Ventilatory responses of healthy subjects to intravenous combinations of morphine and oxycodone under imposed hypercapnic and hypoxaemic conditions.

AIMS: Previous isobolographic analysis revealed that coadministration of morphine and oxycodone produces synergistic antinociception in laboratory rodents. As both opioids can produce ventilatory depression, this study was designed to determine whether their ventilatory effects were synergistic when coadministered to healthy human subjects. METHODS: A placebo-controlled, randomized, crossover study was performed in 12 male volunteers. Ventilatory responses to hypoxaemia and hypercapnia were determined from 1-h intravenous infusions of saline ('placebo'), 15 mg morphine sulphate (M), 15 mg oxycodone hydrochloride (O), and their combination in the dose ratios of 1:2, 1:1, 2:1. Drug and metabolite concentrations in serial peripheral venous blood samples were measured by high-performance liquid chromatography-MS/MS. RESULTS: 'Placebo' treatment was without significant ventilatory effects. There were no systematic differences between active drug treatments on either the slopes or intercepts of the hypoxaemic and hypercapnia ventilation responses. During drug treatment, the mean minute ventilation at PetCO(2) = 55 mmHg (V(E55)) decreased to 74% of the subjects' before treatment values (95% confidence interval 62, 87), 68% (57, 80), 69% (59, 79), 68% (63, 73), and 61% (52, 69) for M15, M10/O5, M7.5/O7.5, M5/O10 and O15, respectively. Recovery was more prolonged with increasing oxycodone doses, corresponding to its greater potency and lower clearance compared with morphine. CONCLUSIONS: Although adverse ventilatory effects of these drugs were found as expected, no unexpected or disproportionate effects of any of the morphine and oxycodone treatments were found that might impede their use in combination for pain management.

Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep.

1. The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. 2. In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects. 3. To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (approximately 50 Kg body weight). After dose-ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 micromol (approximately 2.5 mg) in 8 micromol increments, to either a fatal outcome or a 40 micromol (approximately 12.5 mg) maximum. 4. All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean+/-s.e.mean actual fatal dose: 21.8+/-6.4 micromol), five of seven with levobupivacaine (22.9+/-3.5 micromol), four of six with ropivacaine (22.9+/-5.9 micromol). No significant differences in survival or in fatal doses between these drugs were found. 5. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage.

Tolerability of large-dose intravenous levobupivacaine in sheep.

UNLABELLED: In preclinical pharmacological studies of levobupivacaine (S-bupivacaine), we determined its tolerability, cardiovascular actions, and pharmacokinetics, and we estimated its margin of safety compared with bupivacaine in conscious sheep. Levobupivacaine HCl. H(2)O was infused IV for 3 min into 10 previously instrumented ewes (approximately 50 kg). On subsequent days, the doses were increased by 50 mg from 200 or 250 mg until fatality occurred. All doses produced convulsions, QRS widening, and cardiac arrhythmias. With incremental doses, 4 of 4 animals survived 200 mg, 7 of 10 survived 250 mg, 3 of 7 survived 300 mg, but 0 of 3 survived 350 mg. Death resulted from sudden onset ventricular fibrillation (n = 3, within 2-3 min), electromechanical dissociation-pump failure (n = 5, within 4-5 min), or ventricular tachycardia-induced cardiac insufficiency (n = 2, >10 min). The estimated fatal dose (mean +/- SD) was 277 +/- 51 mg for levobupivacaine (compared with 156 +/- 31 mg found previously for bupivacaine). Pharmacokinetic analysis indicated initial and total distribution volumes = 4.5 (+/-1.6) and 97 (+/-22) L, total clearance = 1.7 (+/-0.4) L/min, and slow half life = 70 (+/-29) min; these values did not differ from those found previously with smaller doses. Heart and brain tissue levobupivacaine concentrations were approximately 3 times those in arterial blood. The doses of levobupivacaine survived were larger than found previously for bupivacaine, indicating its greater margin of safety. IMPLICATIONS: Levobupivacaine produced fatal cardiac toxicity at doses significantly greater than those found in previous studies with bupivacaine. As the two drugs have similar potency for producing clinical nerve blocks, the data imply that levobupivacaine should provide a safer alternative to bupivacaine in practice.

Central Effects Index--a semiquantitative method for the assessment of CNS toxicity of local anaesthetic agents in sheep.

Local anaesthetic agents can cause central nervous system (CNS) and cardiovascular system toxicity. Whereas most previous work has described their behavioural CNS effects qualitatively (i.e., absence or presence of convulsions), we wished to describe their CNS effects more quantitatively. We hypothesised that early CNS excitatory or disinhibitory effects leading to convulsions represent a prodrome to the onset of chaotic dynamics in the form of a bifurcation in the chaotic map. We therefore used a chaotic map with a continuous scale to model their CNS effects. A Central Effects Index (CEI) was developed from our observation of behaviours before and after intravenous (iv) administration of local anaesthetic agents in graded doses to conscious sheep. These behaviours were ranked in severity, and modelled according to a logistic population growth equation using the onset of convulsive behaviour and death as point attractors. The behaviours, scaled to the maximum and area under the curve (AUC) CEI units, were then compared for intravenous doses of (+/-)-RS-bupivacaine and (-)-(S)-bupivacaine (or levobupivacaine), which is being evaluated as a substitute for (+/-)-RS-bupivacaine. (-)-(S)-bupivacaine produced smaller maximum and AUC CEI values at 75 and 100 mg doses, but equivalent values at 150 and 200 mg when the doses exceeded the convulsant threshold. It was concluded that the CEI provides a useful quantitative tool for evaluating these agents in subconvulsant doses, and that the CNS stimulatory potency of (-)-(S)-bupivacaine is less than that of (+/-)-RS-bupivacaine.