Controlled-release oral morphine sulfate in the treatment of cancer pain with pharmacokinetic correlation.

The bioavailability and clinical effects of an oral controlled-release morphine sulfate tablet, MS-contin (MSC; Purdue-Frederick, Norwalk, CT) in comparison to an immediate-release (IRMS) preparation were evaluated in normal subjects and cancer patients, respectively. The inherent slow-release character of MSC was confirmed by 2 1/2 X T1/2 absorption rate, one-half Cmax, and twice Tmax relative to IRMS. The T1/2 elimination of the two morphine preparations was similar, demonstrating insignificant risk of MSC accumulation. The difference in the mean number of side effects experienced by the control group per subject was significant (.70 for MSC and 1.26 for IRMS, P = .05) and was consistent with peak plasma morphine attenuation. The cancer patients were initially switched from their previous analgesic to four hourly IRMS and then to MSC at double the dose every eight hours. The majority had their MSC dosing interval lengthened to every 12 hours with a decrease in the total daily morphine requirement. While the mean duration on MSC was 20.5 days, many patients were followed poststudy for an extended period with no appreciable development of tolerance. Overall, MSC analgesia and side effects were perceived by the patients as superior compared with prestudy opioids. The advantage of less frequent dosing may lead to improvement of the quality of life of cancer patients.

Rescue factor: a design for evaluating long-acting analgesics.

A design is described that uses need for supplemental (rescue) analgesic as a factor predicting effectiveness of a test analgesic. This methodology is especially suited for evaluating long-acting analgesics given repeatedly. Rescue use is measured over dosing intervals as test drug is titrated from a subanalgesic dose to that requiring no or minimal rescue. This design was used to evaluate oral long-acting morphine sulfate (MS Contin) given every 12 hours in a crossover study of cancer pain using oral immediate-release morphine sulfate given every 4 hours as reference. Less morphine was required for MS Contin given every 12 hours relative to immediate-release morphine sulfate given every 4 hours (186 +/- 22 mg vs. 239 +/- 35 mg; p = 0.04). Total daily morphine for both regimens correlated linearly (r = 0.96) with a slope of 1.27 +/- 0.11, significantly (p = 0.03) different from equivalence (slope of unity) in favor of MS Contin. This design features assay sensitivity (dose-response) and provides relative potency estimates for analgesics given at specific regimens.

Steady-state pharmacokinetics of controlled release oral morphine sulphate in healthy subjects.

The pharmacokinetics of oral morphine sulphate as controlled release tablets ('MS-Contin') and solution were compared at steady-state. Plasma morphine concentrations were determined over 24 hours following the last dose of each drug when given in a randomised, crossover fashion to healthy subjects. Radioimmunoassay was used, which was sensitive yet provided good specificity relative to high-performance liquid chromatography. Controlled release tablets had 86% the bioavailability of the solution. Although each dose of controlled release tablets was double that of the solution, their peak plasma concentrations were the same. Time to maximum concentration was 3 times longer for controlled release tablets with an absorption half-life twice that of the solution. Elimination of both drugs was similar and biphasic with the minor terminal portion at 10 times the half-life of the major early process. These data explain the analgesic duration of 12 hours observed in clinical studies and the lack of accumulation with morphine compared with methadone.

Neuromuscular blocking activity of a new series of quaternary N-substituted choline esters.

1. The neuromuscular blocking activity of a new group of mono- and diquaternary N-substituted choline esters of several carboxylic acids has been evaluated in various whole animal preparations in the mouse, rat and cat.2. A basic non-depolarizing mechanism was present in all but one compound-a depolarizing agent, which was studied for comparison. There was evidence of facilitatory activity and nicotinic stimulation in the monoquaternary compounds. These effects were diminished in the diquaternary compounds.3. The presence of a bulky aromatic ring system on the nitrogen atom appeared to increase both neuromuscular blocking potency and facilitatory activity in the experimental animal. A similar relationship had previously been demonstrated in vitro in another study.4. The duration of action, although short in most compounds, did not correlate well with previously determined in vitro hydrolysis rates, possibly because of species differences.5. The general pharmacology of each compound appeared to depend considerably upon the structure of the choline moiety.

