Adjunctive treatment with subantimicrobial doses of doxycycline: effects on gingival fluid collagenase activity and attachment loss in adult periodontitis

Objectives: The therapeutic effects of doxycycline and other tetracyclines in the treatment of periodontitis involve, at least in part, mechanisms that are unrelated to their antimicrobial activity. Previous clinical studies have shown that doxycycline administered orally, at doses below those needed for antimicrobial efficacy, to human subjects with adult periodontitis resulted in significantly reduced collagenase activity in gingival crevicular fluid (GCF) and in extracts of inflamed gingival tissues. The purpose of the present study was to identify clinically effective dosing regimens using subantimicrobial dose doxycycline (SDD) as an adjunctive therapy in patients with adult periodontitis. Material and Methods: A total of 75 adult men and women qualified for enrollment into the three-part, placebo-controlled, double-blind, parallel-group study. Patients were stratified based on repeatedly exhibiting pathologic levels of periodontal attachment (ALv) and GCF collagenase activity at several appointments prior to baseline. Patients were administered a scaling and prophylaxis, then 1 of 5 treatment schedules for 12 weeks (part I), followed by a 12-week period of no drug therapy (part II), a second scaling and prophylaxis, and 12 additional weeks of treatment (part In). Primary determinants of efficacy included reductions in GCF collagenase activity and changes in relative ALV. Results: 66 patients completed the Ist 12 weeks (part I) of the 3-part, 36-week study; 51 patients completed the entire 36-week study. From baseline to week 12 (part I), treatment with specially formulated SDD capsules (20 mg) 2x daily (Ix every 12 h) for up to 12 weeks was shown to significantly reduce GCF collagenase activity and to improve ALV, effects not seen in patients treated with placebo. Continuous drug therapy over the 12-week treatment period was needed to maintain and maximize the reduction in GCF collagenase and the improvement in ALv. Improvements in periodontal disease parameters occurred without the emergence of doxycycline-resistant micro-organisms. In patients administered an "on-off-on" regimen of SDD over 36 weeks (parts I-III), essentially no attachment loss occurred in patients receiving the highest of these SDD regimens (20 mg 2X daily during part I and 20 mg 1X daily in part III), whereas patients administered placebo capsules experienced a mean attachment loss of approximately 0.8 mm at the 24- and 36-week time periods. Conclusions: Doxycycline administered at subantimicrobial doses led to improvements in disease parameters, with no apparent side effects, and appears to have significant potential as an oral adjunctive therapy in the long-term management of adult periodontitis.