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Feature

Subantimicrobial Dose Doxycycline — Host Modulation in the Treatment of Periodontitis


October 1, 2005
by Thomas Zahavi, DMD, MS, Jack G. Caton, DDS, MS



ABSTRACT

The etiology of chronic periodontitis involves complex host-parasite interactions modified by environmental and genetic factors. Contemporary thinking suggests that successful long term management of chronic periodontitis may combine both local mechanical and antimicrobial therapy with modulation of the patients’ systemic (host) response to the bacterial exposure. A drug has been approved by the United States Federal Drug Administration for use as an adjunct to scaling and root planing for treatment of chronic periodontitis. It is low dose doxycycline hyclate 20mg (Periostat) and is effective and safe when taken every 12 hours. Periostat is an inhibitor of matrix metalloproteinases that have been implicated in the plaque-induced pathologic degradation of connective tissue collagen of the periodontal supporting structures. In this review paper, we will answer commonly asked questions regarding the role of subantimicrobial dose doxycycline in the treatment of periodontitis.

THE PROBLEM

Periodontitis appears as a site specific, progressive, and at times episodic disease, affecting the tooth supporting structures, the peridontium.1 Conservative estimates indicate that periodontitis affects approximately 33 percent of the United States population who are above the age of 30 years.2

In addition to tooth loss, periodontitis may expose patients to possible development of various systemic conditions, such as diabetes mellitus, chronic obstructive pulmonary disease, adverse pregnancy outcomes and cardiovascular disease,3,4 therefore, it is essential to address the problem in order to maintain the patient’s general health.5

DISEASE PATHOLOGY

The pathophysiology of periodontal disease is characterized by a sequence of events initiated by the presence of bacteria in the gingival sulcus. Although it was considered that bacteria were the sole cause of periodontal diseases, evidence based data now shows that the breakdown of periodontal tissues is primarily caused by the response of the host to the presence of the bacteria.6 The host response results in the stimulation of cells to release a variety of substances, cytokines, which in turn induce infiltrating and resident cells in the periodontium, and other parts of the body, to release enzymes known as matrix metalloproteinases (MMPs).

MMPs are peptidases that act together as degrading agents of connective tissue proteins including collagen. Prominent amongst the MMPs that promote the breakdown of periodontal supporting structures are neutrophil-derived MMP-8, (collagenase), MMP-9 (gelatinase),7-9 and MMP-13 (collagenase which is bone derived).10, 11

Elevated levels of activated MMPs progressively destroy the collagenous matrix, degrade the gingiva, the periodontal ligament and the supporting alveolar bone in the diseased periodontium, thus creating the clinical signs and symptoms of periodontal disease.

TREATMENTS TO DATE AND THEIR LIMITATIONS

Traditional nonsurgical treatments such as scaling and root planing (SRP) are geared to arrest periodontal disease progression and to stabilize clinical attachment levels. As such, they are directed at minimizing the presence of periopathogens in the gingival sulcus. SRP mechanically reduces the bacterial load in the oral cavity by removing calculus and plaque, in addition to the removal of bacterial endotoxins from the root surface of the teeth. Additional therapies are considered adjunctive to mechanical debridement and include systemic12 and locally delivered13,14 antimicrobial treatment, unique toothbrush designs, surgical procedures and specific home care systems, which all serve the common goal of altering the local environment to minimize the bacterial load.

Traditional antimicrobial treatments present two major limitations:

* Total bacterial elimination is impossible, since the ever present oral flora quickly repopulates even in cases of pocket sterilization.

* Antimicrobial treatment does not address the “host-response” aspect of the disease. Namely, it cannot influence the extent to which the host responds to the presence of the pathogen. Antimicrobial treatment also does not affect the activity of the MMPs, which are the end products of the above mentioned “host response”.

However, it is important to note that antimicrobial treatments do have positive results in that they indirectly decrease MMP activity by reducing the bacterial load, hence reducing the stimuli for host production of destructive MMPs.

It is also true that antimicrobial treatments alone, when administered to patients with abnormal “host responses” (either exaggerated or dysfunctional), or in patients who are refractory to treatment, result in unpredictable and at times suboptimal outcomes.

