In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine

Illicit opioid overdoses are a significant problem throughout the world, with most deaths being attributed to opioid-induced respiratory depression which may involve peripheral mechanisms. The current treatment for overdoses is naloxone hydrochloride, which is effective but induces significant withdrawal. We propose that selectively peripherally acting opioid receptor antagonists, such as naloxone methiodide, could reverse respiratory depression without inducing predominantly centrally mediated withdrawal. Acute administration of morphine (300 mg/kg, i.p.) was found to significantly depress respiratory rate and induce analgesia (P<0.0001). Both naloxone hydrochloride and naloxone methiodide were able to reverse these effects but naloxone methiodide precipitated no significant withdrawal. Naloxone methiodide was also able to reverse opioid-induced respiratory depression (P<0.001) and antinociception (P<0.01) after chronic morphine administration (300 mg/kg/day for 5 days) without inducing significant withdrawal. Therefore, peripherally selective opioid receptor antagonists should be investigated as possible treatments for opioid-induced respiratory depression which do not induce adverse effects, such as withdrawal.     

Pediatric clonidine intoxications

Clonidine is an antihypertensive agent with central and peripheral alpha-2 adrenergic effects. One of the postulated mechanisms of action is the release of endogenous opioids and/or the stimulation of opioid receptors in the central nervous system (CNS). Naloxone, a pure opioid antagonist, has demonstrated reversal effects from clonidine intoxication. During the past 10 y, 25 children with a mean age of 2 y were admitted for clonidine intoxication. Dosage varied widely, but as little as 0.1 mg caused significant signs and symptoms. The most common presenting findings were somnolence-lethargy (96%), miosis (56%), and respiratory depression (48%), a paradoxical hypertensive response (44%) was more common than expected. Supportive management was the mainstay of therapy. Ten patients received naloxone, 50% demonstrated clinical improvement in vital signs and CNS depression. There were no complications as a result of naloxone therapy. Children seem to be unusually sensitive to the depressant effects of clonidine. Naloxone may be an important adjunct to therapy. Expect clonidine intoxications to become more common as the market for antihypertensive drugs expands.     

Naloxone treatment in opioid addiction: the risks and benefits

Naloxone is a non-selective, short-acting opioid receptor antagonist that has a long clinical history of successful use and is presently considered a safe drug over a wide dose range (up to 10 mg). In opioid-dependent patients, naloxone is used in the treatment of opioid-overdose-induced respiratory depression, in (ultra)rapid detoxification and in combination with buprenorphine for maintenance therapy (to prevent intravenous abuse). Risks related to naloxone use in opioid-dependent patients are: i) the induction of an acute withdrawal syndrome (the occurrence of vomiting and aspiration is potentially life threatening); ii) the effect of naloxone may wear off prematurely when used for treatment of opioid-induced respiratory depression; and iii) in patients treated for severe pain with an opioid, high-dose naloxone and/or rapidly infused naloxone may cause catecholamine release and consequently pulmonary edema and cardiac arrhythmias. These risks warrant the cautious use of naloxone and adequate monitoring of the cardiorespiratory status of the patient after naloxone administration where indicated.     

Naloxone treatment in opioid addiction: the risks and benefits

Naloxone is a non-selective, short-acting opioid receptor antagonist that has a long clinical history of successful use and is presently considered a safe drug over a wide dose range (up to 10 mg). In opioid-dependent patients, naloxone is used in the treatment of opioid-overdose-induced respiratory depression, in (ultra)rapid detoxification and in combination with buprenorphine for maintenance therapy (to prevent intravenous abuse). Risks related to naloxone use in opioid-dependent patients are: i) the induction of an acute withdrawal syndrome (the occurrence of vomiting and aspiration is potentially life threatening); ii) the effect of naloxone may wear off prematurely when used for treatment of opioid-induced respiratory depression; and iii) in patients treated for severe pain with an opioid, high-dose naloxone and/or rapidly infused naloxone may cause catecholamine release and consequently pulmonary edema and cardiac arrhythmias. These risks warrant the cautious use of naloxone and adequate monitoring of the cardiorespiratory status of the patient after naloxone administration where indicated.     

Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone : a study in healthy volunteers

BACKGROUND AND OBJECTIVE: Respiratory depression is a potentially life-threatening adverse effect of opioid therapy. It has been postulated that the difficulty of reversing buprenorphine-induced respiratory depression is caused by slow receptor association-dissociation kinetics at the opioid mu receptor. The aim of this study was to characterise the pharmacodynamic interaction between buprenorphine and naloxone in healthy volunteers. METHODS: A competitive pharmacodynamic interaction model was proposed to describe and predict the time course of naloxone-induced reversal of respiratory depression. The model was identified using data from an adaptive naloxone dose-selection trial following intravenous administration of buprenorphine 0.2mg/70kg or 0.4mg/70kg. RESULTS: The pharmacokinetics of naloxone and buprenorphine were best described by a two-compartment model and a three-compartment model, respectively. A combined biophase equilibration-receptor association-dissociation pharmacodynamic model described the competitive interaction between buprenorphine and naloxone at the opioid mu receptor. For buprenorphine, the values of the rate constants of receptor association (k(on)) and dissociation (k(off)) were 0.203 mL/ng/min and 0.0172 min(-)(1), respectively. The value of the equilibrium dissociation constant (K(D)) was 0.18 nmol/L. The half-life (t((1/2))) of biophase equilibration was 173 minutes. These estimates of the pharmacodynamic parameters are similar to values obtained in the absence of naloxone co-administration. For naloxone, the half-life of biophase distribution was 6.5 minutes. CONCLUSIONS: Because of the slow receptor association-dissociation kinetics of buprenorphine in combination with the fast elimination kinetics of naloxone, naloxone is best administered as a continuous infusion for reversal of buprenorphine-induced respiratory depression.     

Reversal of Opioid-Induced Ventilatory Depression Using Low-Dose Naloxone (0.04 mg): a Case Series

Introduction

Naloxone is commonly administered in emergency department (ED) to reverse opioid intoxication. Several naloxone dose recommendations exist for acute management of opioid intoxication based on limited published clinical data. A case series of ED patients with opioid-induced ventilatory depression that was reversed using a low-dose naloxone (0.04 mg with titration) is presented.

Methods

ED patients with opioid-induced ventilatory depression requiring naloxone administration were identified through medical toxicology consultation. Retrospective review of medical records was performed. Collected data included history, and pre- and post-naloxone data, including respiratory rate (RR), pulse oximetry (pulse ox), end-tidal CO₂ level (ET-CO₂), and Richmond Agitation Sedation Scale (RASS).

Results

Fifteen ED patients with moderate to severe opioid-induced ventilatory depression (median RR, 6 breaths/min) who were managed using low-dose naloxone strategy were identified. Twelve of 15 patients reported ingestion of methadone (range, 30 to 180 mg). The median naloxone dose of 0.08 mg (range, 0.04 to 0.12 mg) reversed opioid-induced ventilatory and CNS depression. Two patients experienced acute opioid withdrawal after receiving 0.08 mg.

Conclusion

ED patients with moderate to severe opioid-induced ventilatory depression can be reversed using 0.04 mg IV naloxone with appropriate dose titration.

     

The effects of naloxone on the cardiovascular and respiratory effects of centrally administered corticotrophin releasing factor in conscious rabbits.

1. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of corticotrophin releasing factor (CRF) (0.5 nmol kg-1) were examined in conscious rabbits. The effect of opioid receptor antagonism was examined to determine whether the responses to CRF were mediated by endogenous opioid peptides. 2. After i.c.v. CRF there was a rise in mean arterial pressure (MAP), heart rate (HR), plasma noradrenaline and adrenaline, and increased behavioural activity. Respiration rate increased, PaCO2 fell, but PaO2 was unchanged. 3. The pressor and behavioural effects of i.c.v. CRF were unaltered by high doses of intravenous naloxone (9 mumols kg-1 bolus followed by 9 mumols kg-1 min-1 infusion); these effects of CRF were also not prevented by double this dose of naloxone. Naloxone attenuated the CRF-induced tachycardia, blocked the increase in respiration rate and increased the fall in PaCO2. 4. After i.c. CRF (0.5 nmol kg-1) there were similar changes in MAP, HR, plasma catecholamines, respiration and behaviour. 5. These results indicate that in conscious rabbits the pressor effects of i.c.v. CRF are not mediated by endogenous opioid peptides. The finding that the effects of CRF were similar after i.c.v. and i.c. administration suggests that these responses may result from actions on brainstem rather than periventricular sites.     

Ontogenetic difference in ethanol reinforcing properties: the role of the opioid system

Previous data indicate that ethanol intoxication (3 g/kg, intragastric) on postnatal day (PD) 7 and 8 increases ethanol acceptance, but on PD 10 and 11 generates an aversion in infant rats. We investigated the participation of the opioid system in these effects. Subcutaneous administration of naloxone (1 or 10 mg/kg) followed by ethanol intoxication on PD 7 and 8 prevented the increased ethanol intake effect observed in the younger pups, but when ethanol intoxication occurred on PD 10 and 11, naloxone treatment did not affect the aversion observed at this age. An aversion to ethanol was evidenced in the younger pups administered ethanol and naloxone, but only when exposed to ethanol odor during ethanol intoxication. Results indicate that the increased ethanol acceptance induced by ethanol intoxication in the younger pups is mediated by the opioid system, and that ethanol may also induce conditioned aversions at this early age.     

Use of radiotelemetry to evaluate respiratory depression produced by chronic methadone administration

Illicit and therapeutic opioid administration can result in overdose due to opioid-induced respiratory depression. Research investigating the respiratory depressant effects of opioids has been limited due to difficulties associated with acquiring long-term respiratory data. This study examined the novel use of radiotelemetry to measure respiratory rate, heart rate, locomotor activity and blood pressure in rats treated chronically with methadone. Over 4 days of treatment, respiratory rate decreased, but partial tolerance appeared to develop during active (night) periods. Decreased heart rate was observed during the night periods and tolerance appeared to develop to this effect. Activity and blood pressure did not change with treatment. The effects of naloxone hydrochloride and naloxone methiodide administration on the methadone-treated rats were also examined and both antagonists increased respiratory rate and heart rate, with only naloxone hydrochloride producing significant increases in activity. Radiotelemetry offers a means of evaluating drug effects on respiratory rate continually in ambulatory, unstressed animals.     

非阿片类药物改善阿片类药物致呼吸抑制研究进展

阿片类药物通过作用于阿片受体,激活与受体偶联的G蛋白和(或)β-抑制蛋白等信号通路而发挥镇痛和麻醉等效应,但同时阿片类药物致呼吸抑制(OIRD)则是临床常见的严重问题.目前通常采用阿片受体拮抗剂纳洛酮等改善OIRD,但纳洛酮可能会拮抗阿片类药物的镇痛作用,甚至带来许多不可预知的不良反应.近年来,使用非阿片类药物直接和(...     

海洛因中毒呼吸衰竭47例的抢救体会

目的:探讨急性海洛因中毒呼吸衰竭患者的临床特点及抢救措施.方法:回顾性分析47例急性海洛因中毒致呼吸衰竭患者的临床资料及有关文献.结果:除1例心跳呼吸骤停病例外,46例均以突然昏迷、严重的呼吸抑制,针尖样瞳孔"三联征"为突出特征.入院给予氧改善通气,必要时应用呼吸机,静脉应用纳洛酮均转危为安.结论:"三联征"是急性海洛因中毒的突出特征,尽快明确诊断改善通气,必要时应用呼吸机,静脉应用纳洛酮是抢救成功的关键.     

