Laurence E. Mather

The incidence of postoperative pain in children

Abstract The incidence of pain in 170 children recovering from surgery was surveyed in two major teaching hospitals along with an analysis of analgesic medication prescribed and administered. Analgesic medication was not ordered for 16% of the patients and narcotic analgesic medication ordered was not given for 39% of the patients. In 29% of the patients, where an order for ‘narcotic or non‐narcotic analgesic medication’ was written, the non‐narcotic drug was given exclusively. Irrespective of the treatments received, only 25% of the patients were pain free on the day of surgery and 13% reported severe pain. By the first postoperative day, 53% reported no pain but 17% still reported severe pain. There appeared to be no relationship between ages of patients and severity of pain reported. Analysis of orders written for postoperative analgesics revealed extremely variable prescribing habits of the medical staff and that doses frequently were too small and/or too infrequent. The majority of orders were written ‘PRN’ which often was interpreted by nursing staff as ‘as little as possible.’ Nursing staff also preferred not to give narcotic medications but substituted non‐narcotic analgesics, even soon after surgery. Many of the children surveyed became withdrawn and this was interpreted as coping with pain. Others expressed a dread of ‘the needle’ as a way of administering analgesics and preferred to suffer pain to an injection. We have concluded that there is considerable scope to improve pain management in children after surgery. This improvement must be based on improved education of medical and nursing staff in contemporary clinical pharmacology and on improved communication between staff, parents and patients.

Clinical pharmacokinetics of fentanyl and its newer derivatives.

Fentanyl, a synthetic opiate with a (clinical) potency of 50 to 100 times that of morphine, was introduced into clinical practice in the early 1960s. Usually administered by single intravenous doses, it developed a reputation for having a short duration of action and it was assumed that this was a consequence of rapid removal from the body. However, as clinical experience increased, it was realised that administration of multiple doses or large doses during narcotic-based anaesthesia sometimes led to delayed recovery and prolonged respiratory depression, suggesting that the duration of action was limited by redistribution within the body rather than removal from the body. Recent developments in analytical techniques have allowed pharmacokinetic studies and these have confirmed this opinion; fentanyl is rightly regarded as having a redistribution-limited duration of action after single or infrequent doses (analogous to thiopentone). However, the magnitude of the pharmacokinetic constants reported for fentanyl are remarkably inconsistent even in healthy volunteers, for reasons apparently only explainable by assay differences. Hence, estimates of apparent volume of distribution (area) range from around 60L to over 300L, estimates of terminal half-life range from about 1.5 to 6 hours (15 hours in geriatric patients) and total body clearance ranges from 0.4 to over 1.5 L/min. Renal excretion accounts for up to 10% of the dose; the remainder of the clearance would appear to be predominantly hepatic, but with contributions from other tissues.Continued clinical developments of narcotic-based anaesthetic techniques have resulted in high doses of narcotic being used, with oxygen, as the sole anaesthetic agents. At present these techniques are usually based on fentanyl, and the technique is frequently called ’stressfree anaesthesia’ because of the effects in obtunding the ’stress response’ caused by surgery (elevation of plasma concentrations of cortisol, glucose, ADH, etc. in the intra- and postoperative period) and the lack of deleterious effects on the cardiovascular system.With the hypothesis that increased potency is associated with increased specific opiate effects and decreased nonspecific cardiovascular depressant effects, chemical congeners of fentanyl were developed. Alfentanil has about one-third the (clinical) potency of fentanyl, while sufentanil has about 5 to 10 times the (clinical) potency of fentanyl. Lofentanil and carfentanil have about 20 to 30 times the potency of fentanyl and have yet to find clinical roles.Alfentanil is characterised by a rather small apparent volume of distribution for a base (Varea = 40-70L), short terminal half-life (100 minutes), intermediate total body clearance (0.3–0.5 L/min) and negligible renal clearance. Sufentanil would appear to have pharmacokinetic properties intermediate to those of alfentanil and fentanyl.At physiological pH, approximately 15 to 20% of fentanyl is unbound in plasma compared with 5 to 10% of alfentanil, sufentanil and lofentanil. Except for alfentanil, there is a marked plasma binding dependence on pH. Also except for alfentanil, there is a predominance of ionised drug species and a high octanol: water partition coefficient in the physiological pH range. These factors act to influence the tissue binding of the agents and reflect back on other important factors such as uptake by blood cells. Whole blood: plasma concentration ratios of 0.97, 0.63, 0.74 and 0.71 have been reported for fentanyl, alfentanil, sufentanil and lofentanil, respectively.The range of opiate duration of action has been extended by the appearance of these newer compounds, where alfentanil may be regarded as having an ultrashort duration of action, fentanyl and sufentanil as short acting, while lofentanil has a long duration of action. Knowledge of the pharmacokinetic properties of these agents has provided more information than could be obtained from clinical studies alone, and has added a basis on which to rationalise and enhance their usefulness.