Management of cancer pain with oral controlled-release morphine sulfate.

Morphine sulfate Contin (MSC) is an investigational matrix delivery system for oral morphine sulfate that allows for prolonged blood levels of morphine. Twenty-six patients with inadequately controlled cancer-related pain were examined in an open but controlled study using MSC. Initially, all patients were converted from the prestudy analgesic regimen to an equianalgesic amount of immediate-release morphine sulfate (IRMS) on a q4h dose schedule that was in turn titrated to the level of adequate pain relief. Patients then were switched to MSC q8h and eventually to q12h, starting at doses representing the same total daily amount of morphine that was in the final IRMS dose. Of the 18 patients who completed the study, all achieved satisfactory levels of analgesia on MSC, seven at q8h and 11 at q12h dosing intervals. All patients reported better analgesia while taking MSC compared with their previous regimen. Side effects associated with MSC included sedation and constipation but not nausea or respiratory difficulty. Significant drug tolerance did not develop during a mean follow-up period of four weeks (range, 1-18 weeks). MSC is an effective oral opioid analgesic that allows an increased dose interval without increased side effects or decreased potency. It can improve the quality of life of cancer patients by allowing them to be maintained without frequent dosing or parenteral medication.

Articular chondrocyte tenascin-C production and assembly into de novo extracellular matrix.

Tenascin-C is an oligomeric glycoprotein of the extracellular matrix that is expressed in a variety of processes including development, tissue remodeling, wound healing, cell adhesion/antiadhesion, and cell/matrix interactions. Tenascin has recently been acknowledged as a component of the extracellular matrix of articular cartilage, but its function remains unclear. In this study, bovine articular chondrocytes were grown in alginate beads for 35 days to examine the kinetics of tenascin synthesis and incorporation into de novo extracellular matrix. During the culture period, 6 harvest days were established in which culture medium was recovered, alginate beads were dissociated with an EDTA solution, and chondrocytes were collected and lysed by sonication. Total DNA determination performed on the cell lysates demonstrated chondrocyte survival and proliferation. Western blotting performed on the medium, EDTA/alginate, and lysate samples demonstrated the production of both the 220 and 320 kDa tenascin size variants and their differential compartmentalization within the culture system. Tenascin was incorporated into the alginate bead matrix at a constant rate of 3.8 micrograms/day. The 320 kDa variant was produced in higher quantity, but the 220 kDa fragment was twice as likely to be incorporated into the de novo matrix. Methylene blue/acid fuchsin staining and tenascin immunohistochemistry demonstrated the incorporation of tenascin into a progressively expanding matrix surrounding the chondrocytes. The results suggest a role for tenascin in the assembly of the chondrocyte matrix and as a soluble mediator of chondrocytes with possible diverse functions for the tenascin size variants.

Pseudocholinesterase hyperactivity with succinylcholine resistance: an unusual cause of difficult intubation.

We describe a case of difficult intubation, possibly due to marked pseudocholinesterase hyperactivity that caused rapid inactivation of succinycholine. Possible causes of difficult intubation and pseudocholinesterase hyperactivity are discussed. Literature on genetic variants associated with markedly increased pseudocholinesterase activity are reviewed. It is concluded that pseudocholinesterase hyperactivity may be a rare cause of difficult intubation. We recommend that pseudocholinesterase activity should be determined in all patients who appear to be resistant to the action of normal doses of succinylcholine or mivacurium.

The effect of ondansetron on atracurium-induced neuromuscular blockade.

