A randomized controlled trial comparing zileuton with theophylline in moderate asthma. The Zileuton Study Group.

BACKGROUND: Zileuton, a leukotriene pathway inhibitor, was compared with slowly absorbed theophylline in a randomized, double-blind study of patients with chronic asthma. The primary efficacy measure was improvement in forced expiratory volume in 1 second (FEV1). METHODS: Eligibility criteria included FEV1 of 40% to 80% of predicted, documented reversibility of airway disease, and age 18 to 60 years. Initially, the theophylline dosage was titrated to achieve trough concentrations of 8 to 15 micrograms/mL. After washout and 1-week placebo lead-in, patients were randomly assigned to 13 weeks of the appropriate theophylline dose or zileuton, 400 or 600 mg 4 times daily. The FEV1 was measured before the morning dose at 2-week intervals and serially after the dose on days 36 and 92. Patients kept daily diaries of asthma symptoms, beta-agonist usage, and peak expiratory flow rate; on days 36 and 92, they completed quality-of-life questionnaires. RESULTS: Of 471 eligible patients at 38 centers, 377 were randomly assigned to the study; 313 completed the study. On first-dose administration, all groups showed 11% to 13% improvement in FEV1 within 30 minutes. Patients who received zileuton, 400 mg, had significantly greater improvement at several points than did theophylline-treated patients. The range of long-term maximum improvement in FEV1 in the groups was 30% to 34% (P = .40 for zileuton 600 mg; P = .90 for zileuton 400 mg vs theophylline). Initially, the theophylline group improved significantly more in symptom scores, beta-agonist usage, and peak expiratory flow rate, but at maximal effect there was no significant difference. All groups showed significant improvement in quality of life. No overall differences were observed between the zileuton dosage groups. Adverse events were comparable in all groups. CONCLUSION: Zileuton appears as effective and safe as theophylline in patients with chronic asthma.

Pharmacokinetics and pharmacodynamics of zileuton after oral administration of single and multiple dose regimens of zileuton 600mg in healthy volunteers.

The pharmacokinetics and pharmacodynamics of zileuton were determined after oral administration of single dose (600mg) and multiple dose regimens [600mg every 8 hours (q8h regimen) and 600mg every 6 hours (q6h regimen)] in 12 healthy male subjects aged 18 to 50 years. Steady-state park plasma concentration (Cmax), time to Cmax, apparent total plasma clearance, and apparent terminal phase volume of distribution values after the q8h and q6h regimens were 3.07 +/- 1.13 and 4.37 +/- 1.02 mg/L, 1.5 +/- 0.9 and 1.5 +/- 0.9 hours, 793 +/- 233 and 579 +/- 162 ml/min (47.6 and 34.7 L/h), and 179 +/- 126 and 115 +/- 29L, respectively (mean +/- SD). Trough zileuton plasma concentrations (Cmin) immediately before the morning dose were higher than Cmin immediately before the afternoon dose, suggesting a diurnal variation in the pharmacokinetics of zileuton. Accumulation of zileuton occurred with more frequent dose administration, although there was no unexpected accumulation of the parent drug or the N-dehydroxyzileuton metabolite. The q6h regimen of zileuton 600mg was superior to the q8h regimen in maintaining trough plasma concentrations of zileuton above 1.5 mg/L, corresponding to approximately 70 to 80% inhibition of leukotriene B4 biosynthesis.

The effect of food on the pharmacokinetics of zileuton.

The present study was undertaken to assess the effect of food on the pharmacokinetic parameters of zileuton. In a nonblinded crossover study, 18 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of zileuton 600mg in the presence or absence of food consisting of a standardised breakfast on the following morning. The mean zileuton peak plasma concentration (Cmax) increased significantly by 27% after food intake, while the mean area under the plasma concentration versus time curve increased by only 1.4%, a difference that was not statistically significant. The mean time to Cmax was unaffected by the presence of food, as were the other pharmacokinetic parameters assessed. Overall, the results suggest that food has a relatively small effect on the rate of zileuton absorption compared with the fasting state, while the bioavailability of the drug appears to be unaffected. Thus, it is concluded that it is appropriate to administer zileuton with or without food.

Assessment of the pharmacokinetic interaction between zileuton and digoxin in humans.

