Relief of postoperative pain: advances awaiting application.
Explore the source record for details and available documents.
Analgesics↗
Biomedical subjects
L E Mather
Publications and source records attributed to L E Mather.
Variables of patient-controlled analgesia. 1. Bolus size.
The efficacy of a range of demand doses of morphine for patient-controlled analgesia was studied. Patients who self-administered the smallest dose (0.5 mg) were frequently unable to achieve good pain control; patients who received the largest dose (2 mg) had a high incidence of ventilatory depression. A dose of 1 mg was the best increment under the conditions of this study but the relationship between increment and lockout interval requires consideration.
Abdomen↗
Variables of patient-controlled analgesia. 2. Concurrent infusion.
The effectiveness of morphine after surgery by patient-controlled analgesia alone or with a concurrent infusion was studied. The infusion did not reduce the dose of self-administered analgesic and patients treated in this way received twice as much drug as those who used patient-controlled analgesia alone. Pain control was similar in both groups. The practice of patient-controlled analgesia plus infusion requires critical review.
Abdomen↗
Propofol: assay and regional mass balance in the sheep.
1. Pharmacokinetic data for propofol, a new intravenous anaesthetic agent, indicate that there may be extensive extrahepatic clearance. This was investigated during intravenous infusions of propofol in adult merino ewes with chronic intravascular cannulae using a newly developed simple and rapid assay for propofol in blood and other biological samples. 2. The assay was based on organic solvent extraction of pH 4.5 buffered blood, urine or tissue homogenate, followed by reverse-phase h.p.l.c. with fluorescence detection. 3. A mean total body clearance of propofol of 3.15 l/min, (SD 0.87 l/min; n = 8) was found, consistent with a high hepatic extraction ratio (overall mean 0.87, SD 0.19; n = 8) and clearance (overall mean 1.12, SD 0.25 l/min; n = 7). The difference between total and hepatic clearances consisted principally of pulmonary clearance, but its extent was variable. 4. Other regional pharmacokinetic data were consistent with propofol distribution into muscle and brain tissues and propofol 'production' by the kidney, probably from a propofol metabolite formed elsewhere. 5. If these data are confirmed in humans then clinical pharmacokinetic data so far derived from peripheral venous blood sampling will require re-evaluation.
Animals↗
Myocardial and cerebral drug concentrations and the mechanisms of death after fatal intravenous doses of lidocaine, bupivacaine, and ropivacaine in the sheep.
This paper reports the cardiovascular effects of intentionally toxic intravenous doses of lidocaine, bupivacaine, and ropivacaine and the mechanisms of death. Fatal doses of lidocaine, bupivacaine, and ropivacaine were established in sheep treated with successive daily dose increments of each drug. The mean fatal dose of lidocaine (+/- SD) was 1450 +/- 191 mg (30.8 +/- 5.8 mg/kg), that of bupivacaine was 156 +/- 31 mg (3.7 +/- 1.1 mg/kg), and that of ropivacaine was 325 +/- 108 mg (7.3 +/- 1.0 mg/kg); thus the ratio of fatal doses was approximately 9:1:2. In four out of four lidocaine-treated animals, respiratory depression with bradycardia and hypotension without arrhythmias were the causes of death. Three out of four bupivacaine-treated animals died after the sudden onset of ventricular tachycardia/fibrillation without hypoxia or acidosis; the fourth died in a similar manner to the lidocaine-treated animals. Three out of five animals given ropivacaine died in a manner resembling the fatal effects of lidocaine-treated animals, but unlike the lidocaine-treated animals, in all three sheep there were also periods of ventricular arrhythmias. The remaining two ropivacaine-treated sheep died as a result of the sudden onset of ventricular tachycardia/fibrillation. The mean percentages of the fatal dose found in the myocardium was 2.8 +/- 0.7 for lidocaine-treated animals, 3.3 +/- 0.9 for bupivacaine-treated animals, and 2.2 +/- 1.4 for ropivacaine-treated animals; the corresponding percentages in whole brain were, respectively, 0.71 +/- 0.01, 0.71 +/- 0.21, and 0.89 +/- 0.27.
Amides↗
Hemodynamic and central nervous system effects of intravenous bolus doses of lidocaine, bupivacaine, and ropivacaine in sheep.
