Kg-1 Morphine Research Articles

Intranasal Low-Dose Naltrexone Against Opioid Side Effects: A Preclinical Study.

Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the clinical practice. Unfortunately, together with analgesia, a number of adverse effects can occur such as nausea, vomiting, constipation, gastrointestinal alterations and cognitive impairments. Naltrexone is a competitive antagonist of opioid receptors commonly used to treat opioid addiction; its oral use against agonists side effects is limited by the decrease of opioids-therapeutic efficacy and own adverse effects. The intranasal delivery of naltrexone could offer a quick and effective achievement of CNS based on extracellular mechanisms including perineural and perivascular transport. The aim of the study was to test the efficacy of intranasal low-dose naltrexone in reducing intraperitoneal morphine and oxycodone side effects in rodents. In mice, 1 μg naltrexone intranasally administered 30 min before opioids reduced cognitive impairments and motor alteration induced by 10 mg kg−1 morphine and 60 mg kg−1 oxycodone in the Passive avoidance and Rota rod tests, respectively. Moreover, naltrexone rebalanced opioid-induced reduction of the intestinal transit and latency of feces expulsion as well as food intake inhibition. Importantly, 1 μg naltrexone instillation did not block analgesia as demonstrated by the Hot plate test. In rats, intranasal naltrexone counteracted the opioid-induced pica phenomenon related to emesis and increased water and palatable food intake. The effects were comparable to that achieved by metoclopramide used as reference drug. Treatments did not influence body weight. Lastly, the safety of the intranasal delivery has been checked by hematoxylin–eosin staining that did not show histological alterations of the nasal cavity. In conclusion, intranasal low-dose naltrexone counteracted morphine and oxycodone induced gastrointestinal and CNS side effects without impairing opioid analgesia. It is a candidate to be a valid clinical strategy deserving deep analysis.

Preoperative paracetamol improves post-cesarean delivery pain management: a prospective, randomized, double-blind, placebo-controlled trial

Study ObjectiveTo evaluate the analgesic effect of preoperative single dose intravenous paracetamol on postoperative pain and analgesic consumption within 24hours after elective cesarean surgery. DesignProspective, randomized, double-blind, placebo-controlled clinical trial. SettingUniversity Teaching Hospital. PatientsAmerican Society of Anesthesiologists (ASA) I and II 60 patients between 18–40years of age who were scheduled to undergo elective cesarean section. InterventionsPatients were randomized into two groups to receive either intravenous 1g paracetamol (100mL) (Group P) or 0.9% NaCl solution (100mL) (Group C) 15minutes before the induction of general anesthesia. After delivery of newborn 0.15mg kg-1 morphine was administered to all patients in both groups. Postoperative analgesia was provided with patient-controlled intravenous analgesia with morphine in the postoperative period. MeasurementsPain which is the primary outcome measure was assessed at 15th, 30th minutes and 1st, 2nd, 4th, 6th, 12th, 24th hours by the Visual Analogue Scale. Patients' demographics, hemodynamics, Apgar score, additional analgesic requirement, side effects, patients' satisfaction and postoperative total morphine consumption within 24hours were recorded. Main ResultsMedian visual analogue scale for pain in Group P was significantly lower compared to Group C at all time points except for the score at 24th h postoperatively (P<.05). Additional analgesic requirement during postoperative first hour was lower in Group P (P<.05). Total morphine consumption was higher in Group C compared with Group P (P<.05). There was no difference between groups with respect to Apgar scores, side effects, and patient satisfaction (P>.05). ConclusionsPreoperative use of single-dose intravenous 1g paracetamol was found to be effective in reducing the severity of pain and opioid requirements within 24hours after cesarean section.

Efeitos cardiovasculares e analgésicos da administração epidural de ropivacaína isolada ou associada à morfina, em felinos