The effects of coadministration of zileuton on the pharmacokinetic profile of digoxin were investigated in a double-blind placebo-controlled crossover study in 12 healthy male volunteers. During each study phase, the subjects received zileuton 600mg every 6 hours (regimen A) or placebo (regimen B) for 13 days. In addition, all subjects received concomitant digoxin 0.25 mg/day on study days 1 to 11 during both study phases. The study results provide no evidence of any significant overall effect of zileuton on digoxin plasma concentration-time profiles. Although the mean time to reach the maximum plasma concentration for digoxin was significantly shorter after concomitant administration of digoxin and zileuton than after concomitant administration of digoxin and placebo (0.95 vs 1.43 hours), there were no significant differences between the 2 regimens in the values for maximum plasma concentration, area under the plasma concentration-time curve from 0 to 24 hours, elimination half-life, oral clearance, and apparent volume of distribution associated with the terminal phase. Therefore, it is concluded that digoxin and zileuton may be coadministered without risk of clinically relevant effects on the pharmacokinetic profile of digoxin.

The influence of multiple oral doses of zileuton on the steady-state pharmacokinetics of sulfasalazine and its metabolites, sulfapyridine and N-acetylsulfapyridine.

The effects of zileuton (Abbott-64077) on the pharmacokinetics of sulfasalazine (SASP) and its metabolites, sulfapyridine (SP) and N-acetylsulfapyridine (ASP), were studied in a randomised double-blind placebo-controlled study enrolling 14 healthy male volunteers. All subjects received SASP 1 g every 12 hours for 8 days and zileuton 800mg or placebo administered twice daily from day 4 to day 8 inclusive. Coadministration of zileuton did not significantly affect the area under the plasma concentration-time curve, the maximum (Cmax) or minimum (Cmin) plasma concentration and the time to Cmax of SASP, SP or ASP. Likewise, zileuton did not modify the terminal elimination half-life of SASP. It is concluded that coadministration of zileuton 1.6 g/day has no significant effects on the pharmacokinetics of SASP 2 g/day or its metabolites, SP and ASP.

Pharmacokinetic interactions between zileuton and prednisone.

A randomized double-blind placebo-controlled crossover study evaluated the effects of zileuton 600mg 4 time daily on the pharmacokinetics of prednisolone after a single 400mg oral dose of prednisone. the effects of the single prednisone dose on the steady-state pharmacokinetics of zileuton were also evaluated. Multiple doses of zileuton had no significant effects on mean peak plasma concentration (Cmax), time to Cmax(tmax), or area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity) values for prednisolone after oral administration of prednisone 40mg. A slight but statistically significant increase in the mean half-life (t1/2) of prednisolone was detected with zileuton + prednisone administration compared with prednisone + placebo (from 2.8 to 2.9 hours); however, this change was of no clinical relevance. Mean Cmax values of zileuton after coadministration with prednisone were similar to those of zileuton alone. While the single 40mg dose of prednisone resulted in a slight but statistically significant decrease in the mean zileuton AUC value from 0 to 6 hours (AUC0-6) [from 23 to 20 mg/L/h] and a reduction in tMAX (from 2.3 to 1.7 hours), these results were not considered to be clinically significant. Therefore, it is considered that zileuton and prednisone may be coadministered with minimal risk of a clinically significant pharmacokinetic interaction.

The pharmacokinetic and pharmacodynamic interactions between the 5-lipoxygenase inhibitor zileuton and the cyclo-oxygenase inhibitor naproxen in human volunteers.

The potential pharmacokinetic and pharmacodynamic interactions between zileuton, a 5-lipoxygenase inhibitor, and naproxen, a nonsteroidal anti-inflammatory drug that acts as a cyclo-oxygenase inhibitor, have been investigated in 24 healthy volunteers. Coadministration of these 2 drugs had no effect upon the plasma concentration-time curves of either zileuton (800mg) or naproxen (500mg) when compared with each drug administered alone. Both naproxen plasma concentrations during the elimination phase and area under the plasma concentration-time curve values were statistically significantly raised upon coadministration with zileuton, when compared with naproxen alone. However, these differences in these 2 values were sufficiently small to be of no clinical significance. There is no evidence that the combination of zileuton and naproxen had an effect on leukotriene B4 levels that was different from the inhibitory effect of zileuton alone, or had an effect on serum thromboxane B2 levels that was different from the effect of naproxen alone. Moreover, inhibition of the 5-lipoxygenase pathway by zileuton did not appear to aggravate the gastrointestinal adverse events commonly associated with naproxen administration. It is concluded that zileuton and naproxen may be coadministered with minimal risk of a clinically significant interaction.