Lidocaine hydrochloride (HCl) (80-320 mg), bupivacaine HCl (20-80 mg), and ropivacaine HCl (30-120 mg) were administered as intravenous bolus doses to conscious sheep (n = 18; average body weight 45 kg) that had previously placed intravascular cannulae for hemodynamic monitoring and for obtaining blood samples. The mean convulsive doses and arterial blood concentrations were approximately 110 mg and 40 mg/L, respectively, for lidocaine HCl, 45 mg and 14 mg/L for bupivacaine HCl, and 60 mg and 20 mg/L for ropivacaine HCl. After subconvulsive doses of each agent, there were minimal cardiovascular effects. After convulsive doses, there were marked increases in heart rate, mean arterial pressure, pulmonary artery pressure, cardiac output, systemic vascular resistance, left ventricular end diastolic pressure, and myocardial contractility. Ventricular fibrillation caused death in two sheep after bupivacaine (80 mg) and in two sheep after ropivacaine (90 and 120 mg) administration. With sublethal doses, the hemodynamic responses to these agents were qualitatively and quantitatively similar when compared with their local anesthetic potencies.
Acid-Base Equilibrium↗
The use of mass balance principles to describe regional drug distribution and elimination.
Mass balance principles were used to derive a number of terms that are helpful in describing the rate and extent of regional drug uptake. Regional drug uptake was defined as the net movement of drug from the blood perfusing a region into the extravascular space of the region due to the distribution and/or elimination of the drug. By analogy with the traditional physiological definition of flux, net drug flux was defined as the difference in mass per unit time of drug respectively entering and leaving a region via the arterial and venous blood vessels. The time-integral of net drug flux, net drug mass, was defined as the mass of drug that has entered a region via the arterial blood vessels but has not left the region via the venous blood vessels. For regions in which no drug elimination occurs, the mean regional drug concentration was defined as the net drug mass divided by the mass of the region. When a number of criteria are satisfied, the net drug flux is approximately the rate of drug uptake and the net drug mass is approximately the extent of drug uptake. Several examples are given to demonstrate the broad range of applications of mass balance principles. First, the method was used to characterize the differences between drug distribution and elimination in a hypothetical region using drug concentrations simulated from compartmental models of either distribution alone or distribution with elimination. Second, the whole body distribution net flux was described during a constant rate infusion of iodohippurate (IOH) into a sheep from the difference between the whole body net flux and renal net flux of IOH. Third, the time course of the mean myocardial lignocaine (lidocaine) concentrations in a sheep after an intravenous bolus of lignocaine were described. The time course of the lignocaine-induced depression of myocardial contractility followed more closely the mean myocardial lignocaine concentrations than that of either the arterial or coronary sinus blood concentrations. It is concluded that the use of mass balance principles provides a simple, empirical, and physiologically based method for the determination of the rate and extent of both drug distribution and elimination in regions as simple as single organs or as complex as the whole body.
Lidocaine↗
The uptake and elution of lignocaine and procainamide in the hindquarters of the sheep described using mass balance principles.
Mass balance principles were used to describe the uptake and elution of lignocaine (lidocaine) and procainamide in the hindquarters of the sheep. Each of four sheep received a right atrial infusion of either lignocaine.HCl (2.7 mg/min) or procainamide.HCl (5.5 mg/min) for 180 min. Paired arterial and inferior vena cava (draining the hindquarters) blood samples were taken at 20-min intervals during the infusion and for 180 min after the infusion. Lignocaine and procainamide mean total body clearances were 2.9 L/min (SD 1.1) and 1.3 L/min (SD 0.2), respectively. An index of the uptake and elution of these drugs in the hindquarters was estimated from the net drug mass per unit hindquarter blood flow; indirect evidence suggested that hindquarter blood flow was constant. All the net mass/flow of procainamide that was taken into the hindquarters during the infusion also eluted after the infusion, demonstrating reversible distribution into the tissues. However, uptake of procainamide was still occurring when blood concentrations were constant, indicating that the concentrations of procainamide in the hindquarters were not in equilibrium with the inferior vena cava concentrations. Lignocaine did not reach constant blood concentrations during the infusion and showed no tendency to reach arterio-venous equilibration; an arterio-venous difference of 22% (SD 5%) across the hindquarters was measured during the last 60 min of the infusion. By 180 min after the lignocaine infusions, 79% (SD 8%) of the lignocaine net mass/flow had not eluted from the hindquarters when arterial and venous lignocaine concentrations were not significantly different. This drug could remain uneluted due to metabolism and/or avid tissue binding, and presents difficulties in the interpretation of pharmacokinetic data whether based on arterial or venous blood sampling.
