Postoperative pain control in cats: clinical trials with pre-emptive lidocaine epidural co-administered with morphine or methadone

To evaluate the effectiveness of epidural lidocaine in combination with either methadone or morphine for postoperative analgesia in cats undergoing ovariohysterectomy. Under general anesthesia, 24 cats that underwent ovariohysterectomy were randomly allocated into three treatments groups of eight each. Treatment 1 included 2% lidocaine (4.0 mg/kg); treatment 2 included lidocaine and methadone (4.0 mg/kg and 0.3 mg/kg, respectively); and treatment 3 included lidocaine and morphine (4.0 mg/kg and 0.1 mg/kg, respectively). All drugs were injected in a total volume of 0.25 ml/kg via the lumbosacral route in all cats. During the anesthetic and surgical periods, the physiological variables (respiratory and heart rate, arterial blood pressure and rectal temperature) were measured at intervals of time zero, 10 mins, 20 mins, 30 mins, 60 mins and 120 mins. After cats had recovered from anesthesia, a multidimensional composite pain scale was used to assess postoperative analgesia at 2, 4, 8, 12, 18, and 24 h after epidural. The time to first rescue analgesic was significantly (P <0.05) prolonged in cats that received both lidocaine and methadone or lidocaine and morphine treatments compared with those that received the lidocaine treatment. All cats that received lidocaine treatment alone required rescue analgesic within 2 h of epidural injections. All treatments had significant cardiovascular and respiratory changes but they were within acceptable range for healthy animals during the surgical period. The two combinations administered via epidural allowed ovariohysterectomy with sufficient analgesia in cats, and both induced prolonged postoperative analgesia.

Farmacocinética pré-clínica e avaliação toxicológica do novo composto α2-adrenérgico 3-(2-cloro-6-fluorobenzil)-imidazolidina-2,4-diona - PT-31 GIRSUPAN

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Dual-energy CT-cholangiography in potential donors for living-related liver transplantation: Improved biliary visualization by intravenous morphine co-medication

PURPOSE: To prospectively evaluate whether intravenous morphine co-medication improves bile duct visualization of dual-energy CT-cholangiography. MATERIALS AND METHODS: Forty potential donors for living-related liver transplantation underwent CT-cholangiography with infusion of a hepatobiliary contrast agent over 40min. Twenty minutes after the beginning of the contrast agent infusion, either normal saline (n=20 patients; control group [CG]) or morphine sulfate (n=20 patients; morphine group [MG]) was injected. Forty-five minutes after initiation of the contrast agent, a dual-energy CT acquisition of the liver was performed. Applying dual-energy post-processing, pure iodine images were generated. Primary study goals were determination of bile duct diameters and visualization scores (on a scale of 0 to 3: 0-not visualized; 3-excellent visualization). RESULTS: Bile duct visualization scores for second-order and third-order branch ducts were significantly higher in the MG compared to the CG (2.9±0.1 versus 2.6±0.2 [P<0.001] and 2.7±0.3 versus 2.1±0.6 [P<0.01], respectively). Bile duct diameters for the common duct and main ducts were significantly higher in the MG compared to the CG (5.9±1.3mm versus 4.9±1.3mm [P<0.05] and 3.7±1.3mm versus 2.6±0.5mm [P<0.01], respectively). CONCLUSION: Intravenous morphine co-medication significantly improved biliary visualization on dual-energy CT-cholangiography in potential donors for living-related liver transplantation.

Time series modeling of heroin and morphine drug action

Clinical observations and recent findings suggested different acceptance of morphine and heroin by intravenous drug users in opiate maintenance programs. We postulated that this is caused by differences in the perceived effects of these drugs, especially how desired and adverse effects of both drugs interacted.

Effects of high-dose heroin versus morphine in intravenous drug users: a randomised double-blind crossover study

The purpose of this study is to evaluate the effects of high doses of injected opiates as prescribed maintenance in intravenous drugs users. This was accomplished via a randomised double-blind study with crossover at an outpatient clinic in Bern, Switzerland. The subjects were 39 patients with a long history of intravenous opioid use and persistent abuse despite treatment; they were randomly allocated to two groups. Group A was started on controlled injection of graduated doses of morphine up to a satisfying individual dose and was then switched as a double blind to heroin at a randomly determined day between week three and four. Subsequently this group was given heroin for the remaining two to three weeks of the study. Group B was started on heroin and was then switched to morphine in the same manner. Equipotent solutions of 3% morphine and 2% heroin were administered. The main outcome measures were clinical observations, structural interviews and self report of subjective experiences to assess the effects of the drugs. In 16 cases, the study had to be discontinued owing to severe morphine-induced histamine reactions. Thirteen participants in Group B presented these adverse reactions on the day of the switch-over. Full data were thus only obtainable for 17 participants. Average daily doses were 491 mg for heroin and 597 mg for morphine. The findings indicate that heroin significantly produced a lower grade of itching, flushing, urticaria and pain/nausea. A negative correlation between dose and euphoria was observed for both heroin and morphine. The authors concluded that as heroin produces fewer side effects it is the preferred high-dose maintenance prescription to morphine. The perceived euphoric effects are limited in both substances.

