Soskolne WA, Chajek T, Flashner M An in vivo study of the chlorhexidine release profile of the PerioChip (TM) in the gingival crevicular fluid, plasma and urine. J Clin Periodontol. 1998; 25:1017-1021
Paolantonio M, D'Angelo M, Grassi RF Clinical and microbiologic effects of subgingival controlled-release delivery of chlorhexidine chip in the treatment of periodontitis: a multicenter study. J Periodontol. 2008; 79:271-282
Grenier D, Bertrand J, Mayrand D. Porphyromonas-gingivalis outer-membrane vesicles promote bacterial-resistance to chlorhexidine. Oral Microbiol Immunol. 1995; 10:319-320
Soskolne WA, Heasman PA, Stabholz A Sustained local delivery of chlorhexidine in the treatment of periodontitis: a multi-center study. J Periodontol. 1997; 68:32-38
Jeffcoat MK, Bray KS, Ciancio SG Adjunctive use of a subgingival controlled-release chlorhexidine chip reduces probing depth and improves attachment level compared with scaling and root planing alone. J Periodontol. 1998; 69:989-997
Azmak N, Atilla G, Luoto H, Sorsa T. The effect of subgingival controlled-release delivery of chlorhexidine chip on clinical parameters and matrix metalloproteinase-8 levels in gingival crevicular fluid. J Periodontol. 2002; 73:608-615
Grisi DC, Salvador SL, Figueiredo LC, Souza SLS, Novaes AB, Grisi MFM. Effect of a controlled-release chlorhexidine chip on clinical and microbiological parameters of periodontal syndrome. J Clin Periodontol. 2002; 29:875-881
Jeffcoat MK, Palcanis KG, Weatherford TW, Reese M, Geurs NC, Flashner M. Use of a biodegradable chlorhexidine chip in the treatment of adult periodontitis: clinical and radiographic findings. J Periodontol. 2000; 71:256-262
Rodrigues IFG, Machion L, Casati MZ Clinical evaluation of the use of locally delivered chlorhexidine in periodontal maintenance therapy. J Periodontol. 2007; 78:624-628
Paolantonio M, D'Ercole S, Pilloni A Clinical, microbiologic, and biochemical effects of subgingival administration of a xanthan-based chlorhexidine gel in the treatment of periodontitis: a randomized multicenter trial. J Periodontol. 2009; 80:1479-1492
Cosyn J, Sabzevar MM. A systematic review on the effects of subgingival chlorhexidine gel administration in the treatment of chronic periodontitis. J Periodontol. 2005; 76:1805-1813
Anand V, Govila V, Gulati M, Anand B, Jhingaran R, Rastogi P. Chlorhexidine–thymol varnish as an adjunct to scaling and root planing: a clinical observation. J Oral Biol Craniofac Res. 2012; 2:83-89
Friesen LR, Williams KB, Krause LS, Killoy WJ. Controlled local delivery of tetracycline with polymer strips in the treatment of periodontitis. J Periodontol. 2002; 73:13-19
Williams RC, Paquette DW, Offenbacher S Treatment of periodontitis by local administration of minocycline microspheres: a controlled trial. J Periodontol. 2001; 72:1535-1544
Paquette D, Minsk L, Lessem J, Santucci E. A pharmacokinetic study of a locally delivered minocycline therapeutic system(MPTS). J Clin Periodontol. 2000; 27
Walker C, Santucci E. The effect of a locally delivered minocycline periodontal therapeutic system(MPTS) on the fecal flora. J Clin Periodontol. 2000; 27
Bogren A, Teles RP, Torresyap G, Haffajee AD, Socransky SS, Wennstrom JL. Locally delivered doxycycline during supportive periodontal therapy: a 3-year study. J Periodontol. 2008; 79:827-835
Srirangarajan S, Mundargi RC, Ravindra S, Setty SB, Aminabhavi TM, Thakur S. Randomized, controlled, single-masked, clinical study to compare and evaluate the efficacy of microspheres and gel in periodontal pocket therapy. J Periodontol. 2011; 82:114-121
Leiknes T, Leknes KN, Boe OE, Skavland RJ, Lie T. Topical use of a metronidazole gel in the treatment of sites with symptoms of recurring chronic inflammation. J Periodontol. 2007; 78:1538-1544
