Steady Plasma Concentrations Research Articles

Cognitive and motor function impairments during continuous opioid analgesic infusions

AbstractThis research was supported in part by grants from National Cancer Institute (CA 38552) and assistance from Janssen Research Foundation.Morphine and other opioid analgesics may interfere with normal cognition and motor function during long‐term treatment of cancer‐related pain. In this study, we used individually tailored steady‐state drug infusions to control plasma concentrations of morphine and alfentanil and measured the extent of cognitive and motor impairments produced by each drug in healthy volunteers. The tailored infusions allowed evaluation of cognitive and motor effects at three sequential, steady plasma concentrations of each opioid. During continuous infusion, both drugs caused significant, plasma concentration‐related impairments of ability to process serially‐presented information and of fine motor control at plasma drug concentrations within the usual therapeutic range. We found significant relationships between cognitive and motor function decrements and plasma opioid concentration with both morphine and alfentanil. We conclude that magnitudes of cognitive and motor function impairments are equivalent for these two mu receptor selective agonists at equianalgesic plasma concentrations.

Enhancement of morphine analgesia by fenfluramine in subjects receiving tailored opioid infusions

We evaluated the ability of fenfluramine, a serotonin releaser, to increase the analgesic potency of morphine administered by tailored i.v. infusion. Ten normal volunteers participated in 4 test sessions, involving different treatments on different days: (1) oral placebo/saline infusion, (2) oral placebo/morphine infusion, (3) oral fenfluramine (60 mg)/saline infusion, and (4) oral fenfluramine/morphine infusion. Subjects experienced repetitive painful dental electrical stimuli at strong but tolerable intensities during testing. On the 2 test days involving morphine, the opioid was administered by a computer-pump system that used individual pharmacokinetic parameters to achieve consecutive, steady plasma concentrations near target values of 16, 32 and 64 ng morphine/ml; each morphine concentration plateau was maintained for 45 min. On the saline infusion days, our procedures were identical to morphine test days except that the infused fluid contained no drug. For all sessions outcome measures included subject ratings of pain intensity, dental evoked potential (EP) amplitude, and visual analog scale (VAS) ratings of subjective side-effect intensities (nausea, alertness, dizziness, itching, mood). We obtained these measures during baseline and at each morphine concentration plateau or at corresponding times during saline infusions. Fenfluramine significantly increased the analgesic potency of morphine during the opioid infusion, while fenfluramine alone produced borderline analgesic effects. Fenfluramine alone decreased alertness slightly, but did not significantly increase morphine side effects. Thus, we conclude that fenfluramine enhances the analgesic potency of morphine without a parallel increase in opioid side-effect potency.

Postoperative pain prevention by a single-dose formulation of diclofenac producing a steady plasma concentration

The preoperative single-dose oral administration of a combination of a rapid-and slow-release diclofenac (Voltaren, Ciba-Geigy, Basel, Switzerland) preparation in a placebo-controlled trial proved to be more effective in postoperative pain prevention following third molar removal than the combination of intramuscular diclofenac and an oral depot formula.

Testing computer-controlled infusion pumps by simulation.

The pharmacokinetic behavior of intravenous anesthetic drugs can be described by two- or three-compartment models. Rapid achievement and maintenance of steady plasma concentrations of these drugs requires a complicated delivery scheme, perhaps best controlled by a computer. The authors developed a method of simulating the performance of a computer-controlled infusion pump from the differential equations describing drug transfer between compartments. They also derived a mathematically simple and flexible approximate solution to these equations using Euler's numerical method. They incorporated this approximate solution into a computer-controlled infusion pump for intravenous drugs. They tested their pump by simulating the administration of fentanyl to a hypothetical patient whose fentanyl pharmacokinetics were described by a three-compartment model. The exact analytical solution served as the standard of comparison. The approximation technique, using a 15-s interval between model updates, had a maximum error of 0.35 ng.ml-1, and rapidly converged on the exact solution. The simulations revealed oscillations in the system. The authors suggest that such simulations be used to evaluate computer-controlled infusion pumps prior to clinical trials of these devices.

Relationship of free nortriptyline levels to therapeutic response.

The relationship between the free plasma concentration of nortriptyline and therapeutic response was examined. Eighteen depressed inpatients were treated for 21 days with steady state total nortriptyline plasma concentrations between 50-150 ng/ml. Steady state free nortriptyline concentrations were measured. The therapeutic nortriptyline response was measured by administering the Hamilton and the Carroll Rating scales at day zero and day 21. Statistical relationships between free levels of drug and clinical response were found to be insignificant. Qualitative assessment of the data suggest that free serum levels of nortriptyline in excess of 10 ng/ml may have an inhibitory effect on clinical response.

Plasma concentrations of etomidate during an intravenous infusion over 48 hours.