Pharmacodynamic and stereoselective pharmacokinetic interactions between zileuton and warfarin in humans.

A double-blind parallel randomised study was conducted to assess the effects of multiple oral doses of zileuton (600mg every 6 hours) or matching placebo on the steady-state pharmacokinetics and pharmacodynamics of warfarin titrated to a prothrombin time of 14 to 18 seconds in 24 healthy adult male volunteers. Serial blood samples were collected for assessment of prothrombin times and R- and S-warfarin plasma concentrations. Coadministration of zileuton and warfarin had no effect on S-warfarin pharmacokinetics but statistically significantly increased mean R-warfarin plasma concentrations and decreased mean R-warfarin total oral plasma clearance compared with warfarin alone (by 15%). This stereoselective interaction was accompanied by an increase in mean morning (predose) and evening (12-hour postdose) prothrombin times from 17.5 to 19.8 seconds and 17.1 to 19.1 seconds, respectively; the corresponding changes in the placebo group were from 18.1 to 18.8 seconds and 17.3 to 17.5 seconds. Thus, multiple dose administration of zileuton appears to significantly alter steady-state R-warfarin pharmacokinetics and pharmacodynamics. Careful monitoring of prothrombin times with appropriate dose titration of warfarin is recommended with concurrent therapy of zileuton and warfarin.

Effect of zileuton on theophylline pharmacokinetics.

In controlled trials involving asthma patients, zileuton - a selective 5-lipoxygenase inhibitor - has significantly improved pulmonary function and reduced symptoms. Since theophylline is frequently prescribed for asthma, we designed a placebo-controlled randomised crossover trial to examine the influence of zileuton on theophylline pharmacokinetics. 16 healthy adult males were given theophylline (Slo-Phyllin) 200mg 4 times daily for 5 days and either zileuton 800mg twice daily or a matching placebo. After a 15-day washout period, theophylline was resumed and the other study drugs reversed. During coadministration with zileuton, mean peak theophylline levels rose from 12.14 to 20.99 mg/L (p < 0.001), while the apparent plasma clearance dropped from 3.74 to 1.91 L/h (p < 0.001). The time to the peak theophylline concentration was delayed by 0.5 hours and the half-life was significantly prolonged by 1.5 hours. 14 volunteers reported 44 mild or moderately severe adverse events, possibly or probably related to coadministration of zileuton, and 8 volunteers reported 8 such events with placebo coadministration. Three volunteers receiving theophylline plus zileuton withdrew from the trial prematurely. Thus, a pharmacokinetic interaction that may produce theophylline toxicity exists between zileuton and theophylline. Accordingly, theophylline dosages in patients receiving zileuton should be adjusted to maintain levels within the therapeutic range. Upon initiation of zileuton, the typical asthma patient may require dosage reductions of one-half, and monitoring of plasma theophylline concentrations is recommended.

The pharmacokinetics of single oral doses of zileuton 200 to 800mg, its enantiomers, and its metabolites, in normal healthy volunteers.

The pharmacokinetics of single oral doses of zileuton 200 to 800mg, its R(+) and S(-) enantiomers, and its N-dehydroxylated and glucuronide metabolites have been investigated in a randomised study in 16 normal male healthy volunteers. Zileuton was 93.4% bound to plasma proteins. The overall dispositional pharmacokinetics of zileuton racemate appeared to be linear. The mean dose-normalised area under the concentration-time curve from zero to infinity (AUC0-infinity) remained constant, while the mean dose-normalised peak plasma concentration (Cmax) decreased with the increase in dose, possibly because of dissolution rate-limited absorption at the higher doses. The R(+) and S(-) enantiomers of zileuton may have similar absorption profiles, although the apparent total plasma clearance of the S(-) enantiomer was 49 to 76% higher than the corresponding values for the R(+) enantiomer. The AUC0-infinity of each enantiomer increased proportionately with dose. The pharmacokinetics of the N-dehydroxylated metabolite of zileuton were highly variable, with a more than dose-proportional increase in the mean dose-normalised Cmax and area under the concentration-time curve from zero to 24 hours. The elimination of the glucuronide metabolites of the R(+) and S(-) enantiomers of zileuton was formation rate-limited. The mean percentage of the administered zileuton dose recovered in urine as glucuronide metabolites ranged from 73.1 to 76.5% and showed no dose-related differences. The renal clearance of the glucuronide metabolites of zileuton exceeded the normal glomerular filtration rate, suggesting that these metabolites may be excreted through renal tubular secretion in addition to filtration.