Chaturvedi TP, Srivastava R, Srivastava AK, Gupta V, Verma PK. Evaluation of metronidazole nanofibers in patients with chronic periodontitis: a clinical study. Inter J Pharm Invest. 2012; 2:213-217
Pradeep AR, Sagar SV, Daisy H. Clinical and microbiologic effects of subgingivally delivered 0.5% azithromycin in the treatment of chronic periodontitis. J Periodontol. 2008; 79:2125-2135
Agarwal E, Pradeep AR, Bajaj P, Naik SB. Efficacy of local drug delivery of 0.5% clarithromycin gel as an adjunct to non-surgical periodontal therapy in the treatment of current smokers with chronic periodontitis: a randomized controlled clinical trial. J Periodontol. 2012; 83:1155-1163
Kathariya R, Pradeep AR, Raghavendra NM, Gaikwad R. Evaluation of subgingivally delivered 0.5% clarithromycin as an adjunct to nonsurgical mechanotherapy in the management of chronic periodontitis: a short-term double blinded randomized control trial. J Invest Clin Dent. 2014; 5:23-31
Flemmig TF, Petersilka G, Volp A Efficacy and safety of adjunctive local moxifloxacin delivery in the treatment of periodontitis. J Periodontol. 2011; 82:96-105
Pradeep AR, Rao NS, Naik SB, Kumari M. Efficacy of varying concentrations of subgingivally delivered metformin in the treatment of chronic periodontitis: a randomized controlled clinical trial. J Periodontol. 2013; 84:212-220
Lane N, Armitage GC, Loomer P Bisphosphonate therapy improves the outcome of conventional periodontal treatment: results of a 12-month, randomized, placebo-controlled study. J Periodontol. 2005; 76:1113-1122
Sharma A, Pradeep AR. Clinical efficacy of 1% alendronate gel as a local drug delivery system in the treatment of chronic periodontitis: a randomized, controlled clinical trial. J Periodontol. 2012; 83:11-18
Sharma A, Pradeep AR. Clinical efficacy of 1% alendronate gel in adjunct to mechanotherapy in the treatment of aggressive periodontitis: a randomized controlled clinical trial. J Periodontol. 2012; 83:19-26
Mundy G, Garrett R, Harris S Stimulation of bone formation in vitro and in rodents by statins. Science. 1999; 286:1946-1949
Pradeep AR, Thorat MS. Clinical effect of subgingivally delivered simvastatin in the treatment of patients with chronic periodontitis: a randomized clinical trial. J Periodontol. 2010; 81:214-222
Krayer JW, Leite RS, Kirkwood KL. Non-surgical chemotherapeutic treatment strategies for the management of periodontal diseases. Dent Clin North Am. 2010; 54:13-33
Panwar M, Gupta SH. Local drug delivery with tetracycline fiber: an alternative to surgical periodontal therapy. Med J Armed Forces India. 2009; 65:244-246
van Steenberghe D, Rosling B, Soder PO A 15-month evaluation of the effects of repeated subgingival minocycline in chronic adult periodontitis. J Periodontol. 1999; 70:657-667
Bonito AJ, Lux L, Lohr KN. Impact of local adjuncts to scaling and root planing in periodontal disease therapy: a systematic review. J Periodontol. 2005; 76:1227-1236
Dean of Dentistry and Professor of Restorative Dentistry, School of Dental Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4BW, UK
Local drug delivery systems (LDDs) are mainly used as adjuncts to root surface instrumentation (RSI) in the management of periodontal disease. A range of antibacterial agents have been used for this purpose and include the tetracyclines, chlorhexidine, metronidazole, azithromycin, clarithromycin and moxifloxacin. More recently, other non-antibacterial agents have been incorporated into local delivery devices and include simvastatin, metformin and alendronate. This paper will review the effectiveness of such agents when used as an adjunct to conventional non-surgical periodontal therapy.
