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Biomedical subjects

L E Mather

Publications and source records attributed to L E Mather.

At least 19 recordsLinked to original sources

The pharmacological relief of pain--contemporary issues.

OBJECTIVE: To provide a general description of the pharmacological principles of pain management particularly the management of severe pain with opioid analgetic agents. DATA SOURCES: Literature updating previous reviews by the authors in this Journal and the Proceedings of the VIth World Congress on Pain, Adelaide, 1-6 April 1990. STUDY SELECTION: Studies were selected under the subheadings: opioid receptors; endogenous opioids; development of new agents; recognition of the need to improve analgesia; pharmacokinetics and pharmacodynamics of opioids; and novel drug delivery methods. DATA EXTRACTION: The extracted information was more descriptive than quantitative. DATA SYNTHESIS: The pharmacological relief of pain involves treatment of patients with drugs characterised by extremely large interpatient variability in pharmacokinetics and pharmacodynamics by way of an extremely complex interaction with endogenous control mechanisms. It is not surprising that management of pain in many patients is less than adequate. CONCLUSIONS: Although much vigorous interdisciplinary research is being undertaken to develop a scientific basis for understanding pain and analgesia, improvements in the clinical management of pain can only occur if practitioners recognise the need for individualised methods of pain relief and treat their patients accordingly.

Acute Disease

Failure of the nitrous oxide tissue equilibration method for the determination of brain and myocardial blood flow under controlled conditions.

1. Two adult merino ewes were prepared with intravascular cannule for sampling aortic root blood, sagittal sinus blood and coronary sinus blood. 2. One week after preparation the animals were anaesthetized then ventilated with a gas mixture containing 10% nitrous oxide (N2O) for 60 min. Serial measurements of brain and myocardial blood flow were made using the N2O tissue equilibration method of Kety and Schmidt. 3. N2O failed to achieve matching arteriovenous blood concentration equality and saturation of the relevant tissues. Valid use of the Kety-Schmidt method, therefore, could not be confirmed. 4. Because of the failure of the arteriovenous equilibration, serially determined brain and myocardial blood flows were found to decrease with time. 5. The use of this method in circumstances where tissue saturation with the indicator gas cannot be ascertained is arbitrary.

Animals

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

Do the pharmacodynamics of the nonsteroidal anti-inflammatory drugs suggest a role in the management of postoperative pain?

Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) were regarded as weak analgesic agents with a potent antiplatelet effect that severely limited their perioperative usefulness. However, the recent development of injectable NSAIDs has stimulated a re-evaluation of the potential role of this class of drugs in postoperative pain management. In general surgery, NSAIDs have been shown to be effective analgesics when administered after surgery, as judged by either a reduction in pain scores and/or by an opioid sparing effect. Parenteral NSAIDs alone, notably ketorolac and diclofenac, may be adequate or even preferred analgesic agents after minor surgery. In dental surgery, NSAIDs produce greater initial analgesia than steroids, although the latter produce greater suppression of swelling and less functional loss. NSAID pretreatment results in only modest suppression of swelling compared with placebo. These data suggest that the acute analgesic effects of NSAIDs in oral surgery and probably other models result from suppression of a nociceptive process, rather than a generalised anti-inflammatory effect. This view challenges the traditional association between inhibition of prostaglandin synthesis and the therapeutic effects of these drugs. The variety of NSAIDs leads to a range in half-lives from short, e.g. diclofenac (1 h), intermediate, e.g. ketorolac (5h), to long, e.g. tenoxicam (60h), which has implications for both convenience of the dosage regimen and drug accumulation. For some racemic NSAIDs (e.g. ibuprofen), metabolic 'activation' of the inactive R-enantiomer to the active S-enantiomer occurs. Renal dysfunction may increase both the plasma concentration and body residence time of NSAIDs, thereby increasing the risk of adverse effects. The concomitant effects of anaesthesia have not yet been studied. The principal concern regarding the use of perioperative NSAIDs is the risk of decreased haemostasis and wound healing. Although it has been found that NSAIDs prolong bleeding times in patients, values generally remain below the upper limits of those in generally healthy patients. Healing of gastrointestinal anastomoses may be compromised by NSAID administration but corneal healing and bone remodelling are not. There is a need for further research into the potential for renal side effects with NSAIDs in the perioperative setting, where the effects of anaesthesia and surgery may increase the risk of side effects, particularly in elderly patients. The main benefits of NSAIDs derive from opioid sparing (e.g. reduction in perioperative nausea and vomiting and improvement in ventilation), although some studies allude to an enhanced quality of analgesia from the combination compared with either NSAID or opioid alone. The question of pre- vs postinjury treatment with NSAIDs remains unresolved.