Perioperative variability of binding of lidocaine, quinidine, and propranolol after cardiac operations.

This study examined the effect of changes in plasma concentrations of total protein, albumin, alpha 1-acid glycoprotein, and free fatty acids occurring after heart operations on the protein binding of chemically basic drugs. Plasma protein and free fatty acid concentrations were measured simultaneously with in vitro determinations of the protein binding of lidocaine, quinidine, and propranolol: immediately before operation, immediately on weaning from cardiopulmonary bypass, on arrival in the recovery room, and 12, 24, 72, and 120 hours postoperatively. Initial decreases in the concentrations of all proteins were followed by a rise in alpha 1-acid glycoprotein to 254% of baseline at 72 to 120 hours. The free fractions of drug were initially increased to 168% of baseline for lidocaine, 206% for quinidine, and 200% for propranolol and fell progressively with time, reaching sustained troughs of 65% for lidocaine, 50% for quinidine, and 57% for propranolol at 72 to 120 hours. Regression analysis indicated a major influence of changing alpha 1-acid glycoprotein concentrations on free fractions of all three drugs, with a smaller effect of albumin that reached statistical significance only for lidocaine. There were no significant perioperative changes in plasma concentrations of free fatty acids when the in vitro effects of heparin were controlled. In conclusion, sequential changes in plasma protein concentrations after cardiac operations predictably alter the protein binding of lidocaine, quinidine, and propranolol and should be considered when interpreting total plasma drug concentrations.

Evaluation of the diurnal variation in the pharmacokinetics of zileuton in healthy volunteers.

The diurnal variation in the pharmacokinetic parameters of zileuton were evaluated in 12 healthy male volunteers in a three-period study. Periods I and II constituted a balanced, randomized, crossover study in which a participant received a single dose of 600-mg zileuton either at 7 AM or 11 PM. In period III all participants received 600-mg doses four times daily for 5 days. The differences between the pharmacokinetics of single doses of zileuton administered at 7 AM and 11 PM were not statistically significant. Plasma concentration-time profiles of zileuton during the four daily dose intervals at steady state were also similar. Values for the pharmacokinetic parameters of zileuton after multiple doses were similar to those after single doses, with a minimal accumulation of the drug after multiple doses. Overall, there was little or no diurnal variation in the pharmacokinetic parameters of zileuton after single and multiple doses.

Effects of ABT-761, a novel 5-lipoxygenase inhibitor, on the pharmacokinetics of a single dose of ethinyl estradiol and levonorgestrel in healthy female volunteers.

ABT-761 is a second-generation 5-lipoxygenase inhibitor in clinical development for the treatment of asthma. The effects of ABT-761 on the pharmacokinetics of an oral contraceptive were assessed in 21 female adult volunteers in a phase I, multiple-dose, open-label study. Subjects received a single dose of oral contraceptive (30 microg ethinyl estradiol and 0.15 mg of levonorgestrel) on each of days 1 and 29. Oral doses of 300 mg of ABT-761 were administered once daily beginning on day 15 continuing through day 29. Statistically significant decreases in maximum concentration (Cmax) and area under the concentration-time curve (AUC) of ethinyl estradiol were observed when oral contraceptive was administered concomitantly with ABT-761 compared with administration of oral contraceptive alone. The mean elimination rate constant of ethinyl estradiol increased by 30% (a mean decrease of 3.8 hours in half-life), and the mean apparent volume of distribution during the terminal phase (Vd(beta)/F) of ethinyl estradiol increased by 73% in the presence of ABT-761. Mean Cmax and AUC values for norgestrel decreased by 12% and 10%, respectively, when administered with ABT-761. Mean values for time to Cmax (tmax), terminal rate constant (beta), half-life (t1/2), and Vd(beta)/F of norgestrel were similar when oral contraceptive was administered alone or concomitantly with ABT-761. The mechanism responsible for the effect of ABT-761 on the clearance of ethinyl estradiol remains undefined. Because results of previous multiple-dose studies of ABT-761 do not provide any evidence of autoinduction, the effects of ABT-761 on the pharmacokinetics of ethinyl estradiol are more likely related to absorption of ethinyl estradiol.

Randomized trial of zileuton in patients with moderate asthma: effect of reduced dosing frequency and amounts on pulmonary function and asthma symptoms. Zileuton Study Group.

