COMPARISON OF THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF CONTROLLED-RELEASE AND IMMEDIATE-RELEASE METOCLOPRAMIDE FOR THE MANAGEMENT OF CHRONIC NAUSEA IN PATIENTS WITH ADVANCED CANCER

Background. The short elimination half-life of metoclopramide necessit ates frequent administration for optimal relief of nausea. This study compares a newly developed controlled release preparation of metoclopr amide (CRM) and immediate release metoclopramide (IRM) with respect to efficacy, safety, and pharmacokinetics in patients with chronic nause a associated with advanced cancer. Methods. Thirty-four patients with advanced cancer with nausea lasting more than 1 month and with no evid ence of involvement of the gastrointestinal tract, peptic ulcer or gas tritis, brain metastases, or metabolic abnormalities were randomized, in a double-blind cross-over study, to receive 40 mg of CRM every 12 h ours or 20 mg of IRM every 6 hours for 3 days. Nausea, food intake, an d side effects were assessed four times daily. On Day 3, sequential ve nous samples were taken (12 patients) to determine plasma metocloprami de 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 +/- 17 and 0.6 +/- 0.6 after IRM, versus 8 +/- 9 (P = 0.033) and 0.4 +/- 0.5 (P = 0.055) after CRM, respectively. Vi sual analogue scale nausea scores recorded by time of day and by day f or the 3 treatment days were significantly lower for patients who rece ived CRM compared with those who received IRM (P = 0.047 and P = 0.043 , respectively), but categoric nausea scores were not significantly di fferent between treatments by time of day and by day across the 3 trea tment days. No differences were observed in caloric intake or side eff ects between treatments. In a pharmacokinetic analysis, the CRM/IRM ra tio for area under the curve(0-12) (mu g X hours X L(-1)), C-max (mu g /L), and T-max (hours) was 100%, 98%, and 2.3 fold, respectively. Conc lusion. Controlled release metoclopramide is safe and effective in man aging chronic nausea in patients with advanced cancer. Future studies should focus on characterizing this syndrome more clearly and on deter mining the optimal dose of metoclopramide and the effects of drug comb inations that have proven to be useful in managing chemotherapy-induce d emesis (i.e., metoclopramide plus corticosteroids).