Clinical pharmacokinetics of local anaesthetics.

SummaryThe introduction of the new long acting local anaesthetics, bupivacaine and etidocaine, has stimulated an expansion of interest in regional anaesthesia, particularly for obstetrical applications and pain therapy.Systemic toxicity following injection of local anaesthetics occurs albeit infrequently, and tentative correlations have been made between the onset of CNS and cardiovascular effects and circulating drug concentrations in both adults and neonates. Amongst other factors, interpretation of these relationships depends upon blood distribution and plasma binding of the agents, sampling sites and acid-base balance.The disposition kinetics and placental transfer of the amide type agents have been well characterised. In adults their clearance is almost entirely hepatic but in neonates an increase in the renal component is, in part, a reflection of the immaturity of some of the enzymes responsible for their metabolism. Ester type agents are rapidly hydrolysed by plasma pseudocholin-esterase and this has led to a preference for chloroprocaine in some obstetric procedures.Major determinants of the systemic absorption of the agents after perineural administration include their physicochemical and vasoactive properties, perfusion and tissue binding at the site of injection and whether or not adrenaline has been added. In respect of blood drug concentrations achieved after various regional anaesthetic procedures, the margin of systemic safety appears to favour bupivacaine and etidocaine compared to shorter acting analogues such as lignocaine and mepivacaine. The time course of local anaesthetic remaining at the site of injection has been calculated following intravenous regional anaesthesia and peridural block. This has allowed prediction of the local and systemic accumulation of the drugs following continued dosage.Blood concentrations of local anaesthetics after perineural injection are not closely related to age, weight or pregnancy but may be influenced by diseases associated with haemodynamic changes and by other drugs given at or around the time of regional blockade.

Multiple intramuscular injections: A major source of variability in analgesic response to meperidine☆

&NA; Meperidine (pethidine) blood concentrations following multiple intramuscular injections (100 mg) over 2 days were determined in 10 female patients undergoing elective abdominal hysterectomies or cholecystectomies. Pain was estimated by subjective bioassay and the relationship between concentration and effect determined. The blood concentration‐effect curve was steep with the range from no analgesia to complete analgesia being 0.35–0.45 &mgr;g/ml on day 1 and 0.4–0.5 &mgr;g/ml on day 2. The mean (±S.D.) minimum analgesic blood concentration was 0.5 ± 0.1 &mgr;g/ml (n = 32). Pain control was poor during the first 4‐h dosing interval. The first injection postsurgery was also found to be the least representative of all subsequent injections. Blood concentrations fluctuated in phase with dosing interval, but were highly variable. Intra‐ and inter‐patient peak concentrations varied by 2‐ and 5‐fold and times taken to reach the peaks by 3‐ and 7‐fold, respectively. Hence, meperidine blood concentrations were in excess of the minimum analgesic concentration for only about 35% of each 4‐h dosing interval. Peak concentrations were not consistently correlated with body weight or lean tissue mass. Variable pain control following intermittent intramuscular meperidine injections was shown to be due to inadequate, fluctuating and unpredictable blood concentrations.

