A randomized controlled trial of subantimicrobial-dose doxycycline to prevent unscheduled bleeding with continuous oral contraceptive pill use

Background: Unscheduled bleeding is the main side effect of continuous oral contraceptive pills (OCPs) and has been correlated with the up-regulation of matrix metalloprotineases (MMPs). The study objective was to determine if prophylactic administration of doxycycline (an MMP inhibitor at low subantimicrobial doses) would prevent unscheduled bleeding during the initiation of a continuous OCP. Study Design: Subjects using cyclic hormonal contraceptives (combined OCPs, patch or ring) without unscheduled bleeding were switched to continuous OCPs (20 mcg ethinyl estradiol/100 mcg levonorgestrel). They were randomized to receive daily doxycycline [sustained-release subantimicrobial dose (40 mg daily)] or placebo for the first 84 days and then observed for an additional 28 days on the continuous OCP alone. The number of bleeding/spotting days and the time in days it took to achieve amenorrhea were compared using a t test. Results: Sixty-five subjects were randomized. Although the use of doxycycline did not significantly decrease the number of mean bleeding/spotting days in the first 84 days of the study [doxycycline 14.75 (SE 2.30), placebo 17.78 (2.31), p=.36], women who received doxycycline had a significantly earlier onset of amenorrhea [mean last day of bleeding/spotting doxycycline 61.7 (7.7), placebo 85.2 (6.7), p=.03]. Conclusion: The coadministration of subantimicrobial-dose doxycycline during initiation of continuous OCPs results in a significant reduction in the length of time needed to achieve amenorrhea.