This 6-month, randomized, multicenter study was designed to determine whether patients who had been treated with the leukotriene pathway inhibitor zileuton 600 mg four times daily (QID) for 2 months could be maintained at the same level of pulmonary function, symptom control, and beta-agonist use with less frequent dosing--first 600 or 800 mg three times daily (TID) and then twice daily (BID). A total of 278 patients with chronic asthma, ages 16 to 70, participated at 25 US centers. All had a 1-second forced expiratory volume (FEV1) of 35%-75%, reversible airway disease, and a nonsmoking history of 1 year. An 8-week open-label period (zileuton 600 mg QID) was followed by a 16-week double-blind period, in which patients who responded to the QID treatment were randomized to receive zileuton 600 or 800 mg TID for 8 weeks and then rerandomized to receive zileuton 600 or 800 mg BID for another 8 weeks. Primary outcomes were FEV1 and asthma symptom scores; secondary outcomes were peak expiratory flow rate, beta-agonist use, and asthma exacerbations requiring steroid rescue. Patients who showed improvements in lung function when treated with zileuton 600 mg QID demonstrated minimal decreases in FEV1 and comparable peak expiratory flow rates, symptom control, beta-agonist use, and systemic corticosteroid rescue when being treated with lower doses and/or less frequent doses of zileuton. Patients who demonstrate improved asthma control with zileuton 600 mg QID may be able to reduce their daily dosage and/or frequency while still maintaining the same level of symptom control.

Safety and clinical efficacy of zileuton in patients with chronic asthma.

Zileuton, a leukotriene pathway inhibitor used to treat asthma, improves lung function, relieves symptoms, and is well tolerated. The purpose of this 12-month, parallel-group, open-label study was to assess the efficacy of zileuton and evaluate liver function in patients treated with this drug (approximately 2% of patients treated with zileuton in controlled trials had reversible liver enzyme elevations). A total of 2,947 patients at 233 centers in the United States were randomly assigned in a 5:1 ratio to treatment with zileuton plus usual asthma care or usual asthma care alone. Efficacy variables included asthma exacerbations; need for alternative treatment, steroid rescue, emergency care, and hospitalizations; forced expiratory volume in 1 second (FEV1); and asthma symptom scores. The safety evaluation included measurement of alanine aminotransferase levels. Patients treated with zileuton had significantly fewer corticosteroid rescues (P < 0.001), required less emergency care (P < 0.05), had fewer hospitalizations, and had greater increases in FEV1 (P = 0.048). They also had significantly greater improvements in asthma symptoms. Increases in alanine aminotransferase levels to three times or more the upper limit of normal occurred in 4.6% of patients treated with zileuton and 1.1% of those receiving usual care (P < 0.001); most increases occurred during the first 2 to 3 months. Alanine aminotransferase levels decreased to less than two times the upper limit of normal or to baseline levels during zileuton treatment or after drug cessation. Jaundice or chronic liver disease did not develop in any patient. Adding zileuton to the therapeutic regimens of patients with asthma is likely to improve asthma control and lower utilization of healthcare resources.

High-performance liquid chromatographic determination of diltiazem and four of its metabolites in plasma: evaluation of their stability.

A rapid, specific and reproducible high-performance liquid chromatographic method was developed for the simultaneous determination of diltiazem and four of its metabolites in plasma. The method involves extraction with methyl tert.-butyl ether, back-extraction into 0.017 M phosphoric acid followed by reversed-phase chromatography on a 3-micron particle, 15-cm ODS column with UV detection at 237 nm. Overall the recovery of each compound was reproducible and greater than 85%. Calibration curves were linear over the concentration range 10-250 ng/ml, with within-day or between-day coefficients of variation not exceeding 12%. A stability study indicates that while diltiazem is stable for at least six weeks in frozen plasma, more than 30% degradation of the major metabolite, N-monodesmethyldiltiazem, was observed after four weeks at -20 degrees C. The assay procedure has been applied to monitoring of plasma levels in patients receiving chronic oral therapy.

Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group.