Analgesics

Pharmacokinetics and patient-controlled analgesia.

With patient control over dosage regimens as in PCA, the pharmacodynamic properties of the opioid analgesic agents emerge as being of greater importance than the pharmacokinetic properties in obtaining a salutary result. However, the prescription of opioid analgesic agents for PCA is more complex than for the same drugs under conventional control. There are major differences in the physicochemical, receptor selectivity and pharmacokinetic properties among opioid analgesic agents. Improved understanding of these differences, it is contended, can lead to more optimized strategies for the clinical management of pain whether under conventional or patient control. The impact of these properties on the components of the PCA prescription is discussed.

Analgesia, Patient-Controlled

An assessment of methods for sampling blood to characterize rapidly changing blood drug concentrations.

The accuracy of different blood sampling methods used to characterize rapidly changing blood drug concentrations was examined both in vitro and in vivo. It was shown in vitro that blood sampling methods based on the fraction collection principle failed to characterize a "square wave" change in drug concentration, and there was a 9-16-s delay before achieving 95% of the expected drug concentration. Varying the catheter size and length did not improve the response. This observation is consistent with laminar and/or turbulent flow producing dispersion and mixing of blood of different drug concentrations in the catheter. A sampling method (flush and withdrawal) was developed to minimize these effects. In vivo studies showed that peak blood drug concentrations obtained using this method after an iv bolus of a drug were approximately 25-28% higher than those simultaneously obtained by methods based on fraction collection principles. It is concluded that blood sampling methods based on fraction collection principles can produce significant errors in measured blood drug concentrations. The error is greater the greater the rate of change of the blood drug concentrations.

Animals

Improved method for morphine determination in biological fluids and tissues: rapid, sensitive and selective.

Morphine was assayed using a simple two step solvent extraction--acid back extraction sample preparation method, coupled with normal phase high-performance liquid chromatography (HPLC) and dual electrode coulometric detection. HPLC is performed with a 1.0 M Tris-methanol (5:95) mobile phase with subtle pH adjustments to separate morphine and internal standard from any interfering compounds. The use of normal phase HPLC (silica column) substantially reduces problems from interfering lipophilic substances sometimes encountered with reverse phase HPLC following solvent extraction and which would otherwise require more time-consuming sample preparation. Dual electrode detection further improves the selectivity for morphine and gives excellent sensitivity (0.5 ng mL-1), reproducibility and stability for automated sample injection. This method has proven suitable for pharmacokinetic studies of morphine.

Animals

A pharmacokinetic approach to postoperative pain: continuous infusion of pethidine.

In an attempt to improve postoperative pain management an intravenous infusion of pethidine was designed to provide stable therapeutic blood concentrations. Ten female patients undergoing elective abdominal hysterectomy were studied. After commencement of the infusion, blood pethidine concentrations increased rapidly and exceeded 0.46 microgram/ml after four hours. The mean steady-state concentration of 0.67 microgram/ml was reached by twenty-four hours. This infusion regimen resulted in the abolition of severe pain after three hours and analgesia continued for the duration of the two day study. Significant blood concentrations of the metabolite norpethidine were found although clinically no toxic effects were observed. Side effects of pethidine were infrequent. Controlled continuous intravenous infusion of pethidine produced stable blood concentrations and provided excellent pain control.

Adult

Cardiovascular and subjective central nervous system effects of long-acting local anaesthetics in man.

Intravenous infusions of etiodocaine 50, 75 and 100 mg and bupivacaine 75 mg were carried out over ten minutes in healthy young adult males. Cardiovascular sequelae were generally trivial at all doses. A collection of subjective central nervous system symptoms were described which may be regarded as early warning of impending local anaesthetic toxicity. Plasma concentrations of etidocaine were proportional to dose and ranged from 2 micrograms/ml to 5 micrograms/ml at the termination of the infusion. Plasma concentrations of bupivacaine were similar to those from the same dose of etidocaine but declined more slowly on cessation of infusion.

Acetanilides

Simultaneous quantitation of morphine and paraben preservatives in morphine injectables.

A high-performance liquid chromatographic method for the simultaneous determination of morphine sulfate, methylparaben, and propylparaben in morphine sulfate injection was developed. A reversed-phase system, based on an octadecylsilane stationary phase, was used with a binary solvent mobile phase consisting of methanol--phosphate buffer (pH 4.0) containing methanol (5%) delivered at a constant rate (0.6:0.4 ml/min) using a two-pump system. The detector response at 254 nm was linear with the amount injected over a wide range, allowing rapid and reproducible quantitation of each component.

Chromatography, High Pressure Liquid