THE NOVEL TREATMENT APPROACH

Combining traditional treatments with host modulation

Since adult periodontitis is caused by periopathogens and destructive “host responses”, any management program should include treatments and therapies that consider these two elements, namely, mechanical bacteria-reducing procedures primarily, combined with host-modulating pharmocotherapies administered systemically as treatment adjuncts.

Tetracyclines as host modulatory agents

Tetracyclines, administered in doses of 200 or 100mg/day are known to act as bacteriostats in the treatment of periodontitis. Tetracyclines are also known as inhibitors of tissue-destructive MMPs in crevicular fluid and tissues, independent of their antimicrobial activity.8,9,15-21

Tetracyclines, directly inhibit tissue destructive MMPs, including MMP-8, MMP-9 and MMP-13, whereas doxycycline (a semisynthetic tetracycline) has been shown to be the most potent inhibitor of MMP activity.8,22 Doxycycline acts primarily as a noncompetitive inhibitor of collagenase8 and affects host responses via multiple indirect mechanisms. Since the early 1980s, various pharmocotherapies have been studied to evaluate their potential as host modulating agents. Golub and colleagues identified an unexpected property in the antibiotic class of tetracyclines (including doxycycline) in their ability to arrest the aggressive periodontal destruction seen in animal models of periodontitis.15,17

PERIOSTAT: THE HISTORY

With the knowledge of the potential of tetracyclines to inhibit MMPs, an extensive clinical trial program was initiated to evaluate the use of doxycycline as an adjunctive treatment for adult periodontitis. Results of Phase II trials demonstrated that subantimicrobial doses of doxycycline (SDD), reduced the elevated levels of gingival crevicular fluid collagenase as compared with patients receiving placebo (p<0.05). In addition, in the groups receiving the highest doses of the drug (20mg twice daily), improvements in clinical attachment levels were greater.25

In separate studies, involving healthy volunteers who received a subantimicrobial dose of doxycycline (20mg bid), the doxycycline plasma levels were significantly below the minimum threshold required for antimicrobial efficacy (Fig. 1)25. This confirms the assumption that the host modulatory effects of doxycycline are independent of its antimicrobial properties. In addition it was shown in the Phase II studies that there was no correlation between body weight and plasma levels of doxycycline at steady-state conditions and, therefore, no need to adjust the dose in accordance with body weight.25

Phase III studies were undertaken to establish the safety and efficacy of subantimicrobial dose doxycycline (SDD) 20mg bid used as an adjunct to scaling and root planing in patients with chronic periodontitis.23,24 In 1998, the US Food and Drug Administration (FDA) approved Periostat (20mg doxycycline) for use as an adjunct to SRP in the treatment of adult periodontitis.

Additional molecular evidence for the effect of SDD as a host modulator

Since the original studies done by Go
lub and colleagues in the 1980s, Golub and others further studied the influence of SDD on the host response on a molecular level.

In 1997, Golub and colleagues26 studied whether SDD administration to a population of patients with chronic periodontitis would reduce the amount of specific collagenases and bone-type collagen degradation fragments in gingival crevicular fluid (GCF). Their study design included SRP in 18 subjects with chronic periodontitis, 12 of which received an adjunctive treatment with 20mg bid doxycycline. Both groups were followed up for a period of two months. A significant reduction in neutrophil-type collagenase (MMP-8) and MMP-13, which is associated with bone resorption, as well as a significant (p<0.05) reduction in collagen degradation fragments, was observed. The authors acknowledged that for the first time, in human studies, a reduction of MMP activity was detected with concomitant reduction in levels of collagen degradation fragments.

In a more recent study Choi et al27 further examined the influence of SDD administered for 120 days on clinical measures, as well as known GCF and tissue markers for periodontal disease such as MMP-8, MMP-9, tissue inhibitor of matrix metalloproteinases (TIMP-1) and interleukin-6 (IL-6). In their study 32 patients were randomly divided into a control group (SRP + placebo) and a study group (SRP + 20mg bid doxycycline). After 120 days, a significant (p<0.05) reduction in MMP-8 was detected in the study group as compared to the control. This difference coincided with a significant improvement in the clinical parameters. No significant difference was found between the study and the control group in the levels of MMP-9, TIMP-1 and IL-6.

