title: 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.
abstract: 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 +/- 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. 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 curve0-12 (microgram x hours x L-1), Cmax (microgram/L), and Tmax (hours) was 100%, 98%, and 2.3 fold, respectively.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Palliative Care Program, Edmonton General Hospital, Cross Cancer Institute, University of Alberta, Canada.
authors.forename: E D
authors.initials: ED
authors.lastname: Bruera
authors.forename: T J
authors.initials: TJ
authors.lastname: MacEachern
authors.forename: K A
authors.initials: KA
authors.lastname: Spachynski
authors.forename: D F
authors.initials: DF
authors.lastname: LeGatt
authors.forename: R N
authors.initials: RN
authors.lastname: MacDonald
authors.forename: N
authors.initials: N
authors.lastname: Babul
authors.forename: Z
authors.initials: Z
authors.lastname: Harsanyi
authors.forename: A C
authors.initials: AC
authors.lastname: Darke
mesh_terms: D002908:Chronic Disease; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D006801:Humans; D008787:Metoclopramide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009325:Nausea / Q000097:blood / Q000188:drug therapy*; D009369:Neoplasms / Q000097:blood / Q000150:complications*; D011446:Prospective Studies
chemical_list: D003692:Delayed-Action Preparations; D008787:Metoclopramide