Attempted antagonism of adenosine analogue induced depression of respiration

Intracerebroventricular (ICV) administration of the stable adenosine analogue 2-chloroadenosine (2CA) to hyperoxic halothane-anesthetized rats produced a dose-dependent depression of respiration largely as a result of a decrease in tidal volume. Similar changes were noted after another adenosine analogue, phenylisopropyladenosine (PIA). Higher doses shifted the minute ventilation-PaCO2 curve to the right and decreased its slope. Bradycardia and hypotension were produced at doses which altered respiration. Neonatal destruction of brain serotonin or dopamine-containing nerve terminals did not alter the 2CA-induced respiratory depression. Naloxone significantly antagonized the respiratory and circulatory changes produced by 2CA though the changes produced by PIA were not significantly antagonized. Peripherally and intracerebroventricularly administered theophylline were largely ineffective in reversing the 2CA-induced respiratory depression. Thus, these data suggest that a major part of the respiratory depression produced by 2CA is due to indirect activation of opioid receptors. In contrast, very little of the respiratory depression after PIA is via mechanisms antagonized by naloxone. Thus, putative adenosine agonists appear to vary in the extent to which respiratory depression is provoked by interactions with opioid systems.     

Predator stress engages corticotropin-releasing factor and opioid systems to alter the operating mode of locus coeruleus norepinephrine neurons

The norepinephrine nucleus, locus coeruleus (LC), has been implicated in cognitive aspects of the stress response, in part through its regulation by the stress-related neuropeptide, corticotropin-releasing factor (CRF). LC neurons discharge in tonic and phasic modes that differentially modulate attention and behavior. Here, the effects of exposure to an ethologically relevant stressor, predator odor, on spontaneous (tonic) and auditory-evoked (phasic) LC discharge were characterized in unanesthetized rats. Similar to the effects of CRF, stressor presentation increased tonic LC discharge and decreased phasic auditory-evoked discharge, thereby decreasing the signal-to-noise ratio of the sensory response. This stress-induced shift in LC discharge toward a high tonic mode was prevented by a CRF antagonist. Moreover, CRF antagonism during stress unmasked a large decrease in tonic discharge rate that was opioid mediated because it was prevented by pretreatment with the opiate antagonist, naloxone. Elimination of both CRF and opioid influences with an antagonist combination rendered LC activity unaffected by the stressor. These results demonstrate that both CRF and opioid afferents are engaged during stress to fine-tune LC activity. The predominant CRF influence shifts the operational mode of LC activity toward a high tonic state that is thought to facilitate behavioral flexibility and may be adaptive in coping with the stressor. Simultaneously, stress engages an opposing opioid influence that restrains the CRF influence and may facilitate recovery toward pre-stress levels of activity. Changes in the balance of CRF:opioid regulation of the LC could have consequences for stress vulnerability.     

Fatal respiratory depression after multiple intravenous morphine injections

A 26-year-old female was treated with morphine within the first 2 hours after knee surgery, in an attempt to titrate analgesia. The patient received a total of four intravenous injections of morphine 35 mg in total. Soon after the last injection the patient had adequate pain relief, was in a good clinical state and had adequate blood oxygenation. However, 40 minutes later, the patient had a deep respiratory depression followed by a fatal cardiac arrest. Solving the case in a medico-legal context was possible by applying results of clinical pharmacokinetic research on opioid analgesics, most importantly morphine, to this particular clinical case. This knowledge made it possible to estimate the probable concentrations of morphine at the site of its effect, the brain, during the time of the fatal event, and to show that these concentrations could have produced respiratory depression. We mainly attribute the fatal intoxication of morphine to the lag period needed for the transfer of morphine across the blood-brain barrier. Because of its slow transfer between plasma and the effect site, the CNS effects of morphine are delayed from its plasma concentrations to a clinically relevant degree. Successive injections at short intervals of relatively high amounts of morphine increase the clinical relevance of this delay. The present report demonstrates an important application of clinical pharmacokinetics for explaining clinical observations at a scientific level and transferring theoretical knowledge from clinical pharmacokinetics into daily clinical practice as a basis for rational opioid selection.     