Effect of naloxone-3-glucuronide and N-methylnaloxone on the motility of the isolated rat colon after morphine

The effect of the opioid antagonists naloxone-3-glucuronide and N-methylnaloxone on rat colon motility after morphine stimulation was measured. The rat model consisted of the isolated, vascularly perfused colon. The antagonists (10(-4) M, intraluminally) and morphine (10(-4) M, intra-arterially) were administered from 20 to 30 and from 10 to 50 min, respectively. Colon motility was determined by the luminal outflow. The antagonist concentrations in the luminal and venous outflow were measured by high-performance liquid chromatography. Naloxone-3-glucuronide and N-methylnaloxone reversed the morphine-induced reduction of the luminal outflow to baseline within 10 and 20 min, respectively. These antagonists were then excreted in the luminal outflow and could not be found in the venous samples. Naloxone, produced by hydrolysis or demethylation, was not detectable. In conclusion, highly polar naloxone derivatives peripherally antagonize the motility-lowering effect of morphine in the perfused isolated rat colon, are stable, and are not able to cross the colon-mucosal blood barrier.

The effect of naloxone-3-glucuronide on colonic transit time in healthy men after acute morphine administration: a placebo-controlled double-blinded crossover preclinical volunteer study

BACKGROUND: Constipation is a significant side effect of opioid therapy. We have previously demonstrated that naloxone-3-glucuronide (NX3G) antagonizes the motility-lowering-effect of morphine in the rat colon. AIM: To find out whether oral NX3G is able to reduce the morphine-induced delay in colonic transit time (CTT) without being absorbed and influencing the analgesic effect. METHODS: Fifteen male volunteers were included. Pharmacokinetics: after oral administration of 0.16 mg/kg NX3G, blood samples were collected over a 6-h period. Pharmacodynamics: NX3G or placebo was then given at the start time and every 4 h thereafter. Morphine (0.05 mg/kg) or placebo was injected s.c. 2 h after starting and thereafter every 6 h for 24 h. CTT was measured over a 48-h period by scintigraphy. Pressure pain threshold tests were performed. RESULTS: Neither NX3G nor naloxone was detected in the venous blood. The slowest transit time was observed during the morphine phase, which was significantly different from morphine with NX3G and placebo. The pain perception was not significantly influenced by NX3G. CONCLUSIONS: Orally administered NX3G is able to reverse the morphine-induced delay of CTT in humans without being detected in peripheral blood samples. Therefore, NX3G may improve symptoms of constipation in-patients using opioid medication without affecting opioid-analgesic effects.

Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

AIMS: In the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose. METHODS: Opioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose. RESULTS: The maximum plasma concentration (C(max)) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 micromol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 micromol). CONCLUSIONS: Oral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.

Why does low dose morphine augment fentanyl analgesia?

Opioids dominate the field of pain management because of their ability to provide analgesia in many medical circumstances. However, side effects including respiratory depression, constipation, tolerance, physical dependence, and the risk of addiction limit their clinical utility. Fear of these side effects results in the under-treatment of acute pain. For many years, research has focused on ways to improve the therapeutic index (the ratio of desirable analgesic effects to undesirable side effects) of opioids. One strategy, combining opioid agonists that bind to different opioid receptor types, may prove successful.^ We discovered that subcutaneous co-administration of a moderately analgesic dose of the mu-opioid receptor (MOR) selective agonist fentanyl (20μg/kg) with subanalgesic doses of the less MOR-specific agonist morphine (100ng/kg-100μg/kg), augmented acute fentanyl analgesia in rats. Parallel [35S]GTPγS binding studies using naïve rat substantia gelatinosa membrane treated with fentanyl (4μM) and morphine (1nM-1pM) demonstrated a 2-fold increase in total G-protein activation. This correlation between morphine-induced augmentation of fentanyl analgesia and G-protein activation led to our proposal that interactions between MORs and DORs underlie opioid-induced augmentation. We discovered that morphine-induced augmentation of fentanyl analgesia and G-protein activity was mediated by DORs. Adding the DOR-selective antagonist naltrindole (200ng/kg, 40nM) at doses that did not alter the analgesic or G-protein activation of fentanyl, blocked increases in analgesia and G-protein activation induced by fentanyl/morphine combinations. Equivalent doses of the MOR-selective antagonist cyprodime (20ng/kg, 4nM) did not block augmentation. Substitution of the DOR-selective agonist SNC80 for morphine yielded similar results, further supporting our conclusion that interactions between MORs and DORs are responsible for morphine-induced augmentation of fentanyl analgesia and G-protein activation. Confocal microscopy of rat substantia gelatinosa showed that changes in the rate of opioid receptor internalization did not account for these effects.^ In conclusion, fentanyl analgesia augmentation by subanalgesic morphine is mediated by increased G-protein activation resulting from functional interactions between MORs and DORs, not changes in MOR internalization. Additional animal and clinical studies are needed to determine whether side effect incidence changes following opioid co-administration. If side effect incidence decreases or remains unchanged, these findings could have important implications for clinical pain treatment. ^