STUDY OBJECTIVE: To determine whether treatment with ondansetron, a new antiemetic drug, affects nondepolarizing neuromuscular blockade. DESIGN: Randomized, double-blind, prospective study. SETTING: Operating room at a university medical center. PATIENTS: 30 ASA physical status I and II patients scheduled for elective surgery. INTERVENTIONS: After the induction of anesthesia with midazolam 2 to 4 mg/kg, sodium thiopental 6 to 8 mg/kg, and fentanyl 4 to 8 micrograms/kg, the ulnar nerve was stimulated at the wrist through subcutaneous needle electrodes at a frequency of 0.15 Hz. The response to stimulation was measured and recorded with a force-displacement transducer applied to the thumb. Patients were randomized to one of three treatment groups. A steady baseline to ulnar nerve stimulation with nitrous oxide-oxygen-opioid-thiopental anesthesia was established. The first study group (Group 1) received a placebo, the second group (Group 2) received 8 mg of ondansetron, and the third group (Group 3) received 16 mg of ondansetron as an intravenous infusion over 5 minutes. Patients were then given incremental doses of atracurium 0.05 mg/kg at 3-minute intervals to establish approximately 95% twitch inhibition so as to construct a dose-response curve. An atracurium infusion was then begun to maintain a constant degree of neuromuscular blockade. At the end of surgery, patients were allowed to recover spontaneously, or pharmacologic antagonism of residual neuromuscular blockade was achieved with neostigmine 0.05 mg/kg and glycopyrrolate 0.01 mg/kg. Mechanomyographic response to train-of-four stimuli (2 Hz for 2 seconds) every 20 seconds was monitored during the atracurium infusion and recovery from neuromuscular blockade. MEASUREMENTS AND MAIN RESULTS: Log dose-response curves were determined for the study groups and compared using analysis of variance (ANOVA). The 50%, 75%, and 95% effective doses (ED50, ED75, and ED95) were calculated from the equation describing the log dose-response. Maintenance infusion rates were determined, and the neostigmine-accelerated recovery index of 25% to 75% was measured for each group. The results were compared using ANOVA. There were no significant differences among the treatment groups with respect to maintenance infusion rate (7.8 +/- 1.8 micrograms/kg/min for Group 1, 7.7 +/- 2.5 micrograms/kg/min for Group 2, and 7.3 +/- 2.3 micrograms/kg/min for Group 3) or neostigmine-accelerated recovery interval of 25% to 75% (4.5 +/- 2.3 minutes, 4.4 +/- 3.1 minutes, 6.6 +/- 3.9 minutes in Groups 1, 2, and 3, respectively). The log dose-response data for Groups 1, 2, and 3 did not differ significantly (p = 0.068), and the calculated ED95 in each treatment group demonstrated no dose-related change (0.254 +/- 0.022, 0.279 +/- 0.033, and 0.240 +/- 0.022 for Groups 1, 2, and 3, respectively). CONCLUSIONS: Ondansetron is an antiemetic drug that can be used in the perioperative period without concern for potentiation of nondepolarizing neuromuscular blockade, change in atracurium maintenance dose, or change in rate of neostigmine-induced recovery from neuromuscular blockade with atracurium.

Principles of cancer pain management. Use of long-acting oral morphine.

Oral morphine is increasingly recognized as the pharmacologic standard for cancer pain management. Yet for the primary care physician and oncologist alike, misconceptions of the safety and efficacy of oral morphine along with lack of recognized guidelines for use have often resulted in inadequate cancer pain therapy. Use of controlled-release oral morphine sulfate (MSC) requires additional guidelines for optimum analgesia. Proposed are ten principles of dosing oral morphine, especially MSC, which were followed in a clinical trial involving cancer patients. MSC dosed at 8-, 10-, and 12-hour intervals was compared with immediate-release morphine (IRMS) dosed every four hours, and with prestudy analgesics. Patients achieved satisfactory analgesia at daily doses (mean +/- SE) of 118.0 +/- 8.6 mg and 111.4 +/- 12.6 mg (P greater than .05) for IRMS and MSC, respectively. Dosing endpoints were determined by titration with IRMS and MSC to a minimal and equivalent amount of supplemental short-acting analgesic. Side effects were typical for opioids and tolerated except for one dropout on IRMS (nausea and constipation). The ten principles have been incorporated into a dosing scheme as a practical guide for MSC therapy.