Endogenously released opioids mediate meal-induced gastric relaxation via peripheral mu-opioid receptors

Aliment Pharmacol Ther 2011; 33: 607–614

Summary

Background The centrally acting mu‐opioid receptor antagonist naloxone inhibits meal‐induced gastric accommodation. Aim To study the role of peripheral mu‐opioid receptors in the regulation of gastric tone and food intake by comparing the effects of naloxone with the peripherally restricted mu‐opioid receptor antagonist methylnaltrexone. Methods Methylnaltrexone (12 mg s.c.), naloxone (20 μg/kg/h intravenous infusion after 0.4 mg bolus) and placebo were studied in 23 healthy volunteers. Gastric volume was recorded using an intragastric bag held at constant pressure connected to a barostat, with administration of a nutrient drink after 30 min. Pressure in the stomach was measured during intragastric nutrient drink infusion until the volunteers scored maximal satiation. Results Methylnaltrexone inhibited significantly the volume increase after food intake as assessed with the barostat (P < 0.01). During nutrient drink infusion the intragastric pressure significantly decreased as compared with the preprandial pressure after placebo treatment. Both methylnaltrexone and naloxone significantly inhibited this intragastric pressure decrease (P < 0.001 and P < 0.05, respectively). Volunteers scored maximal satiation after 979 ± 96, 958 ± 84 and 1124 ± 107 mL nutrient drink infused (for naloxone, methylnaltrexone and placebo treatment, respectively; P < 0.05). Conclusions These results indicate that endogenous opioids mediate gastric accommodation and satiation via peripheral mu‐opioid receptors. Effects were less pronounced after naloxone treatment, which indicates that centrally involved mu‐opioid receptors mediate an opposing effect.     

Cardio-respiratory toxicity of propoxyphene and norpropoxyphene in conscious rabbits

The toxic effects of alpha-d-propoxyphene (P) and its primary metabolite alpha-d-norpropoxyphene (NP) were compared to intravenous infusions (100 min.) of equimolar doses of P and NP (80 micronmol/kg equivalent to 30 mg/kg P HCl) in conscious rabbits. During P infusion severe respiratory depression and convulsions were seen in all animals, and six of the nine animals died. During NP infusion, however, only minimal respiratory depression was seen and all the animals survived. Considerable prolongation of the QRS complex and cardiac arrhythmias like intermittent A-V block and ventricular extrasystoles were seen in the ECG during both P and NP infusion, while the arterial blood pressure was unchanged. In P injection experiments (6 mg/kg P HCl), ECG changes preceded reduction in respiratory rate and during NP infusion only minor changes were seen in arterial blood gases, demonstrating that the ECG changes produced by P and NP are independent of respiratory depression. The ECG changes were found to be similar to those reported in quinidine intoxication. The QRS prolongation was markedly correlated with plasma concentrations during and after P and NP infusion. The results of the present investigation favour the hypothesis that the contribution of NP to the toxicity of oral P overdosage in man is ascribed to its cardiotoxic action whereas P is responsible for the CNS toxicity (respiratory depression and convulsions) as well as cardiotoxicity.     

Naloxone and diprenorphine reduce responding for brain self-stimulation in a fixed-ratio schedule in rats

Rats were implanted with bipolar stimulating electrodes in the midbrain-central gray area (MID-CG) and trained to lever-press for intracranial self-stimulation (ICSS) on a continuous reinforcement schedule (CRF). When behavior was stable, animals were tested in 30 min ICSS sessions following the administration of either naloxone or diprenorphine, both over the dose-range 0.001-10 mg/kg, or with vehicle. Following testing on the CRF schedule, animals were re-trained on a fixed-ratio:30 (FR:30) schedule. When behavior had again stabilized, testing with naloxone, diprenorphine and vehicle was repeated. In the CRF tests, neither naloxone nor diprenorphine had any effects on response rates over the 10,000-fold dose-range used. In the FR:30 tests, however, both drugs significantly reduced response rates at the 10 mg/kg dose, and the reduction produced by naloxone was significantly greater than that produce by diprenorphine. These results suggested that diprenorphine is qualitatively similar to naloxone in altering the rate of responding maintained by ICSS, but is less potent than the prototypical opioid antagonist in this paradigm.     

