticular nucleus-centred amplifying effect. In the spino-caudal ventrolateral medulla loop, the ascending branch is under potent excitation of substance P (SP) released from primary afferents, which is likely to trigger the intense descending inhibition detected in acute pain. During chronic pain, the activity in the lateral reticular formation of the caudal ventrolateral medulla changes, so that the action of the caudal ventrolateral medulla upon SP-responsive spinal neurons shifts from inhibitory to excitatory. The mechanisms of this modulatory shift are unknown but probably relate to the decresed expression of µ-opioid, ,-opioid and GABAB receptors. Normalizing receptor expression in the caudal ventrolateral medulla or controlling noci-evoked activity at the dorsal reticular nucleus or caudal ventrolateral medulla by interfering with neurotransmitter release is now possible by the use of gene therapy, an approach that stands out as a unique tool to manipulate the supraspinal endogenous pain control system. [source] The superior colliculus of the camel: a neuronal-specific nuclear protein (NeuN) and neuropeptide studyJOURNAL OF ANATOMY, Issue 2 2006E. P. K. Mensah-Brown Abstract In this study we examined the superior colliculus of the midbrain of the one-humped (dromedary) camel, Camelus dromedarius, using Nissl staining and anti-neuronal-specific nuclear protein (NeuN) immunohistochemistry for total neuronal population as well as for the enkephalins, somatostatin (SOM) and substance P (SP). It was found that, unlike in most mammals, the superior colliculus is much larger than the inferior colliculus. The superior colliculus is concerned with visual reflexes and the co-ordination of head, neck and eye movements, which are certainly of importance to this animal with large eyes, head and neck, and apparently good vision. The basic neuronal architecture and lamination of the superior colliculus are similar to that in other mammals. However, we describe for the first time an unusually large content of neurons in the superior colliculus with strong immunoreactivity for met-enkephalin, an endogenous opioid. We classified the majority of these neurons as small (perimeters of 40,50 µm), and localized diffusely throughout the superficial grey and stratum opticum. In addition, large pyramidal-like neurons with perimeters of 100 µm and above were present in the intermediate grey layer. Large unipolar cells were located immediately dorsal to the deep grey layer. By contrast, small neurons (perimeters of 40,50 µm) immunopositive to SOM and SP were located exclusively in the superficial grey layer. We propose that this system may be associated with a pain-inhibiting pathway that has been described from the periaqueductal grey matter, juxtaposing the deep layers of the superior colliculus, to the lower brainstem and spinal cord. Such pain inhibition could be important in relation to the camel's life in the harsh environment of its native deserts, often living in very high temperatures with no shade and a diet consisting largely of thorny branches. [source] Sex Differences in Salivary Cortisol Levels Following Naltrexone Administration,JOURNAL OF APPLIED BIOBEHAVIORAL RESEARCH, Issue 2 2000Laura Cousino Klein Effects of endogenous opioid peptide blockade by naltrexone on salivary Cortisol levels were examined in healthy men (n= 8) and women (n= 6). Participants received naltrexone (100 mg) during one laboratory session and a placebo pill during another session. Drug order was counterbalanced across participants. Saliva samples were collected 24 hr after each pill was administered. Among women, salivary Cortisol levels significantly increased following naltrexone administration compared with a placebo pill. Naltrexone administration did not alter salivary Cortisol levels in men. Results suggest sex differences in neuroendocrine sensitivity to opioid blockade, a finding that may hold significance with regard to the treatment of alcohol addiction with naltrexone. [source] |