Emingil et al28 used GCF laminin-5 (Ln-5) levels, a marker for apical epithelial cell migration in periodontal pocket development, to evaluate the effect of SDD in conjunction with SRP. Thirty chronic periodontitis patients were randomly assigned to a control group (SRP + placebo) and a study group (SRP + 20mg bid doxycycline for three months). The groups were monitored every three months up to one year. It was found that Ln-5 levels were significantly lower in the study group as compared to the control, for every time interval. In a second publication by the same research group, a significantly greater reduction was reported in MMP-8 levels in the SDD group as compared to the control.29

THE CLINICAL STUDIES

What is the effect of SDD treatment in conjunction with SRP on patients with chronic periodontitis?

The most extensive study was published by Caton et al in 2000.30 This study included 190 patients in five dental centers in the United States. All patients received SRP and then were assigned to receive 20mg doxycycline or placebo bid, for nine months. Baseline measurements included probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and per patient percentage of sites with CAL gain and PD reduction = 2mm and = 3mm. This manner of presenting the results provides better information regarding the clinical applicability and efficacy of the treatment. The results were divided into three patient groups: tooth sites with baseline PD of 0-3mm were considered normal; tooth sites with baseline PD of 4-6mm were considered mildly-moderately diseased and tooth sites with baseline PD = 7mm were considered as severely diseased. The patients were monitored every three months up to nine months. In the mild to moderate and severe groups the improvement in CAL and PD was significantly greater (p<0.05) in the study group than in the control for all time frames. The percentage of tooth sites with CAL gain = 3mm was 60%, 30%, and 25% greater in the SDD group as compared to the placebo at three, six, and nine months, respectively. The percentage of tooth sites with PD reduction = 3mm was 152%, 82%, and 68% greater in the SDD group as compared to the placebo at three, six, and nine months, respectively. It was apparent from this study that adjunctive use of SDD with SRP is more effective than the use of SRP alone.

Since this study, other groups31-33 have studied long term (nine months) use of SDD as an adjunctive treatment to SRP, and all have found the SDD treatment groups to be superior to SRP alone.

Two studies,28,34 examined the effect of the short-term use of SDD on the clinical outcome when combined with SRP. In a unique study design, Golub et al34 evaluated 51 patients up to 36 weeks. After supra- and subgingival scaling and prophylaxis, the patients were divided into 5 groups: 1) doxycycline 12 weeks 20mg bid, 2) doxycycline 12 weeks 20mg qd, 3) doxycycline 4 weeks 20mg bid then 8weeks 20mg qd, 4) doxycycline 4 weeks 20mg bid then placebo 8 weeks, 5) placebo 12 weeks. Following the first period of the study (12 weeks) the patients were monitored for an additional 12 weeks, and then received a second course of treatment. Groups 1 to 3 received doxycycline 20mg qd for 12 weeks and groups 4 and 5 received placebo qd for 12 weeks. The authors measured PD, CAL, and GCF collagenase at baseline and every 12 weeks.

In all three groups receiving SDD a reduction in GCF collagenases and gain of CAL was observed as compared to the placebo groups.4,5 It appears that during the 12 weeks after the first course of treatment (from week 13 to 24), all groups started to loose CAL. This tendency ceased during the second course of treatment, which included scaling and SDD (qd) or placebo (from week 25 to 37). Only in the group receiving the highest dose of SDD (doxycycline 20mg bid + 20mg qd) there was no loss of CAL at 36 weeks as compared to approximately 0.8mm attachment loss at 24 and 36 weeks in the other groups.

From this study it appears that the beneficial effect of three months doxycycline 20mg bid, was not maintained without a second course of SDD treatment. It should be mentioned that the maintenance (i.e. scaling and prophylaxis) intervals, in this study were six months and not three months as recommended by several other human studies.35-38 All groups maintained stability, if not a gain of CAL in the first three months, which was followed by a rapid loss of CAL from week 12 to week 24.

A second study28,29 evaluated the effect over a 12 month period of adjunctive three months SDD administration to SRP. Thirty patients with chronic periodontitis were randomly assigned to the control (placebo) or study (doxycycline 20mg bid) groups. Measurements and prophylaxis were conducted every three months for the one year period. Measurements included: GCF, PD, CAL Gingival Index (GI), and Plaque Index (PI). This group studied the MMP-8 and Laminin-5 (Ln-5) levels in the GCF. In both groups (i.e. study and control), there was a significant improvement in the clinical and molecular measurements as compared to the baseline.