Cardio-Respiratory Toxicity of Propoxyphene and Norpropoxyphene in Conscious Rabbits*

Abstract The toxic effects of α-d-propoxyphene (P) and its primary metabolite α-d-norpropoxyphene (NP) were compared by intravenous infusions (100 min.) of equimolar doses of P and NP (80 μmol/kg equivalent to 30 mg/kg P HCl) in conscious rabbits. During P infusion severe respiratory depression and convulsions were seen in all the animals, and six of the nine animals died. During NP infusion, however, only minimal respiratory depression was seen and all the animals survived. Considerable prolongation of the QRS complex and cardiac arrhythmias like intermittent A-V block and ventricular extrasystoles were seen in the ECG during both P and NP infusion, while the arterial blood pressure was unchanged. In P injection experiments (6 mg/kg P HC1), ECG changes preceded reduction in respiratory rate and during NP infusion only minor changes were seen in arterial blood gases, demonstrating that the ECG changes produced by P and NP are independent of respiratory depression. The ECG changes were found to be similar to those reported in quinidine intoxication. The QRS prolongation was markedly correlated with plasma concentrations during and after P and NP infusions. The results of the present investigation favour the hypothesis that the contribution of NP to the toxicity of oral P overdosage in man is ascribed to its cardiotoxic action whereas P is responsible for the CNS toxicity (respiratory depression and convulsions) as well as cardiotoxicity.     

Morphine-6-glucuronide might mediate the prolonged opioid effect of morphine in acute renal failure

1. A 43-year-old male developed acute kidney failure due to ethylene glycol poisoning. He was treated with bicarbonate to combat metabolic acidosis, ethanol as an antimetabolite and haemodialysis to remove the glycol and its toxic metabolites. He was kept on a respirator and sedated with morphine. Peritoneal dialysis was given for 36 d. Following sedation with morphine for 11 d, the patient was given naloxone and then extubated. The antidote had to be continued for 14 d to prevent respiratory depression, until kidney function improved. 2. Only morphine-6-glucuronide (M-6-G) was found in the plasma and CSF at concentrations which might explain the opioid effects observed in the patient during the days after the cessation of morphine treatment. The ratio of the area under the concentration-time curve (AUC) of morphine-3-glucuronide (M-3-G) to M-6-G was 2:1. The elimination half-lives of M-3-G and M-6-G were 55 and 82 h, respectively. The clearance data indicate that most of the glucuronides were eliminated by peritoneal dialysis during renal failure. 3. The data suggest that M-6-G exerts opioid effects and is retained in acute kidney failure. Morphine should therefore not be used preferentially as a sedative/analgesic in pronounced kidney failure.     

The effects of a new opioid analgesic, meptazinol, on the respiration of the conscious rat.

In the conscious rat arterial PCO2 was measured as an index of respiratory status. The opioid analgesic meptazinol (7.5 - 30 mg kg-1) evoked small but significant increases in arterial PCO2 which were attenuated by naloxone. Meptazinol significantly reduced the increase in arterial PCO2 evoked by morphine. The respiratory depression induced by meptazinol, but not that induced by morphine, was enhanced by pretreatment with atropine. The (+)-enantiomer, but not the (-)-enantiomer of meptazinol increased arterial PCO2. In contrast, only the (-)-enantiomer reduced the respiratory depressant effect of morphine. It is proposed that the degree of respiratory depression induced by meptazinol is limited by its opioid antagonist and cholinomimetic properties.