Clinical Relevance: The benefits of adjunctive use of local drug delivery in the management of periodontal disease will be discussed.
Article
Chlorhexidine (CHX)
Chlorhexidine gluconate is active against a broad spectrum of microbes. The CHX molecule, owing to its positive charge, reacts with the microbial cell surface, destroys the integrity of the cell membrane, penetrates into the cell, precipitates the cytoplasm, and the bacterial cell dies.
In the early 1980s, the first slow release device containing CHX incorporated into a non-degradable matrix was introduced. A second generation slow release device was formulated and this is now available as the product PerioChip®. The chip is rounded at one end for insertion into periodontal pockets. Its physico-chemical properties are shown in Table 1. One PerioChip® is inserted into a periodontal pocket with a probing pocket depth (PD) greater than or equal to 5 mm. Up to 8 PerioChips® may be inserted at different sites in a single visit. Treatment is recommended once every three months in pockets with PD remaining greater or equal to 5 mm. The periodontal pocket should be isolated and the surrounding area dried prior to chip insertion up to its maximum depth. The PerioChip® does not need to be removed as it biodegrades completely and releases CHX over a 7–10 day period.
Active Ingredient
Product
Concentration
Vehicle
Release Characteristics
Chlorhexidine
PerioChip®
2.5 mg chlorhexidine gluconate
Cross-linked hydrolyzed gelatine matrix, glycerine and water
CHX is released in a biphasic manner. 40% CHX released by diffusion over the first 24 hrs, the remaining CHX is released in an almost linear fashion for 7–10 days.
Chlo-site®Xan-CHX gel
A concentration of 1.5% CHX of which 0.5% is CHX digluconate and 1% is CHX dichloride
2.5% xanthan gum. This is a polysaccharide consisting of galactose and mannose residue
A progressive release of highly efficient concentrations of CHX into the GCF. Spontaneously degrades in 15–30 days.
Tetracycline
Periodontal Plus AB®
2 mg tetracycline hydrochloride
25 mg fibrillar collagen
TC is released consistently from day 1 over a period of 10–14 days with the concentration peaking at 4–5 days.
Minocycline
Periocline®/Dentomycin®
2.1% minocycline hydrochloride
Hydroxyethyl-cellulose, aminoalkyl-methacrylate, triacetine and glycerine
GCF concentrations of 1000 micrograms per ml is evident 1 hr after administration. GCF in excess of 100 micrograms per ml is maintained through the first 6 hrs.
Arestin®
1 mg minocycline hydrochloride
Polymer of poly(glycolide -co-dl-lactide)
A sustained local release of antibiotic where a concentration of 340 micrograms per ml has been measured in the GCF after 14 days.
Doxycycline
Atridox®
10% by weight doxycycline hyclate, 50 mg
33% by weight poly (dl-lactide) 57% by weight N-methyl-2-pyrrolidone
A controlled release of drug for a period of 7 days. Doxycycline levels in GCF peak 2 hrs following treatment with Atridox®. These levels remain above 1000 micrograms per ml through 18 hrs at which time the levels begin to decline gradually.
DOXY®
14% doxycycline free amine
Polyethylene glycol-lactid/glycolid copolymer gel
Release of doxycycline peaks in GCF at 15 mins. 577.41 +/- 127.34 micrograms per ml after 3 days. Up to 10 days after application the mean concentration in GCF is 34.24 +/- 15.80 micrograms per ml.