BACKGROUND: Leukotrienes produced by the 5-lipoxygenase pathway of arachidonic acid metabolism may mediate bronchoconstriction and inflammatory changes important in the pathophysiology of asthma. Leukotriene inhibition may be effective in asthma management. OBJECTIVE: This clinical trial was performed to assess the long-term efficacy and safety of zileuton, an inhibitor of 5-lipoxygenase. METHODS: In this multicenter, double-blind, parallel-group, placebo-controlled trial, 600 mg of zileuton, 400 mg of zileuton, or placebo was given orally, each four times daily for 6 months. Patients with mild to moderate asthma (n = 373), 18 to 62 years of age, being managed with regularly inhaled beta-agonist alone, were randomized to the zileuton or placebo groups (n = 122 to 126). Outcome measures included serial spirometry, daily peak expiratory flow rates, daytime and nocturnal symptoms, frequency of beta-agonist use, and number of asthma exacerbations treated with systemic corticosteroids. RESULTS: An acute bronchodilatory effect was observed 2 to 5 hours after the initial dose of medication in both 400 mg zileuton and 600 mg zileuton groups compared to the placebo group. Both zileuton groups had significantly greater improvements in FEV1 than did the placebo group by day 8. On day 36, FEV1 improved 16% and 12% from baseline for patients treated with 600 mg zileuton and 400 mg zileuton, respectively, compared with an improvement of 6% for the placebo-treated group (p < 0.01, zileuton 600 mg vs placebo). Blood eosinophil levels were significantly reduced in both zileuton-treated groups compared with the placebo group. In the group receiving 600 mg zileuton, morning peak expiratory flow rate improved by 7% to 10%; daytime and nocturnal symptoms decreased by 37% and 31%, respectively; beta-agonist use decreased by 31%; and the proportion of patients requiring steroid rescue medication during the study was reduced by 62% (p < 0.05 for all comparisons of zileuton, 600 mg, vs placebo). Improvements were sustained over 6 months. Adverse events were similar in the three groups with no apparent, dose-related side effects. CONCLUSION: Zileuton produces objective and subjective improvements in patients with mild to moderate asthma and is well tolerated.

Washin and washout of isoflurane during cardiopulmonary bypass.

To help decide when an inhalational agent should be discontinued during cardiopulmonary bypass (CPB), its rate of washin and washout must be known. Isoflurane one per cent was administered to 14 patients undergoing CPB and isoflurane blood concentrations were measured to determine the time course of washin and washout of this agent. Bubble oxygenators were used for seven patients and membrane oxygenators for the remaining seven. During the administration of isoflurane, isoflurane blood concentrations rose slowly and did not reach a steady state during the time available for washin. Isoflurane blood concentrations decreased by at least 50 per cent within two minutes of turning off the vaporizer, and by 15 minutes the concentration had dropped by 75 per cent. There was a tendency for more rapid elimination of isoflurane in patients undergoing rewarming during this period. There did not appear to be an important difference between bubble and membrane oxygenators in the rate of washin and washout of isoflurane. Within 15 minutes of turning off the vaporizer only 25 per cent of the original blood concentration of isoflurane will remain. The anaesthetist must decide what concentration of isoflurane is acceptable during separation from CPB. Knowledge of the time course of isoflurane washout will allow more accurate determination of when to discontinue its administration in order to reach an acceptable concentration by the time separation from CPB occurs.

Prevention of epidural morphine-induced respiratory depression with intravenous nalbuphine infusion in post-thoracotomy patients.

The efficacy of nalbuphine, an agonist/antagonist opioid, in preventing respiratory depression from epidural morphine analgesia after thoracotomy, was assessed in a randomized double-blind placebo controlled trial. After a standardized general anaesthetic and 0.15 mg.kg-1 of epidural morphine, patients received a bolus and then a 24 h infusion of nalbuphine (200 micrograms.kg-1 + 50 micrograms.kg-1.hr-1, 100 micrograms.kg-1 + 25 micrograms.kg-1.hr-1, or 50 micrograms.kg-1 + 12.5 micrograms.kg-1.hr-1) or placebo. Blood gases, analgesia, sedation, side effects, and blood nalbuphine concentrations were assessed every two hours for the next 24 h. Fifty-three per cent of placebo-treated patients had a PaCO2 greater than 50 mmHg and 89 per cent of these received naloxone. A 200 micrograms.kg-1 bolus of nalbuphine followed by a 50 micrograms.kg-1.hr-1 infusion achieved a mean steady state blood level of 38.2 ng.ml-1 and prevented CO2 retention greater than 50 mmHg in all but two patients, neither of whom required naloxone. There was no difference in the incidence of side effects among groups, and analgesia appeared to be unaffected by nalbuphine.