Epidural opiates and local anaesthetics for the management of cancer pain.
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Analgesia, Epidural↗
Biomedical subjects
J L Plummer
Publications and source records attributed to J L Plummer.
Analysis of effects of drug combinations.
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Anesthetics↗
Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil.
We have examined interactions between midazolam, propofol and alfentanil using two end-points of light sedation (hypnosis) and anaesthesia. Quantal dose-response curves were determined in 400 female patients for the drugs individually and in combination. At the hypnotic end-point, interactions were analysed by fitting the data to a mathematical model where the response depended on the doses of the three drugs with additional terms included to describe non-additive interactions of the various combinations of the three drugs. There were significant interactions for hypnosis; the decrease in expected ED50 for the various combinations were: midazolam-propofol = 37%, midazolam-alfentanil = 46%, propofol-alfentanil = 20%, midazolam-propofol-alfentanil = 42%. Whilst all responses to the two-drug combinations were synergistic, the three-drug combination led to a response that was less than that expected from the effects of the individual agents and their two drug interactions. For anaesthesia, dose-related effects could not be demonstrated for midazolam or alfentanil when used alone. The decrease in ED50 of propofol in the presence of the other compounds was propofol-midazolam = 52%, propofol-alfentanil = 73%, propofol-midazolam-alfentanil = 82%. When comparing the different combinations, the responses varied markedly at each end-point assessed and could not be predicted from the responses of the individual agents.
Adolescent↗
Oxyhaemoglobin saturation following elective abdominal surgery in patients receiving continuous intravenous infusion or intramuscular morphine analgesia.
Oxygen saturation was continuously measured using computerised pulse oximetry for 8 h overnight pre-operatively and for the first 24 h postoperatively in 40 patients receiving intermittent intramuscular morphine or continuous infusion of morphine following elective upper abdominal surgery. The proportion of time with an oxygen saturation less than 94% was used as an index of desaturation. Patients receiving continuous infusion analgesia received a larger morphine dose and achieved better analgesia than the intramuscular group. Postoperatively, the duration of desaturation increased 10-fold over pre-operative values, 'intramuscular' patients spending 39.0% (SD, 37.0%) and 'continuous infusion' patients 40.0% (SD, 37.5%) of the time below 94% saturation. Although newer therapies (e.g. epidural analgesia and patient-controlled analgesia) are currently receiving greater attention, the sequelae of these more traditional analgesic techniques warrant further study.
Abdomen↗
An automated system for testing the accuracy of patient-controlled analgesia devices.
A system was developed to test the accuracy of patient-controlled analgesia devices in situations simulating clinical use. Bolus requests are made automatically at predetermined intervals, and the infusate delivered is measured and recorded without the need for operator presence. To ensure clinical relevance, the bolus request times used in this study corresponded to a pattern typical of those requested by patients on the ward. Graseby, Abbott Provider 5500 and IVAC patient-controlled analgesia devices were tested and found to deliver reasonably accurately over a 24 h period. However, when an infusion was started in an unprimed system or after a period of no bolus requests in a bolus-only mode the Graseby and IVAC machines under-delivered. This system provides a means of testing patient-controlled analgesia devices operating in any delivery mode.
Analgesia, Patient-Controlled↗
Postoperative course of plasma protein binding of lignocaine, ropivacaine and bupivacaine in sheep.
The plasma protein binding of the 2,6-xylidide local anaesthetic agents lignocaine, ropivacaine and bupivacaine enantiomers was determined by equilibrium dialysis in plasma obtained from chronically catheterized sheep before and up to 21 days after surgery. Three concentrations (1, 5 and 10 mg L-1), were used for each agent. Concentration-dependent binding was evident for each agent throughout the study period. R(+)-Bupivacaine was more extensively bound than S(-)-bupivacaine at the higher concentrations. Compared with pre-surgery, binding of each agent was less on the first postoperative day but did not differ significantly from days 8 to 21.
Amides↗
Assessment of antinociceptive drug effects in the presence of impaired motor performance.
The hot-plate (HP) and tail-flick (TF) tests are widely used to assess analgesic activity of drugs. These tests do not directly measure the intensity of the noxious stimulus perceived by the animal, but only the animal's response to it, and so may be affected by non-analgesic drugs. Sedatives and muscle relaxants, for example, may impair the ability to respond and hence be wrongly considered to have analgesic activity. We examined response of rats in the HP (55 degrees C, cutoff time 25 sec) and TF (cutoff time 5 sec) tests following administration of pentobarbitone, diazepam or pancuronium. These drugs all impaired motor performance as assessed by reduction in mean rotarod performance times to 6-32% of predrug values. However, HP and TF latencies were not appreciably prolonged. We also found that pancuronium did not alter effects of morphine on HP or TF latencies, despite reduction in rotarod performance to 38% of predrug values. Our results support the validity of HP and TF tests as analgesic assays even in the presence of substantial impairment of motor performance.
