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Background. The short elimination half-life of metoclopramide necessitates frequent administration for optimal relief of nausea. This study compares a newly developed controlled release preparation of metoclopramide (CRM) and immediate release metoclopramide (IRM) with respect to efficacy, safety, and pharmacokinetics in patients with chronic nausea associated with advanced cancer. Methods. Thirty-four patients with advanced cancer with nausea lasting more than 1 month and with no evidence of involvement of the gastrointestinal tract, peptic ulcer or gastritis, brain metastases, or metabolic abnormalities were randomized, in a double-blind cross-over study, to receive 40 mg of CRM every 12 hours or 20 mg of IRM every 6 hours for 3 days. Nausea, food intake, and side effects were assessed four times daily. On Day 3, sequential venous samples were taken (12 patients) to determine plasma metoclopramide concentrations. Results. In 29 evaluable patients, the intensity of nausea on Day 3, measured by a 0-100-mm visual analogue scale and 0-3 categoric scale was 15 [+ or -] 17 and 0.6 [+ or -] 0.6 after IRM, versus 8 [+ or -] 9 (P = 0.033) and 0.4 [+ or -] 0.5 (P = 0.055) after CRM, respectively. Visual analogue scale nausea scores recorded by time of day and by day for the 3 treatment days were significantly lower for patients who received CRM compared with those who received IRM (P = 0.047 and P = 0.043, respectively), but categoric nausea scores were not significantly different between treatments by time of day and by day across the 3 treatment days. No differences were observed in caloric intake or side effects between treatments. In a pharmacokinetic analysis, the CRM/IRM ratio for area under the [curve.sub.0-12] ([mu]g x hours x [L.sup.-1]), [C.sub.max] ([mu]g/L), and [T.sub.max] (hours) was 100%, 98%, and 2.3 fold, respectively. Conclusion. Controlled release metoclopramide is safe and effective in managing chronic nausea in patients with advanced cancer. Future studies should focus on characterizing this syndrome more clearly and on determining the optimal dose of metoclopramide and the effects of drug combinations that have proven to be useful in managing chemotherapy-induced emesis (i.e., metoclopramide plus corticosteroids).

Background. The short elimination half-life of hydromorphone necessitates 4-hourly dosing to maintain optimal levels of analgesia in patients with chronic cancer pain. The purpose of this study was to compare the clinical efficacy and safety of controlled release hydromorphone administered every 12 hours and immediate release hydromorphone administered every 4 hours in patients with chronic severe cancer pain. Methods. Forty-eight patients with stable chronic severe cancer pain were randomized, in a double-masked crossover study, to controlled release hydromorphone every 12 hours or immediate release hydromorphone every 4 hours for 7 days each. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed using a VAS. Assessments were made by the patient four times a day at 7:00 a.m., 11:00 a.m., 3:00 p.m., and 7:00 p.m. Use of rescue hydromorphone also was recorded by the patient. Results. Forty-five patients completed the study (26 women, 19 men; mean age, 57.1 [+ or -] 13.6 years) and received a mean daily dose of 76 [+ or -] 133 mg (range, 6-768 mg). There were no significant differences between controlled release hydromorphone and immediate release hydromorphone in overall VAS pain intensity scores (19 [+ or -] 14 vs. 20 [+ or -] 14 mm), ordinal pain intensity scores (1.2 [+ or -] 0.8 vs. 1.2 0.8) and pain scores by day of treatment or time of day. The daily rescue analgesic consumption during controlled release hydromorphone and immediate release hydromorphone did not differ significantly overall (1.1 [+ or -] 1.1 vs. 1.0 [+ or -] 1.1 doses per day) or with respect to time of day. There were no significant differences in overall VAS sedation scores (18 [+ or -] 18 mm vs. 19 [+ or -] 18 mm) and in overall mean VAS nausea scores (12 [+ or -] 15 mm vs. 11 [+ or -] 14 mm) between controlled release hydromorphone and immediate release hydromorphone. Conclusion. Controlled release hydromorphone administered every 12 hours is as effective as immediate release hydromorphone administered every 4 hours in the management of patients with chronic severe cancer pain. The benefits of controlled release hydromorphone lie in the convenience of its capsule formulation, which can be sprinkled on soft food, and its 12-hour duration of action, which allows patients uninterrupted sleep and improved compliance. Cancer 1994; 74:1808-16.

SUMMARYObjective: Toconduct a preliminary evaluation of a new oral formulation of controlled-release (CR) oxybutynin tablet taken once-daily in patients with urinary urge incontinence.Research design and methods: A single-centre, open-label, 8-week study was conducted. Patients with urodynamically-confirmed detrusor instability, micturition frequency (> 8 voids/day) and/or urinary incontinence (> 2 incontinence periods/day) were enrolled. The study duration was 8 weeks: patients received IR oxybutynin (2.5-5 mg bid) for 2 weeks, followed by a 2-week washout/baseline period to avoid carryover effects, and oral CR oxybutynin (15 mg OD) for 4 weeks. Daily void frequency, fluid intake, urinary incontinence episodes, and spontaneously reported adverse events were recorded in a daily diary for five consecutive days in each treatment period.Results: Of 12 enrolled patients, 9 patients completed the study and were evaluable for efficacy; all patients were evaluable for safety. Compared to baseline/washout, CR oxybutynin reduced UI episodes/day by 45 (p  0.13) and micturitions/day by 15 (p  0.07). Treatment with IR oxybutynin (mean dose: 6.7 ± 2.5mg/day) reduced UI episodes/day from baseline by 7 (p  0.58) and voids/day by 6 (p  0.29). Fluid intake remained consistent at approximately 2 litres/day during all study periods. The most common adverse event was dry mouth.Conclusion: Based on the reductions in daily frequency of incontinence and micturition following 4-weeks treatment, CR oxybutynin (15 mg OD) was at least as effective as the patients' previous dose of IR oxybutynin (mean dose: 6.7 ± 2.5 mg/day). These improvements were achieved without restriction of fluid intake. Initial 15mg doses of CR oxybutynin appear to be well tolerated.