The SDD group compared to the placebo had a significant lower PD in nine and 12 months intervals. A significant reduction in MMP-8 levels was noted only in the sixth month and Ln-5 reduction in the third month. As mentioned earlier, in this study, both groups underwent three months maintenance intervals. This may be the reason for the improved and stable results in both groups, and the lack of statistical significance between the two groups in some of the time intervals.

From the short and long term studies conducted thus far, it appears that SDD treatment in conjunction with SRP, whether given for a short period (three months) or for a longer time (nine months), is superior to SRP treatment alone.

Is the beneficial effect of SDD stable?

Caton et al examined patients from the large study,39 three months after the patients stopped the SDD and placebo treatment (i.e. after one year). The aim of this study was to examine whether the beneficial effect of SDD administered for nine months had a lasting effect. The results indicated that, within each disease severity group, the initial improvement in PD and CAL remained stable for the additional three months without treatment. Novak40 et al also reported stable results three months
after six months of SDD use. Emingil et al28,29 in a study described earlier, reported stable results with significantly greater reductions in PD, in the SDD group, as compared to the control after 12 months (nine months without treatment). In the study of Golub et al34 the initial beneficial results achieved after three months of SDD treatment were lost, when additional SDD treatment was discontinued. A further three months of SDD treatment corrected this.

Does SDD have an antibacterial effect on the subgingival microflora?

The anticollagenase activity of doxycycline had been shown to be independent of its antimicrobial activity.3,8,15,41,42 Multiple studies failed to identify an antimicrobial effect of SDD on the subgingival microflora.30,43,44 Walker et al44, for instance, found no microbiological differences between the study groups for coccoid forms, motile and non-motile rods, fusiforms and filamentous rods. Only the small and large spirochetes group was found to be significantly lower in the SDD group as compared to the placebo group. The authors explained this finding as not being associated with the antimicrobial effect of doxycycline, but rather with the overall improvement in gingival health due to the anti-inflammatory and anticollagenase properties of doxycycline.

No study has found evidence for multi-antibiotic resistance or cross resistance at any point in time.30,39,43

Is SDD treatment well tolerated by patients?

In pivotal studies, each patient recorded adverse events in a personal diary. Only three out of 190 patients discontinued the study due to adverse effects, two in the placebo, and one in the SDD group. No significant difference in adverse effects, such as: headache, influenza, toothache, sinus congestion, periodontal abscess, sore throat etc. could be detected between the study and control group. It appears that the use of SDD is well tolerated by the patient.30,32

Does SDD have a beneficial effect also on generalized aggressive periodontitis?

In 2002 Novak et al40 published a study on the effect of SDD treatment for six months in conjunction with SRP on patients with aggressive periodontitis. All 20 patients were 45 years old or younger. They were randomly divided into study and control groups (10 patients per group). All the patients received supra- and subgingival debridement and plaque control instructions. The study group received doxycycline 20mg bid for six months, while the control group received placebo. In this study, the maintenance protocol was very strictly adhered to, with each patient receiving prophylaxis at each recall appointment (1, 3, 6, and 9 months). At the end of the study (three months without SDD treatment) a statistically greater reduction in PD was observed in the study group as compared to the control (3.02mm vs. 1.42mm). In the SDD group about 40% of the sites with initial PD = 7mm, had PD reduction = 4mm, as compared to less than 10 percent in the control group. Probably one of the most important observations was the very low incidence of PD increase in the study group (two sites) as compared to the placebo group (10 sites). This study failed to demonstrate a significant gain of CAL in the SDD group as compared to the placebo group, although the tendency was obvious.

From this study it appears that the use of SDD in conjunction with full mouth debridement is beneficial in patients with aggressive periodontitis.

What should be the minimal duration of treatment with SDD?

Several treatment modalities have been used in the treatment of periodontal diseases in conjunction with SDD. Caton30 and Preshaw,31,32 in long term (nine months) prospective studies of chronic periodontitis patients, found the SDD treatment to be superior to the placebo group, with stable results up to three months without the SDD treatment. Novak40 used SDD treatment on generalized aggressive cases for a six month period and reported stable superior results for the study group as compared to the control group. These results were maintained for an additional three months. Emingil28,29 in a three month treatment with SDD, found stable superior results in the study group as compared to the control group for up to a year.