Metronidazole
Elyzol®
25% metronidazole benzoate
Glyceryl mono-oleate and sesame oil
A concentration greater than 100 micrograms per ml of metronidazole is present for at least 8 hrs and a concentration of greater than 1 microgram per ml at 36 hrs. The plasma concentration reaches its maximum after 4 hrs.
Azithromycin
0.5% azithromycin
Poly(lactic-co-glycolic acid)
GCF concentration peaks at 2 hrs at 2041 micrograms per ml. This decreases to 324 micrograms per ml on day 7 and to 3 micrograms per ml on day 28.
The average concentration of CHX in gingival crevicular fluid (GCF) is <125 micrograms per ml.1 This was reported to be inhibitory to 99% of the bacteria isolated from the periodontal pocket. An initial peak concentration of 2007 micrograms per ml of CHX in GCF at 2 hours post chip insertion was detected;1 1300–1900 micrograms per ml CHX were maintained over the next 96 hours. The concentration then progressively decreased with 57 micrograms per ml present at 10 days. CHX was not detected in the plasma or urine samples at any point in the study. PerioChip® can maintain clinically effective levels of CHX in the GCF of periodontal pockets for over 1 week with no detectable systemic absorption.
Studies with PerioChip® showed reduction in the number of the putative periodontopathic organisms after placement of the chip.2 Organisms include Aggregatibacter actinomycetemcomitans, Eikenella corrodens, Porphyromonas gingivalis, Campylobacter rectus, Prevotella intermedia, Fusobacterium nucleatum, Tannerella forsythia and Treponema denticola.2
The disadvantages of PerioChip® include a reported low subgingival substantivity due to CHX's poor adherence to root surfaces and/or the compound's high affinity for salivary or serum proteins.1 There is also evidence that Porphyromonas gingivalis releases vesicles that bind to and inactivate CHX, protecting themselves and other bacteria from this agent.3
Multicentre trials have proven the effectiveness of the CHX chip in conjunction with RSI. These are reviewed in Table 2. Adjunctive use of PerioChip® has been shown to reduce pocket depths and maintain clinical attachment levels over a 6–9 month period.4,5 However, other studies have failed to confirm these results.6,7 A large multicentre study of CHX chips plus RSI offered statistically significant benefit over RSI alone: 15% of sites subject to RSI alone continued to experience a degree of bone loss over the 9-month study period, however, no sites in the RSI + CHX chip demonstrated such bone loss.8
Improvement in PD with PerioChip® + RSI at 1 month was similar to RSI alone. After 6 months a significant greater reduction in PD seen in PerioChip® + RSI compared to RSI alone 1.16 +/- 0.058 mm vs 0.70 +/- 0.056 mm in RSI alone (p ≤ 0.0001). CAL gain at 6 months was greater in the test group 0.47 +/- 0.062 mm vs 0.31 +/- 0.06 mm in the RSI alone (p < 0.05).
Adjunct to RSI PerioChip® reduction in PD seen in placement repeated at 3 and 6 months if pocket depth was greater or equal to 5 mm
7 days, 6 weeks, 3, 6 and 9 months
PD, CAL
At 9 months a greater PerioChip®+ RSI compared to RSI alone. 0.95 +/- 0.05 mm vs 0.65 +/- 0.05 mm (p < 0.001). The CAL gain was also greater in the test group 0.75 +/- 0.06 mm vs 0.58 +/- 0.06 mm in the RSI alone (p < 0.05).
No statistically significant difference was found between RSI alone and RSI +PerioChip®. At 9 months PerioChip®+ RSI had mean reduction in PD of 2.2 mm vs 2.4 mm in RSI alone (p > 0.05). At 9 months the mean gain in RAL was 1.0 mm for the RSI alone vs 0.6 mm for PerioChip® + RSI (p > 0.05).
PI and BI were similar for RSI and RSI + Chlo-site. There was a greater reduction in PD in the Chlo-site® + RSI group compared to RSI alone. The differences in the PD reduction between the treatments were 0.87 mm and 0.83 mm (p < 0.001) at 3 and 6 months, respectively, and the gain in CAL was 0.94 and 0.90 mm (p < 0.001), respectively.