The autonomic margins of safety of metocurine and d-tubocurarine in the cat.

The potencies of metocurine and d-tubocurarine for neuromuscular and autonomic blockade and histamine release were determined in cats anesthetized with chloralose and pentobarbital. The autonomic margins of safety of these drugs were determined by measuring the ratios of ED50 for sympathetic block to ED95 for neuromuscular block; ED50 for vagal block to ED95 for neuromuscular block; ED50 for histamine release to ED95 for neuromuscular block. Metocurine is 14 times more potent than d-tubocurarine as a neuromuscular blocking agent in the cat, but its autonomic blocking action is three times weaker than the of d-tubocurarine and its histamine-releasing action is less than half that of d-tubocurarine. The combination of higher neuromuscular blocking potency and weaker autonomic effect gives metocurine a much higher autonomic margin of safety than d-tubocurarine in the cat.

The future of the benzylisoquinolinium relaxants.

The benzylisoquinolinium relaxants currently include the intermediate-acting agent, atracurium, and the short-acting agent, mivacurium. This class of relaxants has always retained the distinct advantages of rapid degradation, enzymatic metabolism, or both in the plasma, resulting in short half-lives and fast, complete recovery, unrelated to dose or duration of administration. Any improvements in this class of relaxants must focus on retaining this property at the same time as decreasing or eliminating histamine release, which has always been the major disadvantage of the benzylisoquinoliniums. The introduction of 51W89, an isomer of atracurium, may represent an advance in the development of this class of relaxants.

Stimulus frequency and dose-respone curve to d-tubocurarine in man.

The relationship of the frequency of motor-nerve stimulation to the dose--response to d-tubocurarine was studied in 45 adult patients during nitrous oxide--oxygen--morphine--thiopental anesthesia. One of five stimulus frequencies, 0.1, 0.15, 0.25, 0.5, and 1.0 Hz, was employed in each of five groups of nine patients. Cumulative dose-response curves for inhibition of evoked thumb adduction were constructed at each frequency on log probit scales and the ED50 and ED95 values were determined. The apparent potencies of d-tubocurarine at 0.5 and1.0 Hz were significantly different from that at 0.1 Hz; for example, at 0.1 Hz the ED50 and ED95 were 0.25 and 0.52 mg/kg, respectively. The corresponding values at 1.0 Hz were 0.07 and 0.15 mg/kg, respectively, or approximately 3.5 times less. The durations of recoveries of the twitch from 5--25 per cent of control at 1.0 and 0.5 Hz were 13 +/- 2 min (mean +/- SE) and 20 +/- 2 min, respectively. These durations were significantly different from that at 0.1 Hz (30 +/- 2 min). These results emphasize the importance of defining the stimulus frequency for meaningful interpretation of the dose--response relationships for nondepolarizing relaxants in man. Slow stimulus rates (0.1--0.15 Hz) are most useful clinically, since all levels of clinical relaxation can be achieved at these rates without abolishing the evoked twitch response.

Cumulative dose-response curves for gallamine: effect of altered resting thumb tension and mode of stimulation.

Neuromuscular blockade studies often use the thumb adductor twitch response to ulna nerve stimulation. Two factors that may influence the results are the resting muscle tension (initial fiber length) and the pattern of the stimulus wave form. This study was undertaken to improve understanding of the effect of these factors and lead to better controlled study conditions and more consistent data. During nitrous oxide-barbiturate-narcotic anesthesia in 10 normal adult patients, as the resting thumb tension was increased from 50 to 200 g, the evoked thumb adductor twitch response (Grass stimulator, 0.25 Hz) was augmented by 28%. There was only a 2.5% increase in the evoked (developed) tension when the resting tension was further increased from 200 to 300 g. Developed tension at 50 g was significantly (p less than 0.001) less than at the other resting tensions. The developed tension at 100 g was also significantly (p less than 0.05) less than at resting tensions of 200 or 300 g. Cumulative dose-response curves for gallamine in nine patients were not significantly altered by increasing resting tension from 50 to 200 g. Biphasic (Block-Aide monitor) or single square wave (Grass stimulator) stimuli wave forms in nine normal adult patients yielded gallamine dose-response curves that were not statistically different. The muscle response to biphasic stimulation during a non-depolarizing blockade was not affected by the average muscle refractory period. Because of the significantly lower developed tension at resting tension settings of 50 to 100 g, a practical consideration during neuromuscular function studies would be to have the resting thumb tension adjusted and rechecked for each patient and kept within the 200-300-g range to ensure maximum uniform developed tension. The type of stimulus wave form selected will not affect results as long as it is used consistently throughout the study.