Visando avaliar os efeitos cardiovasculares e analgésicos de dois protocolos epidurais em felinos submetidos à OSH, 16 gatas mestiças, adultas, que, após indução à anestesia geral, receberam anestesia epidural (L7 - S1) com 0,26mL kg-1 de ropivacaína 0,75%, isolada (GR) ou associada a 0,1mg kg-1 morfina (GRM). A ETCO2, f, FC, PAS, T°R e relaxamento muscular foram avaliados no momento basal, 30 minutos após epidural, após incisão de pele, ligadura dos pedículos ovarianos e cérvix, final da celiorrafia e cirurgia, sendo administrado fentanil, caso ocorresse aumento de 20% na PAS, FC ou f em relação ao momento basal. Ao final do procedimento, foram avaliados, com auxílio de uma escala multidimensional de dor aguda em felinos, durante 12 horas, e, quando a pontuação fosse ≥8, era realizado resgate analgésico com morfina 0,2mg kg-1. Não ocorreram diferenças entre ETCO2, f, T°C e relaxamento muscular. A PAS aumentou em ambos os grupos durante o pinçamento dos pedículos ovarianos e cérvix, quando 100% dos animais do GR e 87,5% do GRM necessitaram fentanil transoperatório. Em 100% dos animais do GR, houve necessidade de morfina pós-operatória às 2 e 4 horas de avaliação, comparados com 50% e 37,5% no GRM. Nos momentos seguintes aos resgates, o somatório de pontos foi semelhante entre grupos. Conclui-se que a administração epidural de ropivacaína associada à morfina em gatas submetidas à ovariosalpingohisterectomia reduz o requerimento analgésico pós-operatório em até 56,2%, durante as primeiras 4 horas, e promove analgesia adequada durante 12 horas, quando comparado à ropivacaína isolada

Cardiopulmonary effects and eyeball centralization with low-dose atracurium in spontaneously breathing, anesthetized dogs

The objective was to determine the cardiopulmonary effects and eyeball centralization time obtained with 15 or 30µg kg-1 of atracurium in anesthetized dogs under spontaneous breathing. Eighteen healthy adult mixed-breed dogs were used, which received 0.1mg kg-1 acepromazine and 0.5mg kg-1 morphine IM, followed by 4mg kg-1 propofol IV and maintained on isoflurane anesthesia with spontaneous breathing. Animals received 1mL 0.9% NaCl IV (CG), 15µg kg-1 (G15) or 30µg kg-1 (G30) of atracurium IV. Eyeball centralization time was measured; heart rate (HR), systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressures, respiratory rate (RR), tidal volume (Vt) and minute volume (Vm) were determined every 5min, and pH, arterial CO2 pressure (PaCO2 ), arterial O2 pressure (PaO2 ), hemoglobin oxygen saturation (SaO2 ), bicarbonate (HCO3-) and base excess (BE) every 15min until 60min. Both doses of atracurium produced a similar period of eyeball centralization. Vt in groups treated with atracurium was lower than in CG up to 15min. Vm in G15 differed from CG up to 10min and in G30 up to 25min. No differences were observed for cardiovascular parameters, RR, SaO2, PaO2, HCO3- and BE. pH decreased in CG between 30 and 60min and in G15 and G30 at 15min. G30 differed from CG between 15 and 30min. PaCO2 in GC differed from baseline between 30 and 60min and in G15 differed at 15min. Atracurium at the dose of 15µg kg-1 is adequate for short corneal procedures in inhalant-anesthetized dogs under spontaneous breathing.

Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine.

Concentrations in the cerebrospinal fluid (CSF) are a useful approximation to the effect site for drugs like morphine. However, CSF samples, are available only in rare circumstances. If they can be obtained they may provide important insights into the pharmacokinetics/pharmacodynamics of opioids. Nine neurological and neurosurgical patients (age 19-69 years) received 0.5 mg kg-1 morphine sulphate pentahydrate as an intravenous infusion over 30 min. Plasma and CSF were collected for up to 48 h. Concentration time-course and interindividual variability of morphine (M), morphine-3-glucuronide (M3G) and morphine-6 glucuronide (M6G) were analysed using population pharmacokinetic modelling. While morphine was rapidly cleared from plasma (total clearance = 1838 ml min-1 (95% CI 1668, 2001 ml min-1)) the glucuronide metabolites were eliminated more slowly (clearance M3G = 44.5 ml min-1 (35.1, 53.9 ml min-1), clearance M6G = 42.1 ml min-1 (36.4, 47.7 ml min-1)) and their clearance could be described as a function of creatinine clearance. The central volumes of distribution were estimated to be 12.7 l (11.1, 14.3 l) for morphine. Transfer from the central compartment into the CSF was also rapid for M and considerably slower for both glucuronide metabolites. Maximum concentrations were achieved after 102 min (M), 417 min (M3G) and 443 min (M6G). A P-glycoprotein exon 26 polymorphism previously found to be linked with transport activity could be involved in CSF accessibility, since the homozygous mutant genotype was associated (P < 0.001) with high maximum CSF concentrations of M but not M3G or M6G. From the population pharmacokinetic model presented, CSF concentration profiles can be derived for M, M3G and M6G on the basis of dosing information and creatinine clearance without collecting CSF samples. Such profiles may then serve as the link between dose regimen and effect measurements in future clinical effect studies.