PI and GI improved in both groups. The reduction in PD was greater in the TC + RSI group than RSI alone PD reduction of 1.85 mm in RSI + multiple TC strips after 6 months vs reduction of 0.98 mm in RSI alone (p = 0.033). The CAL gain was also greater for the multiple strip TC + RSI group than for RSI alone 0.35 +/- 0.68 mm vs -0.13 +/- 0.71 mm.
7 sites with BOP for RSI vs 4 sites for Periodontal Plus AB® + RSI. After 90 days mean PD 4.13 +/- 1.27 mm for RSI and 3.62 +/- 1.08 mm for Periodontal Plus®+ RSI.
Mean PD reduction was greater for Periocline® + RSI than RSI alone 1.9 mm reduction vs 1.2 mm. The CAL gain was also greater in this test group 0.9 mm vs 0.5 mm (p = 0.0001).
Minocycline + RSI is more effective than RSI alone. At 9 months a reduction in PD of 1.08 mm RSI vs 1.32 mm Arestin® + RSI. The difference is statistically significant (p = 0.001).
3 and 6 months, 1 year, 18 months, 2 years, 30 months and 3 years
PI, BOP, PD, Relative attachment level (RAL)
Mean PD reduction between baseline and 3 yrs was 1.2 mm in Atridox®+ RSI and 1.1 mm in RSI alone (p < 0.001). At 1, 2 and 3 yrs there was no statistically significant difference between the two groups. At 3 months the RAL was 0.8 mm in Atridox® + RSI and 0.5 mm in RSI alone (p < 0.1). At 3 yrs the gain was 0.9 and 0.7 mm (p > 0.05).
There was no statistical difference in the results of Elyzol® + RSI compared to RSI alone. 1.9 mm vs 1.8 mm in PD reduction (p = 0.001), 1.6 mm compared to 1.0 mm in gain CAL and 38.1% compared to 33.3% reduction in BOP.
A greater reduction in PD in Azithromycin + RSI compared to RSI alone. At 3 months mean PD reduction of 2.13 +/- 0.35 mm for RSI alone vs 2.53 +/-0.52 mm RSI + AZM (p < 0.05). Mean CAL gain in 3 months is 0.60 +/-0.63 mm in RSI group compared to 1.07 +/- 0.70 mm AZM + RSI (p < 0.05).
It is still unclear at what phase of therapy the CHX chip is most beneficial.9 Based on evidence from clinical trials, it seems that CHX has a better place during supportive periodontal treatment when applied to non-responding sites. The use of this drug in the second phase of therapy, applied in specific sites, could be more or equally effective and less time consuming than a second session of RSI.
Other chlorhexidine preparations
In addition to liquid and solid carrier-based devices containing CHX, gel-based devices have been designed. These gels have up to 15x greater CHX concentration than liquid carriers.10 The high viscosity of the gel can reduce the clearance of the active agents from the periodontal pocket. Other advantages of gels over solid carriers relate to the ease and speed of administration and the avoidance of possible tissue injury during the subgingival placement. Despite these considerations, a systematic review on the effects of subgingival CHX gel administration in the treatment of periodontitis concluded that no meaningful data were available, indicating that the treatment outcomes of RSI benefit from the adjunctive subgingival administration of a CHX gel are minimal.11
Chlo-site® (Xan-CHX) is a novel carrier containing 2.5% xanthan gum and was developed with the aim of increasing the retention of CHX gel in the periodontal pocket. Xanthan gum has a capacity to produce a large increase in the viscosity of a liquid. It is stable over a wide temperature and pH range and has bio-adhesive properties. This helps to limit the clearance of CHX from the periodontal pocket. A multicentre trial10 showed that the adjunctive subgingival administration of Xan-CHX gel significantly improved the positive therapeutic effects of extensive RSI on chronic periodontitis. Maximum benefits were noted at 3 months after treatment (Table 2).
