Tolerance during 5 months of dosing with ranitidine, 150 mg nightly: a placebo-controlled, double-blind study

Abstract

Repeated dosing with an H2-receptor antagonist results in a modest decrease in antisecretory potency termed "tolerance." The object of this prospective study was to determine whether tolerance is a progressive phenomenon or whether it levels off during prolonged dosing with a standard maintenance dose of an H2-antagonist. The effect of continuous dosing with ranitidine, 150 mg nightly, was compared with intermittent dosing (27 days of placebo each month) with active ranitidine, 150 mg nightly, only on the night of each experiment. Simultaneous 24-hour intragastric acidity and plasma gastrin concentration were measured monthly for 5 months in 17 healthy subjects (7 continuous and 10 intermittent dosing). In the intermittent-dosing group, the antisecretory response to ranitidine, 150 mg nightly, was preserved throughout the 141-day trial period; the median nocturnal integrated acidity decreased from 557 mmol.h/L (day 0) to 38 mmol.h/L on day 1 of dosing, and it ranged between 32 and 55 (median, 45) mmol.h/L during days 29-141. In the continuous-dosing group, there was a significant return of nocturnal intragastric acidity on days 29 and 85 compared with day 1 of dosing. The median nocturnal integrated acidity decreased in the continuous-dosing group from 554 mmol.h/L (day 0) to 87 mmol.h/L on the first day of dosing, and it ranged between 145 and 287 (median, 170) mmol.h/L during days 29-141. Either intermittent or continuous dosing with ranitidine was associated with an elevation of plasma gastrin concentration, which remained constant throughout the 5-month study. Tolerance does develop in healthy subjects during the first month of dosing with ranitidine, 150 mg nightly, but it is not a progressive phenomenon, and it is probably not of clinical relevance.