From studies available in the literature so far, it appears reasonable to suggest the following treatment approach: An initial three months course of SDD in conjunction with SRP, and then evaluation of the results. Patients maintaining stable PD and CAL should be placed on a three months maintenance interval. Should deterioration be detected, SDD adjunctive treatment should be resumed for another three months.34,45 To date, no study has examined the effect of SDD treatment for a period longer than nine months.

How beneficial is the treatment with SDD on smokers?

Preshaw et al46 in a retrospective analysis of the results from a prospective randomized clinical trial, reported that, SDD treatment in conjunction with SRP, for a period of nine months, showed better results as compared to the placebo in both smokers and non-smokers groups. Interestingly, when comparing the two groups (smokers vs. non-smokers) the smokers study group (with SDD) accomplished more PD reduction and CAL gain when compared to the non-smokers placebo group.

Although smokers are known to gain less beneficial clinical outcomes from periodontal treatment, whether surgical or nonsurgical, it seems, from the information known to date, that SDD treatment improves the nonsurgical treatment outcome in smokers compared to that of the non-smoker group.46

What is the effect of SDD on surgical treatment?

To date only one study has been conducted to evaluate the effect of SDD treatment on the outcome of periodontal surgery.47 Twenty-four patients, after having undergone periodontal flap surgery were assigned either to receive SDD treatment or placebo for a total of six months. The patients were evaluated 12 months post-surgery (i.e. six months without SDD treatment). After 12 months, the combination of SDD with the flap surgery resulted in greater PD reduction in the treated sites that were initially > 6mm.

Is the combination treatment of SDD and non-steroidal anti-inflammatory drugs synergistic?

So far, the use of SDD, when combined with either surgical or nonsurgical treatment, has been shown to be beneficial and superior to these treatments without SDD.

The use of non-steroidal anti-inflammatory drugs (NSAIDS) has been shown to reduce prostaglandin-E2 (PGE2) and other inflammatory mediators, which are known to induce bone resorption and periodontal attachment loss.48,49 This beneficial “antidestructive” effect seems to be hindered by the rebound phenomena occurring after cessation of the NSAIDS administration and the potential toxicity of their long-term use.50

A new approach considered combining of SDD treatment with a low-dose flurbiprofen (LDF).51 Nineteen patients with chronic periodontitis were randomly assigned to 1) only LDF (50mg qd), 2) only SDD (20mg bid), 3) a combination of LDF and SDD. These prescribed treatments were given after an initial treatment of oral hygiene instructions and SRP. Smokers were excluded from this study. The examiners evaluated the following tissue breakdown markers from gingival biopsies taken before medications were initiated and after three weeks of treatment: collagenase, gelatinase, elastase and others. Treatment with LDF alone produced no statistically significant reduction in any of the markers. SDD alone significantly reduced the host-derived neutral proteinases. However, a short term (three weeks) therapy, which combined LDF and SDD produced a synergistic effect, with a significant reduction in collagenase, gelatinase, and elastase activities. A 46%-75% reduction in the markers with the combination therapy, as compared to 21%-29% with SDD alone was observed. This novel approach still has to be evaluated for long-term safety and efficacy.

CONCLUSION

The efficacy of biomechanical treatment for periodontitis can be improved when combined with systemi
c treatment that specifically addresses the host-response aspect of periodontitis. Periostat suppresses tissue-destructive enzymes, and when used as an adjunct to SRP or flap surgery, has proven to be safe and efficacious in improving treatment outcomes in patients with chronic and aggressive periodontitis. A significant beneficial effect has also been proven for smokers. The adjunctive use of Periostat in patient management constitutes an important and novel approach in the treatment of various types of periodontitis.

Acknowledgment

The authors would like to thank Sam Pivo for his assistance in the editing of this article.

Dr. Thomas Zahavi is a Graduate Student, Division of Periodontics, University of Rochester, Eastman Dental Center, Rochester, New York.

Dr. Jack G. Caton is the past-president of the American Academy of Periodontology (AAP), a Professor, Program Director and Chair, Division of Periodontics, University of Rochester, Eastman Dental Center, Rochester, New York.

Oral Health welcomes this original article.

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