CHX has also been combined with thymol as a varnish preparation (Cervitec plus®). When used as an adjunct to RSI, those sites treated with the varnish showed a significant improvement (p < 0.001) in reduction in gingival inflammation and probing pocket depths when compared to the non-varnish treated sites.12 However, the study only reviewed patients at 3 months after treatment and the longterm benefits of the varnish need to be evaluated.
Tetracyclines
The tetracyclines (TC) comprise a group of broad spectrum antimicrobial agents and were introduced into clinical practice in the late 1940s.
These are mainly bacteriostatic agents that exert antimicrobial activity by inhibiting protein synthesis. They are effective against many Gram negative species such as Aggregatibacter actinomycetemcomitans (Aa). The value of this group of drugs in the management of periodontal diseases may also be related to their non-antimicrobial actions. These include collagenase inhibition (matrix metalloproteinase, MMPs 8, 9, 11, 13), anti-inflammatory actions, inhibition of bone resorption and their ability to promote the attachment of fibroblasts to root surfaces.
Tetracyclines have been incorporated into a variety of local delivery devices including fibres, strips, microspheres and gels.
Tetracycline delivery system
Tetracyclines were first incorporated into a fibre and this has now been replaced with a TC strip. Adjunctive use of the TC strip appears to be superior to RSI alone13 with respect to reduction in probing pocket depths. This study also showed that multiple strip placements provided greater reduction in bleeding on probing than single strip placement.
Periodontal Plus AB (PPAB) ®
This product is based on the collagen fibril delivery system. Fibrillar collagen is not cross-linked and is impregnated with tetracycline hydrochloride, which is leached out as the fibrils degrade. The fibrils also release anticollagenase enzymes as they degrade. The system is dispensed in vials containing 25 mg fibrillar collagen and 2 mg tetracycline hydrochloride. The material has to be moistened with sterile water prior to placement. Once moist, it is easy to handle.
The vehicle is an effective tool in carrying tetracycline to the site of action. Most of the tetracycline is released by 10 days. PPAB releases tetracycline consistently from day 1 and over a period of 10–14 days, with the concentration (1500 mcg/mi in GCF) peaking at 4–5 days. This concentration is highly toxic to periodontal pathogens. Once the tetracycline has been released and utilized, the vehicle starts coming into action. There is no need to remove the fibrils since the collagen fibrils are very soft and are an organic product and do not interfere with repair potential within the periodontal pocket. They play a positive enzymatic role in repairing the periodontium. By 6–12 weeks the collagen fibrils have dissolved.
The collagen matrix has a natural haemostatic ability – a healthy clot is initiated. The collagen is high purity type 1 collagen and so there is no adverse immunogenic response in patients.
The efficacy of Periodontal Plus AB® is shown in Table 2.
Minocycline and doxycycline
Minocycline and doxycycline are third generation tetracyclines. These are preferred over the original tetracycline because they resorb better, bind to proteins, can diffuse into tissue structures due to their higher lipid solubility and have a prolonged duration of action.
Minocycline
Minocycline is active against a broad spectrum of Gram +ve and Gram −ve anaerobes, including those associated with periodontitis. Products containing minocycline include Periocline®/Dentomycin® (Periocline and Dentomycin are the same product, just a different brand name) and Arestin®. The physico-chemical profiles and efficacy of these products are shown in Tables 1 and 2, respectively.