Dopamine-dependent responses to morphine depend on glucocorticoid receptors

Previous work has shown that glucocorticoid hormones facilitate the behavioral and dopaminergic effects of morphine. In this study we examined the possible role in these effects of the two central corticosteroid receptor types: mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). To accomplish this, specific antagonists of these receptors were infused intracerebroventricularly and 2 hr later we measured: (i) locomotor activity induced by a systemic injection of morphine (2 mg/kg); (ii) locomotor activity induced by an infusion of morphine (1 μg per side) into the ventral tegmental area, which is a dopamine-dependent behavioral response to morphine; (iii) morphine-induced dopamine release in the nucleus accumbens, a dopaminergic projection site mediating the locomotor and reinforcing effects of drugs of abuse. Blockade of MRs by spironolactone had no significant effects on locomotion induced by systemic morphine. In contrast, blockade of GRs by either RU38486 or RU39305, which is devoid of antiprogesterone effects, reduced the locomotor response to morphine, and this effect was dose dependent. GR antagonists also reduced the locomotor response to intraventral tegmental area morphine as well as the basal and morphine-induced increase in accumbens dopamine, as measured by microdialysis in freely moving rats. In contrast, spironolactone did not modify dopamine release. In conclusion, glucocorticoids, via GRs, facilitate the dopamine-dependent behavioral effects of morphine, probably by facilitating dopamine release. The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction.

Chronic morphine induces the concomitant phosphorylation and altered association of multiple signaling proteins: A novel mechanism for modulating cell signaling

Traditional mechanisms thought to underlie opioid tolerance include receptor phosphorylation/down-regulation, G-protein uncoupling, and adenylyl cyclase superactivation. A parallel line of investigation also indicates that opioid tolerance development results from a switch from predominantly opioid receptor Giα inhibitory to Gβγ stimulatory signaling. As described previously, this results, in part, from the increased relative abundance of Gβγ-stimulated adenylyl cyclase isoforms as well as from a profound increase in their phosphorylation [Chakrabarti, S., Rivera, M., Yan, S.-Z., Tang, W.-J. & Gintzler, A. R. (1998) Mol. Pharmacol. 54, 655–662; Chakrabarti, S., Wang, L., Tang, W.-J. & Gintzler, A. R. (1998) Mol. Pharmacol. 54, 949–953]. The present study demonstrates that chronic morphine administration results in the concomitant phosphorylation of three key signaling proteins, G protein receptor kinase (GRK) 2/3, β-arrestin, and Gβ, in the guinea pig longitudinal muscle myenteric plexus tissue. Augmented phosphorylation of all three proteins is evident in immunoprecipitate obtained by using either anti-GRK2/3 or Gβ antibodies, but the phosphorylation increment is greater in immunoprecipitate obtained with Gβ antibodies. Analyses of coimmunoprecipitated proteins indicate that phosphorylation of GRK2/3, β-arrestin, and Gβ has varying consequences on their ability to associate. As a result, increased availability of and signaling via Gβγ could occur without compromising the membrane content (and presumably activity) of GRK2/3. Induction of the concomitant phosphorylation of multiple proteins in a multimolecular complex with attendant modulation of their association represents a novel mechanism for increasing Gβγ signaling and opioid tolerance formation.

Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the "shell" as compared with the "core" of the rat nucleus accumbens.