Two groups of six patients who had undergone major maxillofacial surgery and who required intermittent positive pressure ventilation, analgesia and sedation for about 48 hours postoperatively were studied. Analgesia in the postoperative period was maintained by an infusion of fentanyl 0.034 micrograms/kg/minute. Sedation was maintained with an intravenous infusion of etomidate such that the patients slept but opened their eyes when addressed and obeyed commands. An assay method was developed which enabled the measurement of plasma concentration of etomidate for periods of up to 24 hours after stopping the infusion. The steady state plasma concentration associated with the technique which produced the required degree of sedation was found to be 158 micrograms/litre (SEM 36). Etomidate exhibited linear pharmacokinetics and the decrease in plasma concentration of etomidate after stopping the infusion was consistent with a three-compartment pharmacokinetic model. All the patients recovered within 1 hour of stopping the infusion. The use of results obtained from the first group of six patients enabled a dosage regimen to be calculated that used a two stage infusion. This regimen enabled a reduction in the time taken to establish the appropriate degree of sedation in the second group of six patients. The two-stage infusion technique provides a means of rapid sedation and of maintaining a suitable clinical response for the prolonged periods that may be necessary when patients are transferred to an intensive therapy unit.

A METHOD FOR ACHIEVING RAPIDLY STEADY-STATE BLOOD CONCENTRATIONS OF I.V. DRUGS

The theoretical basis of a pharmacokinetic method to obtain rapidly and maintain a steady plasma concentration of an i. v. drug is described. Computer simulations of morphine disposition in man, using pharmacokinetic constants obtained from the literature, are provided as examples of steady-state dose regimens. The usefulness and potential limitations of the method are discussed.

INFUSION MODEL FOR FENTANYL BASED ON PHARMACOKINETIC ANALYSIS

The calculation of pharmacokinetic parameters after a bolus injection of fentanyl allowed an i.v. infusion scheme which guarantees analgesia for the entire duration of surgery, with the advantage of steady plasma concentration and body content. In the initial phase after bolus injection, the serum concentration decreased rapidly for about 10 min, indicating extensive transfer to the peripheral compartment. This was followed by a slower elimination phase with a half-life of about 2 h. The total volume of distribution of 80 litre exceeded the body weight only slightly. The total plasma clearance was 500ml min-1. In developing a model for total i.v. anaesthesia we considered two different consecutive infusion rates. The pharmacokinetic model proved to be valid for all patients. The plasma concentrations duration anaesthesia coincided well with the predicted steady state plasma concentrations and provided continuous analgesia during operation.

LABELLED DECAMETHONIUM IN CAT MUSCLE

1 Tritium-labelled decamethonium was infused intravenously in 12 cats at final rates of 1.3-4.2 nmol kg-1 min-1 to produce a steady plasma concentration which ranged between 0.21-1.3 mumol/l in different experiments. Muscle contractions were elicited by nerve stimulation and the potential at the end-plate regions of superficial fibres was recorded by extracellular electrodes. 2 Under these conditions, it was not possible to obtain a steady degree of neuromuscular block. The initial decrease in muscle contractions was followed by recovery towards the original value although the concentration of decamethonium in the plasma remained constant, or in some cases rose. The initial depolarization of the end-plate region also waned during the constant infusion of the drug. 3 Once the twitch tension had returned to control values during infusion of the drug, prolongation of the infusion for a total of four hours did not produce a secondary neuromuscular block. 4 Scintillation counting showed that during infusion of labelled decamethonium the radioactivity of the muscles increased progressively with time. The uptake was less in the soleus muscle than in the fast-contracting flexor longus digitorum and extensor longus digitorum muscles. Muscles which had been denervated 12-13 days previously showed a greater uptake of labelled drug than control muscles from the contralateral limb. 5 The labelled drug was localized by autoradiography of frozen sections of leg muscles following intra-arterial injection of decamethonium. Grain counts in individual fibres showed that small amounts of decamethonium had entered the muscle fibres along their entire length, and there was increased uptake of the drug into the cell in the region of the end-plate. 6 The mechanisms underlying the waning of the pharmacological response during constant application of depolarizing drugs are discussed.

Passage of solid spherical particles across the blood-lymph barrier.

AbstractSolid spherical particles (radius 300–700 Å) of methyl‐methacrylate marked with a fluorescent dye were administered to dogs by continuous intravenous injection in order to obtain a steady plasma concentration. Lymphatics were cannulated and lymph collected from four regions of the body: leg, liver, heart and bronchial lymphatics. The passage of particles across the blood‐lymph barrier was measured by means of simultaneous concentration measurements in blood and lymph, Particles up to 700 Å radius readily passed into liver lymph with a lymph‐plasma ratio of approximately 0.20 in the “steady state”. No measurable amounts of these particles were found in the lymph from leg, heart or bronchial lymphatics. In these regions protein molecules of “effective diffusion radii” up to 120 Å pass into lymph. If the large proteins pass by “bulk flow” through water filled pathways the size of these pathways or “capillary leaks” would lie between 120–300 Å radius.