Effect of Nω‐nitro‐l‐arginine methyl ester, a nitric oxide synthesis inhibitor, on stress‐ and morphine‐induced prolactin release in male rats

1. The effect of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was investigated on stress- and morphine-induced prolactin (PRL) secretion in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Three doses of L-NAME were tested (1, 10 and 30 mg kg-1) and were given intraperitoneally one hour before blood sampling; control rats received saline. After the first blood sample, rats received an initial intravenous injection of morphine (3, 6 or 12 mg kg-1) or were subjected to immobilization stress. In the case of a morphine administration, rats received a second dose of morphine (3, 6 or 6 mg kg-1, respectively) 90 min later, when tolerance had developed, while rats subjected to immobilization stress received 6 mg kg-1 morphine 90 min after onset of stress. 3. L-NAME had no effect on basal plasma PRL concentration. However, it potentiated acute morphine-induced PRL secretion and attenuated the subsequent tolerance in a dose-dependent way. Immobilization stress-induced PRL secretion was inhibited dose-dependently by L-NAME, as was its subsequent tolerance to morphine; however, in this case, in a reversed dose-dependent way. 4. When the highest dose of morphine (12 mg kg-1) was combined with the highest dose of L-NAME pretreatment (30 mg kg-1), all rats showed a dramatic potentiation of the morphine-induced PRL rise compared to controls. Moreover, all of these rats died within 90 min after the administration of morphine. 5. These results show that NO plays a role in the acute opioid action on PRL release during stress as well as in the development of tolerance to the opioid effect, and some possible mechanisms are discussed.

N‐methyl‐d‐aspartate receptor antagonists potentiate morphine's antinociceptive effect in the rat

The interaction between morphine and three antagonists of the N-methyl-D-aspartate (NMDA) receptor. MK-801 (non-competitive channel blocker), dextromethorphan (clinically available non-competitive antagonist) and CGS19755 (competitive receptor antagonist), was examined in rats with the hot plate test. The NMDA antagonists were administered intraperitoneally and none of them caused antinociception at doses that did not produce motor deficits (0.1 mg kg-1 MK-801, 30 mg kg-1 dextromethorphan and 5 mg kg-1 CGS19755). However, pretreatment with the NMDA antagonists at these doses 30 min prior to subcutaneous injection of 5 mg kg-1 morphine significantly potentiated the antinociceptive effect of morphine, with strongest effect observed with dextromethorphan. It is suggested that blockade of NMDA receptors enhances the antinociceptive effect of morphine and NMDA antagonists may improve the analgesic efficacy of morphine in the clinic.

The CCK-B receptor antagonist Cl 988 reverses tolerance to morphine in rats.

The ability of the selective cholecystokinin-B (CCK-B) receptor antagonist Cl 988 to reverse tolerance to morphine's antinociceptive effect was investigated with the hot-plate test in Sprague-Dawley rats. Tolerance was induced by subcutaneous (s.c.) injection of 10 mg kg-1 morphine twice daily for four days. On the fifth day rats were administered CI 988 (10 mg kg-1) or saline plus 5 mg kg-1 morphine s.c. Significant antinociception was observed in the group that received the CCK-B antagonist plus morphine, whereas the saline plus morphine group exhibited total tolerance. These results suggest that upregulation of the endogenous CCK system during repeated morphine administration may have an important role in the development of opiate tolerance.

The CCK-B antagonist CI988 enhances the reflex-depressive effect of morphine in axotomized rats.

We have examined and compared the effect of systemic CI988, an antagonist of the cholecystokinin B receptor, and morphine on the flexor reflex in rats with intact sciatic nerves and after unilateral axotomy. Intravenous injection of 1 mg kg-1 morphine caused a moderate depression of the flexor reflex in normal and axotomized rats. The duration of morphine-induced depression was significantly shortened in axotomized animals. In contrast, the brief depressive effect of intravenous CI988 on the flexor reflex was significantly enhanced in axotomized rats. Combination of morphine and CI988 resulted in a significant potentiation of reflex depression in rats with intact or sectioned sciatic nerves. It is concluded that blockade of CCK-B receptor potentiated morphine-induced antinociception in rats after peripheral nerve injury.