Animals↗
The scientific basis of patient-controlled analgesia.
The current practice of patient-controlled analgesia has grown from empirical observations. Although several variants of patient-controlled analgesia, bolus doses, infusions, or combinations of both, have been suggested, a scientific basis for advocating one variant over the others has been lacking. Most systems have been based on the simplest system, bolus demand, although the use of a combined bolus and background infusion method has theoretical merit. Similarly, a scientific basis for setting the variables of patient-controlled analgesia, drug choice, incremental dose, maximum dose and lockout interval, also has been lacking. Settings for these variables may be rationalised post hoc on the basis of the physicochemical properties and global pharmacokinetic properties of the opioids used but knowledge of these properties has not helped in setting the variables a priori. Foremost, the drug choice should be based on therapeutic index. Knowledge of the regional kinetics of drug (influx and efflux) from brain may provide a more logical basis for setting the patient-controlled analgesia variables but such information can only come from animal experiments. More research is required if patient-controlled analgesia is to become anything but an empirical tool in the quest for improved analgesia in patients.
Analgesia↗
The development and clinical use of patient-controlled analgesia.
Patient-controlled analgesia has successfully made the transition from research tool to clinical acceptability. Reliable and sophisticated patient-controlled analgesia systems are commercially available. The technique has been most used for control of postoperative pain but has been successfully used during labour, after burns and other trauma and in terminal care. Virtually every opioid has been administered by patient-controlled analgesia using almost every route of administration. It is more effective than the traditional techniques of pain control after surgery but is not automatically so. Choice of opioid and the settings chosen for demand dose and lockout interval greatly influence effectiveness. Patient-controlled analgesia requires active participation by the patient but the psychology of patient-controlled analgesia has generally been under-estimated. Patient-controlled analgesia has developed empirically and many assumptions have been made; there is a need for fundamental research.
Analgesia↗
The influence of drug sorption on pharmacokinetic studies of chlormethiazole and lignocaine.
The influence of drug sorption on the measurement of dose and blood concentrations during pharmacokinetic studies of chlormethiazole and lignocaine in a chronically catheterized sheep preparation has been examined. There was no sorption to soda glass tubes, borosilicate glass volumetric flasks or soda glass microlitre syringes but minor sorption to polypropylene syringes, polypropylene pipette tips and rubber bottle stoppers after 240 min contact. During infusions through administration sets including either polyvinyl chloride or polyethylene catheters, no significant loss of lignocaine occurred, but only 41.7-63.9% of the chlormethiazole dose was delivered. No significant decreases in either drug occurred from blood sampled through an intravascular catheter and stopcock system. There was negligible degradation of the samples over 4 h. Sorption of chlormethiazole or lignocaine to the laboratory equipment used was not a significant source of error but polyvinyl chloride infusion catheters could result in significant reductions in chlormethiazole dose.
Absorption↗
Opioid pharmacokinetics in relation to their effects.
The chemical structure of drug molecules determines their fundamental pharmacological properties by 'fit' to the receptor, but the physicochemical properties, particularly lipid solubility and fraction un-ionised, dominate in determining distribution in the body and the rate of access to the biophase containing the drug receptors. For example, fentanyl appears much more potent than morphine because similar effective biophase concentrations are achieved with much smaller doses. Pharmacokinetic and pharmacodynamic investigations of the relationships between dose and the time-courses of blood concentrations and pharmacological effects of opioid drugs have helped explain the commonly observed variability between patients and have been useful in deriving effective dosage regimens of opioids such as pethidine, morphine, fentanyl and methadone where blood concentrations are a determinant of pharmacological response and 'target' analgetic blood opioid concentrations have been identifiable. However, there are instances when blood opioid concentrations are not determinants of the analgetic response. Examples include opioids, such as buprenorphine, for which the drug-receptor dissociation rate determines the duration of action, heroin which first has to be metabolised to become an agonist, pentazocine which is an agonist at some opioid receptors and an antagonist at others, and opioids placed intra-spinally acting on receptors in the spinal cord.
Analgesics, Opioid↗
The effects of general anaesthesia on tocainide clearance in the sheep.