Clinical Pharmacokinetics Pethidine

Pethidine is commonly used in single doses as a preoperative medication or in multiple doses as an analgesic. The clinical consequences of altered disposition are more likely to result from its analgesic use. Correlations between plasma pethidine concentration, analgesia and side effects such as respiratory depression, have been established, but considerable overlap exists between concentrations producing therapeutic and non-therapeutic effects. The current practice of intermittent pethidine administration (intravenous, intramuscular and oral) for analgesia results in fluctuations in pethidine plasma concentrations which are associated with incomplete pain relief and side effects. Continuous intravenous infusion of pethidine may avoid these difficulties.Changes in pethidine disposition have been observed in patients with liver disease and in the elderly. Measurement of plasma pethidine concentrations may be helpful as an aid to the management of such patients. In renal disease, metabolites may accumulate and cause side effects.

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 timeintegral 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.

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 (5.5mg/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 arteriovenous equilibration; an arteriovenous difference of 22%(SD5%) 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.

Clinical pharmacokinetics applied to patients with intractable pain: Studies with pethidine

Abstract The minimum effective analgetic blood concentration (MEAC) of pethidine following intravenous administration was identified in 3 patients with intractable pain. In two patients this value remained the same whether the pethidine was given intravenously, orally or rectally. In the third patient, whose enteral bioavailability was only 20%, the MEAC was not obtained. However, intramuscular administration reliably achieved the MEAC and was useful clinically. During the study period of 3–12 months, the individual patients MEAC remained similar. Two patients developed dependence on, and tolerance to, pethidine but neither the dependence nor the tolerance appeared to be related to the MEAC. These studies confirm the importance of clinical pharmacokinetic measurements in the investigation and treatment of patients with intractable pain.

The in vitro uptake and metabolism of lignocaine, procainamide and pethidine by tissues of the hindquarters of sheep

1. In vitro studies using tissue slices or tissue homogenates of liver, skeletal muscle, fat skin and blood were conducted to determine whether the uptake of procainamide, lignocaine and pethidine into the hindquarters of sheep was due to distribution or metabolism. Both homogenates and slice preparations of liver showed significant metabolism or uptake, confirming the viability of the preparations. 2. None of the drugs was metabolized in blood and there was minimal uptake of the drugs into the skin. 3. There was metabolism of pethidine in skeletal muscle and substantial uptake of pethidine into fat, indicating that the rapid rate of uptake and prolonged elution of pethidine in the hindquarters was due to both distribution and metabolism. 4. No metabolism of lignocaine in muscle was found, but there was substantial uptake into fat, indicating that the rapid rate of uptake and prolonged elution of lignocaine in the hindquarters was due to its distribution into fat. 5. There was negligible uptake of procainamide into either muscle or fat, presumably due to its relatively low lipophilicity.

The in vivo blood, fat and muscle concentrations of lignocaine and bupivacaine in the hindquarters of sheep

1. A method was developed for sampling muscle and fat from the hindquarters of sheep undergoing spinal anaesthesia. The method was used to measure the concentrations of lignocaine and bupivacaine in the blood, muscle and fat of the hindquarters of sheep during and after 180 min constant-rate infusions of the drugs. 2. For both drugs the muscle drug concentrations were a relatively constant ratio of the simultaneous arterial blood drug concentrations during and after the infusion. 3. There was uptake of both lignocaine and bupivacaine into subcutaneous fat during the infusions. At the end of the infusion the ratio of the fat: arterial blood drug concentrations were 1.54 (SD = 0.57, n = 4) and 3.1 (SD = 1.4, n = 4) for lignocaine and bupivacaine, respectively. 4. The drug concentrations in fat declined relatively slowly after the infusion. The ratio of the fat: arterial blood drug concentrations 180 min after the end of the infusion was 21.5 (SD 4.0, n = 3) and for lignocaine, and 120 min after the end of the infusion was 9.54 (SD 5.2, n = 3) for bupivacaine. 5. It was concluded that the concentrations of lignocaine and bupivacaine in muscle were essentially in equilibrium with the arterial concentrations during and after the infusion. However, the concentrations of lignocaine and bupivacaine in fat were not in equilibrium with the arterial concentrations in the post-infusion period.