Pharmacokinetics of morphine and its surrogates XI: Effect of simultaneously administered naltrexone and morphine on the pharmacokinetics and pharmacodynamics of each in the dog

There were no dramatic modifications of the pharmacokinetics in the dog of i.v. bolus doses of 0.5, 2.7 and 5 mg kg-1 morphine by coadministering i.v. 5 mg kg-1 naltrexone as bolus injections over 15-20s and 12.3 mg kg-1 by continuous infusion. Morphine's terminal half-life, clearances, apparent volumes of distribution (except for that of the central compartment), percentages of drug and conjugated metabolite excreted in urine and bile did not differ significantly by paired t-test (probability (p) greater than 0.05 for rejection of the null hypothesis of no difference) when naltrexone was coadministered. There were no statistically significant (by t-test) modifications of the plasma pharmacokinetics in the dog of i.v. bolus doses of 5 mg kg-1 naltrexone with and without morphine coadministration except for the coefficient of the second (or terminal) exponential of the sum that fitted the plasma concentration-time data of naltrexone. Although morphine coadministration did not significantly affect the terminal half-life of naltrexone, its clearances or apparent volumes of distribution by t-test of the differences between averages (with each dog equally weighted), drug coadministration did significantly (by t-test) affect the fraction of naltrexone dose secreted into bile as conjugate (fB), the fraction of the dose excreted as conjugate in urine, and the fraction excreted elsewhere (f'B). Although naltrexone reversed the central action of morphine in affecting monitored pupil diameters, it did not antagonize the peripheral effects of morphine in perturbing renal and biliary flow rates. This led to a larger fraction of the naltrexone dose being metabolized to conjugate on morphine coadministration. Since less naltrexone conjugate was renally and biliary excreted initially, due to morphine inhibition of the initial renal and biliary processes, naltrexone conjugate plasma concentrations were higher when morphine was coadministered.

The steady‐state and rebreathing methods compared during morphine administration in humans.

1. We examined the quantitative and qualitative differences between the steady-state and rebreathing methods of determining CO2-response curves before and after each of two doses of intravenous morphine (0.07 and 0.14 mg kg-1) in four healthy male humans. 2. During each study session steady-state and rebreathing CO2-response curves were determined as an ordered pair (separated by 15 min). Carbon dioxide-response curves were determined for control, after 0.07 mg kg-1 morphine, and after a total of 0.21 mg kg-1 morphine. Each subject was studied on a second occasion when the order of the CO2-response pairing was reversed. 3. The results are discussed and related to a model that may account for the differences based on the step increase in CO2 at the onset of rebreathing, the rate of rise of CO2 during rebreathing and the time constant for the central chemoreflex. 4. Our empirical conclusion is that morphine causes a parallel right shift of the steady-state CO2-response curve and causes a non-specific decrease in the slope of the rebreathing CO2-response curve. We suggest that the parallel shift of the steady-state CO2-response curve is specific to drugs acting on opioid receptors.

Micturition in naive and morphine-dependent rats.

Voiding responses were recorded in conscious water-loaded rats. Morphine sulphate (5 mg kg-1) elevated the volume threshold for micturition (MV); the group mean MV of 16 rats after morphine was 40% larger than control. Micturition was nevertheless complete since no urine remained in the bladder afterwards. The implantation of 2 or 4 morphine-base pellets (150 or 300 mg morphine) elevated for 12 days the MV in water-loaded rats. On the 3rd to the 10th day following implantation the group mean was approximately twice that of untreated controls. After micturition was over no residual urine was found in the bladder. Within 3 days the rats became tolerant to the antinociceptive action of the morphine-base pellets but little apparent tolerance developed to their action on micturition. On the 1st day after the pellets were removed, the mean MV was reduced. When withdrawal was precipitated by the administration of naloxone the MV was often too small to measure. This component of a withdrawal syndrome could be elicited in the rats throughout the 12 days of morphine pellet implantation. The administration of 20 mg kg-1 morphine sulphate to anaesthetized rats did not decrease the contractions of the urinary bladder to repetitive stimulation of its motor nerves at 1 and 20 Hz.