Epiphyseal replacement in a murine model.

Epiphyseal replacement was performed via knee transplantation using donor tissue of different developmental times in a murine model. The performance of syngeneic donor tissue in a resection defect in 4-day-old mice of the same inbred strain was assessed over 2 weeks for cell viability, tritiated thymidine incorporation, and ability to attract a host blood supply, and at 2 months, with the existence of a joint and growth. Although there was variability within experimental groups, the syngeneic transplant was able to survive pending vascular invasion from the host. Growth occurred, although it never equaled normal growth. One possible approach to the difficult problem of joint reconstruction in the immature skeleton is to divide the endeavor into two parts: develop models of syngeneic joint transplantation in inbred strains of animals to assess the various problems that would occur were this tissue available and develop models of joint "synthesis" with autogeneic chondrocytes.

Potential clinical uses of short-acting nondepolarizing neuromuscular-blocking agents as predicted from animal experiments.

It is readily evident that a short-acting nondepolarizing agent suitable for clinical use would be of value in anesthesiology. The most commonly used short-acting relaxant, succinylcholine, is a depolarizing drug, with all the side effects inherent in such agents. The authors have investigated the actions of several short-acting nondepolarizing ester neuromuscular-blocking drug in comparison with succinylcholine, and theri interactions with d-tubocurarine, and inhibitors of true and plasma cholinesterase. Two experimental agents, HH-85 and JJ-142, are examples. Tests in animals suggest areas of extrapolation to human use.

Comparative haemodynamic effects of tubocurarine and metocurine in the dog.

On accout of its histamine releasing and ganglion blocking properties tubocurarine is known to have significant haemodynamic effects. Methylation of the compound produces metocurine and should decrease both histamine release and ganglionic blockade. The haemodynamic effects of these two compounds were compared in 10 mongrel dogs anaesthetized with chloralose and morphine. Haemodynamic measurements were made 2 min before and 2, 5, 10 and 20 min after administration of the drugs. Each animal received three doses of each drug with a 2-h rest period between doses: tubocurarine 0.35 (muscle twitch ED95), 0.7 and 1.4 mg kg-1 and metocurine 0.2 (2 x ED95), 0.4 and 0.8 mg kg-1. All doses of tubocurarine produced an increase in heart rate (212, 197 and 212% of control respectively). The mean arterial pressure decreased significantly with 0.7 mg kg-1 (48% of control; P less than 0.05). Metocurine produced no significant haemodynamic effects except for the largest dose (8 x ED95). The data suggest that the haemodynamic margin of safety with metocurine in the dog is eight times that of tubocurarine.

Metocurine in infants and children: neuromuscular and clinical effects.

A cumulative dose--response curve for metocurine based on body weight was determined in 30 infants and children during halothane (1.2 per cent inspired), nitrous oxide and oxygen (60/40 per cent) anesthesia. The mean and range of twitch depression and time for recovery from maximal neuromuscular blockade were not significantly different over an age range from newborn to 7 years. Metocurine is twice as potent as d-tubocurarine in children, and their requirement is more than that for adults. The rate of recovery from metocurine in children was the same as that from d-tubocurarine. In another 30 children, use of metocurine at a large dose (0.5 mg/kg) for endotracheal intubation caused no significant change in blood pressure or pulse rate. Cardial arrhythmias were not seen.