Analgesics↗
Hepatic fibrosis and cirrhosis after chronic administration of alcohol and "low-dose" carbon tetrachloride vapor in the rat.
Rats were exposed to carbon tetrachloride vapor, 5 days/wk, 6 hr/day, for periods of 5 or 10 wk at a concentration that by itself caused only fatty change with minimal liver cell necrosis and no fibrosis. The same carbon tetrachloride exposure when given in association with chronic alcohol feeding resulted in extensive hepatic fibrosis at 5 wk and established micronodular cirrhosis at 10 wk. The periodicity of the exposure profile was chosen to simulate that of human exposure to environmental toxins, albeit at a higher dose than would be permitted in the workplace. The development of significant liver injury in this animal model raises the possibility that some chronic liver injury in humans may be due to alcohol potentiation of other hepatotoxins present in the environment at subtoxic levels.
Alanine Transaminase↗
The reproducibility of bioavailability of oral morphine from solution under fed and fasted conditions.
The reproducibility in bioavailability of orally administered morphine (as a solution) under fed and fasted conditions was studied in 5 patients with chronic pain on three occasions over 1 yr (0, 6, and 12 mo). During each study period (i.e.. 0, 6, and 12 mo), patients received the 50 mg oral dose both in the fasted state (10 hr since food) and immediately after a high fat content breakfast, in randomly determined sequence. Frequent blood samples were collected for 10 hr after the dose. There was no significant difference in the maximum blood morphine concentration (Cmax) or the time to Cmax among the three study periods or between the fed and fasted states. Bioavailability, as assessed by log(AUC), was significantly greater in the fed compared to the fasted state (P less than .01) but did not differ over the three study periods (Two-factor analysis of variance). Intrapatient variability contributed 32% and 54% to total variation in log(AUC) under fed and fasted conditions, respectively.
Administration, Oral↗
Hypnotic and anaesthetic action of thiopentone and midazolam alone and in combination.
This study examined the interaction between i.v. administered midazolam and thiopentone on the loss of response to verbal command ("hypnosis") and the loss of response to transcutaneous electrical stimulation of the ulnar nerve ("anaesthesia") in patients presenting for minor elective surgery. Dose-response curves for thiopentone and midazolam individually and in combination were determined using the two end-points in 300 unpremedicated patients. For hypnosis a highly significant (P less than 0.001) supra-addictive (synergistic) interaction was found, the combination having 1.8 times the expected potency of the individual agents. Although midazolam failed to produce anaesthesia in the dose range used, the dose of thiopentone required to produce anaesthesia was reduced by 50% in the presence of midazolam. The mechanism of interaction and the potential role of benzodiazepine-barbiturate combinations are discussed and the observed synergistic anaesthesia interaction is used to explain the potentially dangerous combination of benzodiazepines with other potent CNS depressants such as barbiturates and alcohol.
Adult↗
Peri-operative drug prescribing pattern and manufacturers' guidelines. An audit.
Many patients admitted for surgery are receiving regular drug therapy. Adverse effects may occur, either as a result of these drugs being stopped suddenly or because staff are unaware of significant interactions between certain drugs and anaesthetic agents or techniques. This study aimed to find out how regular drug medication is actually given in the peri-operative period. In addition, pharmaceutical companies were contacted and asked for information about the effects of sudden withdrawal of their products and potential interactions with anaesthetic agents. We found that many drugs were omitted peri-operatively with potentially significant effects. Pharmaceutical companies do not seem to appreciate the importance of this problem and not all of them give clear recommendations relevant to practising anaesthetists.
Anesthesia↗
The influence of rectal cisapride on morphine-induced gastric stasis.
The effect of a new formulation of the gastric prokinetic agent cispride on opioid-induced gastric stasis was investigated. Forty patients were randomly allocated to one of four therapies administered as premedication; group A, placebo suppositories only; group B, placebo suppositories and intramuscular morphine 10 mg; group C, rectal cisapride 30 mg and intramuscular morphine 10 mg and group D, rectal cisapride 60 mg and intramuscular morphine 10 mg. Gastric emptying was assessed from the small bowel absorption of paracetamol following oral absorption. The kinetics of the suppository formulation were determined from venous blood samples. Rectal cisapride in the two doses used did not prevent opioid-induced gastric stasis. This may reflect an inability of this formulation to produce adequate plasma concentrations.
Acetaminophen↗
Variation in the blood concentration/analgesic response relationship during patient-controlled analgesia with alfentanil.