The nucleus accumbens is considered a critical target of the action of drugs of abuse. In this nucleus a "shell" and a "core" have been distinguished on the basis of anatomical and histochemical criteria. The present study investigated the effect in freely moving rats of intravenous cocaine, amphetamine, and morphine on extracellular dopamine concentrations in the nucleus accumbens shell and core by means of microdialysis with vertically implanted concentric probes. Doses selected were in the range of those known to sustain drug self-administration in rats. Morphine, at 0.2 and 0.4 mg/kg, and cocaine, at 0.5 mg/kg, increased extracellular dopamine selectivity in the shell. Higher doses of cocaine (1.0 mg/kg) and the lowest dose of amphetamine tested (0.125 mg/kg) increased extracellular dopamine both in the shell and in the core, but the effect was significantly more pronounced in the shell compared with the core. Only the highest dose of amphetamine (0.250 mg/kg) increased extracellular dopamine in the shell and in the core to a similar extent. The present results provide in vivo neurochemical evidence for a functional compartmentation within the nucleus accumbens and for a preferential effect of psychostimulants and morphine in the shell of the nucleus accumbens at doses known to sustain intravenous drug self-administration.

Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment.

Ultra-low picomolar concentrations of the opioid antagonists naloxone (NLX) and naltrexone (NTX) have remarkably potent antagonist actions on excitatory opioid receptor functions in mouse dorsal root ganglion (DRG) neurons, whereas higher nanomolar concentrations antagonize excitatory and inhibitory opioid functions. Pretreatment of naive nociceptive types of DRG neurons with picomolar concentrations of either antagonist blocks excitatory prolongation of the Ca(2+)-dependent component of the action potential duration (APD) elicited by picomolar-nanomolar morphine and unmasks inhibitory APD shortening. The present study provides a cellular mechanism to account for previous reports that low doses of NLX and NTX paradoxically enhance, instead of attenuate, the analgesic effects of morphine and other opioid agonists. Furthermore, chronic cotreatment of DRG neurons with micromolar morphine plus picomolar NLX or NTX prevents the development of (i) tolerance to the inhibitory APD-shortening effects of high concentrations of morphine and (ii) supersensitivity to the excitatory APD-prolonging effects of nanomolar NLX as well as of ultra-low (femtomolar-picomolar) concentrations of morphine and other opioid agonists. These in vitro studies suggested that ultra-low doses of NLX or NTX that selectively block the excitatory effects of morphine may not only enhance the analgesic potency of morphine and other bimodally acting opioid agonists but also markedly attenuate their dependence liability. Subsequent correlative studies have now demonstrated that cotreatment of mice with morphine plus ultra-low-dose NTX does, in fact, enhance the antinociceptive potency of morphine in tail-flick assays and attenuate development of withdrawal symptoms in chronic, as well as acute, physical dependence assays.

Morphine-3-glucuronide's neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: Mechanistic studies in embryonic cultured hippocampal neurones

Indirect evidence indicates that morphine-3-glucuronide (M3G) may contribute significantly to the neuro-excitatory side effects (myoclonus and allodynia) of large-dose systemic morphine. To gain insight into the mechanism underlying M3G' s excitatory behaviors, We used fluo-3 fluorescence digital imaging techniques to assess the acute effects of M3G (5-500 muM) on the cytosolic calcium concentration ([Ca2+](CYT)) in cultured embryonic hippocampal neurones. Acute (3 min) exposure of neurones to M3G evoked [Ca2+](CYT) transients that were typically either (a) transient oscillatory responses characterized by a rapid increase in [Ca2+](CYT) oscillation amplitude that was sustained for at least similar to30 s or (b) a sustained increase in [Ca2+](CYT) that slowly recovered to baseline. Naloxone-pretreatment decreased the proportion of M3G-responsive neurones by 10%-25%, implicating a predominantly non-opioidergic mechanism. Although the naloxone-insensitive M3G-induced increases in [Ca2+](CYT) were completely blocked by N-methyl-D-aspartic acid (NMDA) antagonists and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (alphaamino-3-hydroxy-5-methyl-4-isoxazolepropiordc acid/ kainate antagonist), CNQX did not block the large increase in [Ca2+](CYT) evoked by NMDA (as expected), confirming that N13G indirectly activates the NMDA receptor. Additionally, tetrodotoxin (Na+ channel blocker), baclofen (gamma-aminobutyric acid, agonist), MVIIC (P/Q-type calcium channel blocker), and nifedipine (L-type calcium channel blocker) all abolished M3G-induced increases in [Ca2+](CYT), suggesting that M3G may produce its neuro-excitatory effects by modulating neurotransmitter release. However, additional characterization is required.