The haemodynamic effects and regional clearances of tocainide were investigated in sheep with chronic intravascular cannulae to measure blood flow through, and drug extraction by, lungs, kidneys, liver and gut. 2. Tocainide, at arterial blood concentrations in the therapeutic range, caused no haemodynamic effects and was significantly extracted only by the liver. 3. In the presence of general anaesthesia with halothane, the mean hepatic blood flow and tocainide extraction ratio were each reduced by approximately 25% so that the mean hepatic clearance and intrinsic clearance of tocainide each were reduced by approximately 50%. Thus arterial blood tocainide concentrations were increased by 50%. 4. While the clinical implications of this interaction are unclear because of insufficient information about the margin of safety of tocainide, the pharmacological implications are plain. Because general anaesthesia may alter the relationship between dose and blood drug concentrations, pharmacokinetic and pharmacodynamic data should not be interchanged between awake and anaesthetized subjects.
Anesthesia, General↗
The influence of acidosis on the distribution of lidocaine and bupivacaine into the myocardium and brain of the sheep.
To test the hypothesis that acidosis can increase the toxicity of bupivacaine more than that of lidocaine by increasing the distribution into the brain, myocardium, or both, studies were performed to measure the in vivo tissue:blood partition coefficients during continuous steady state intravenous infusions of these agents in anesthetized sheep during normal acid-base status and during combined respiratory-metabolic acidosis. Acidosis decreased the partition coefficient of both agents into the myocardium and that of bupivacaine into the brain but did not systematically change that of either agent into skeletal muscle or fat. Total body and hepatic drug clearances were not affected systematically, but plasma binding of both agents was decreased. Thus predictions based on the pH partition hypothesis about the effects of acidosis on myocardial:blood partition coefficients being a basis for explaining the relative toxicity of these agents were not supported.
Acidosis↗
Pharmacology of opioids. Part 2. Clinical aspects.
Explore the source record for details and available documents.
Administration, Oral↗
Pharmacology of opioids. Part 1. Basic aspects.
Explore the source record for details and available documents.
Animals↗
A sheep preparation for studying interactions between blood flow and drug disposition. VI: Effects of general or subarachnoid anaesthesia on blood flow and chlormethiazole disposition.
Blood flow through and chlormethiazole extraction ratios across lungs, liver, kidneys and gut were measured in awake unrestrained sheep (controls) and with the same animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic subarachnoid blockade with amethocaine. In the control-drug studies, chlormethiazole infused to sub-sedative blood concentrations produced no significant changes in haemodynamics or in the kinetics of iodohippurate (renal and hepatic blood flows). Chlormethiazole was eliminated predominantly by the liver (mean extraction ratio and clearance, respectively, 0.90 and 1.3 litre min-1) and lungs (0.15; 0.6 litre min-1). Renal clearance was absent or negligible (greater than 0.1 litre min-1). Because of pulmonary clearance, mean total body clearance was derived from analysis of pulmonary arterial concentrations. Under general anaesthesia, there were significant reductions in mean cardiac output, hepatic and renal blood flow (to 54%, 63% and 43% of control); chlormethiazole mean hepatic extraction ratios and clearance were reduced, respectively, to 82% and 56% of control, and its pulmonary and renal clearances were abolished. With subarachnoid anaesthesia there were no significant changes in haemodynamics or in chlormethiazole extraction ratios or clearances.
Anesthesia, General↗
A sheep preparation for studying interactions between blood flow and drug disposition. V: The effects of general and subarachnoid anaesthesia on blood flow and pethidine disposition.
Blood flow through and pethidine extraction ratios across lungs, liver, kidneys and the gastrointestinal tract were measured in awake unrestrained sheep (controls) and with the animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic subarachnoid block with amethocaine. In the control studies, pethidine infused to several times the blood concentrations required for postoperative analgesia in man produced no significant changes in haemodynamics or in the kinetics of iodohippurate (renal and hepatic blood flow); pethidine hepatic extraction ratios were consistently greater than 0.97; renal extraction ratios ranged from negligible to 0.30; and there was negligible extraction across the lungs and the gastrointestinal tract. Under general anaesthesia there were significant reductions in mean cardiac output (46%), mean hepatic blood flow (46%), mean renal blood flow (55%), mean arterial pressure (30%) and mean iodohippurate clearance (17%); but mean arterial blood concentrations of pethidine were doubled, mean hepatic clearance of pethidine was reduced to 60% of control and renal clearance was virtually abolished. With subarachnoid anaesthesia there were no significant changes in haemodynamics or in pethidine or iodohippurate extraction ratios or clearances. Summed measured regional clearances accounted for only one- to two-thirds of the total body clearance of pethidine; the rest was by extravisceral clearance or high affinity tissue binding.
Anesthesia, General↗