The effect of supplementing postoperative patient-controlled analgesia (PCA) with a mandatory fixed-rate infusion was studied using alfentanil. Patients were assigned by lottery to receive alfentanil PCA with a bolus of 200 or 300 mcg or alfentanil PCA with a bolus of 100 or 200 mcg plus an infusion of 900 mcg/hr, such that ten patients received each treatment. Seven patients receiving PCA only, compared to two in the groups receiving infusion, were withdrawn due to inadequate pain relief (0.1 greater than P greater than 0.05). One patient receiving PCA only was withdrawn because of a low respiratory rate, whereas three patients receiving PCA plus infusion developed respiratory depression. Patients prescribed PCA plus infusion received significantly more alfentanil but did not describe less pain than patients prescribed PCA only. The blood alfentanil concentration immediately prior to demands was significantly higher in the PCA plus infusion groups. These results suggest that during PCA therapy the drug prescription influences the blood concentration associated with satisfactory analgesia.
Abdomen↗
Statistical modeling of the effects of drug combinations.
A method is described for identifying and quantitating departures from additivity (i.e., synergism and antagonism) when drugs having like effects are given in combination. It is applicable for both graded and quantal (e.g., after probit or logit transformation) responses. Log(dose)-response curves of both drugs should be linear but need not be parallel. The following model is fitted to dose-response data for both the individual drugs and combinations of drugs: Y = beta 0 + beta 1 log(A + P.B + beta 4(A.P.B)1/2) where Y is the response, A is the amount of drug A, B is the amount of drug B, and P is a relative potency of the drugs given by log(P) = beta 2 + beta 3 log(B'), in which B' is the solution to B' - B - A/P = 0. If log(dose)-response curves of the two drugs are parallel, beta 3 = 0, and P becomes a constant parameter to be estimated. A positive value of beta 4 corresponds to synergism and a negative value to antagonism. Hypothesis tests may be carried out to determine whether beta 4 is significantly different from zero.
Dose-Response Relationship, Drug↗
Leakage of fluid administered epidurally to rats into subcutaneous tissue.
Epidural catheters were implanted in rats under halothane/nitrous oxide anaesthesia. Contrast medium (Iopamidol) was injected via the catheter under fluoroscopic control 24-48 h after implantation. In 15 of 20 rats contrast could be seen leaking out of the epidural space, usually after only 25 microliters was administered. Leakage was associated with diminished antinociceptive response to morphine administered via the catheter. Both leakage and decreased response to morphine could be largely prevented by applying a drop of Supa-Glue over the site of entry of the catheter to the epidural space at the time of catheter implantation. Investigators using epidurally cannulated rats should document that leakage does not occur or discard results from rats showing evidence of leakage.
Analgesia, Epidural↗
Variables of patient-controlled analgesia. 3: Test of an infusion-demand system using alfentanil.
Patient-controlled infusion-demand analgesia was studied using alfentanil. We were unable to identify an optimal dose and administration rate; doses required range from 100 to 900 micrograms alfentanil. The mean concentration of alfentanil in blood associated with return of pain (i.e. immediately before demand) was 58 ng/ml on day 1 and 37 ng/ml on day 2. This difference was despite similar drug consumption on both days.
Adolescent↗
Variables of patient-controlled analgesia 4: the relevance of bolus dose size to supplement a background infusion.
A range of self-administered demand doses of morphine (0.4, 0.7 and 1.0 mg) were prescribed to supplement a fixed-rate infusion (1.5 mg/hour) for pain control after gynaecological surgery. The number of demand doses administered during the first 25 hours after surgery was not significantly influenced by size of demand dose. There was a significant linear trend to increasing amount of demanded morphine with increasing bolus size. These results cast doubt on the usefulness of the concept of a minimum effective analgesic concentration of morphine.
Adult↗
Influence of enzyme induction and exposure profile on liver injury due to chlorinated hydrocarbon inhalation.
Rats were exposed for four weeks either to air or to vapours of chloroform, carbon tetrachloride or 1,1-dichloroethylene given either as a constant concentration (continuous profile) or as repeated exposures for 6 hr per day, 5 days per week (fluctuating profile). Vapour concentrations were used such that the total exposure (concentration x time) was the same for the two profiles. Within each group, some animals received the enzyme-inducing agents, phenobarbitone or 1,3-butanediol, in their drinking water. Separate experiments were conducted to determine the influence of enzyme inducers and vapour concentration on chlorocarbon uptake and metabolism. In the case of chloroform, hepatic injury was more severe in animals exposed to constant vapour concentration, while dichloroethylene was more toxic when given as a fluctuating profile, especially in butanediol-treated rats. Carbon tetrachloride hepatotoxicity was similar in the two exposure profiles but was exacerbated by butanediol treatment. Butanediol-treated animals in the fluctuating profile group showed evidence of developing cirrhosis. These results could not be fully explained on the basis of the effect of enzyme inducers and exposure profile on amount of agent metabolized. Both the amount of toxic metabolites and the temporal pattern of their formation appear to be important determinants of liver injury.
Administration, Inhalation↗