Arestin®
Arestin contains minocycline hydrochloride (1 mg) in a micro-encapsulated bio-absorbable polymer of poly(glycolide-co-dl-lactide) or PGLA. Each sphere measures 20–60 micrometres in diameter, and the resulting microspheres are administered in powder form into periodontal pockets. Immediately on contact with moisture, the polymer begins to hydrolyse and releases minocycline. Once inserted it immediately adheres to the periodontal pocket. The gingival crevicular fluid hydrolyses the polymer. Tiny holes in the microspheres provide ‘escape routes’ for the drug to be slowly released and absorbed into the surrounding periodontal tissues. Water-filled channels form inside the microspheres allowing a controlled sustained release of minocycline. Eventually the microspheres themselves fragment through hydrolysis of the polymer and are completely bio-resorbed in 21 days. Similar to Atridox® (see later), the delivery vehicle PLA/PGA degrades to lactic and glycolic acid. This may interfere with repair and regeneration. The antibiotic maintains therapeutic drug levels and remains in the pocket for 14 days.
The administration results in a sustained local release of antibiotic whereby concentrations of 340 micrograms per ml have been measured in GCF after 14 days.14 These concentrations far exceed the minimum inhibitory concentrations for periodontal pathogens. An independent study showed minocycline microspheres to be highly effective against local periodontal pathogens.14
Arestin® is the first locally administered antibiotic with microspheres that has been proven to be more effective than RSI alone.14 Information on this study can be seen in Table 2.
Relatively little systemic absorption occurs following local administration with minocycline microspheres15 and no development of resistant bacteria were found in faecal samples.16
The first resorbable doxycycline local antibiotic system was Atridox®. This system involved mixing a powder and a liquid and squeezing the material from a syringe into the pocket. Atridox® is absorbed after 7 days and reports of antibiotic concentrations of 250 mcg per ml of GCF in the pocket have been reported. The application of Atridox® can be tedious as the material tends to pull out of the pocket when the syringe is removed. To overcome this problem, an alternative system was developed (Atrigel®), which adheres to the pocket wall more effectively than Atridox®.
The gel solidifies to a waxy consistency within minutes, delivering doxycycline over a period of 21 days. During this time, the gel biodegrades, forming lactic acid and glycolic acid monomers. These are acidic and necrotic monomers which may have an adverse effect on the regenerative process of the periodontal tissues.
Atridox® promotes clinical attachment gain, reduces probing depth and reduces bleeding on probing when used as an adjunct to RSI (Table 2). It allows placement of the material to the depth of most pockets in a manner that allows it to conform to the shape of the pocket. Although short-term effects on clinical parameters were found with the adjunctive use of Atridox®,17 repeated applications annually had no clinical or microbiologic effects beyond those observed with RSI alone in maintenance patients.
Doxycycline microspheres
Doxycycline has been incorporated into microspheres comprising polyactic acid-co-glycolic acid and poly-caprolactone.18 The spheres contained doxycycline at a 10% w/w concentration. The doxycycline microspheres were evaluated in a randomized controlled trial as an adjunct to RSI. Patients were followed up at 1, 3, 6 and 9 months post-treatment. Those patients treated with the doxycycline microspheres demonstrated a significant (p = 0.01) improvement in plaque scores and gingival inflammation when compared to the control patients. However, there was no difference between the treatment groups regarding probing pocket depth reduction. Whilst this outcome may be disappointing, it may be related to the rate of release of doxycycline from the spheres.
Metronidazole
Systemic metronidazole has been extensively investigated in the adjunctive management of periodontal diseases. Thus it is not surprising that local application of this antimicrobial has been applied to local drug delivery status. Metronidazole has been incorporated into a wax preparation (Elyzol®) and also into nanofibres.
Elyzol ®
Elyzol® was the first metronidazole-containing local drug delivery system and the physico-chemical profile of this product is shown in Table 1.
Elyzol® gel has a melting point below body temperature and fills the periodontal pocket on application. When it contacts the GCF, the gel becomes more viscous and is retained in the periodontal pocket. The minimum inhibitory concentration (MIC) for metronidazole for susceptible anaerobic bacteria generally ranges from 0.1–8.0 micrograms per ml. Elyzol® gel will, in contact with GCF, form reverse hexagonal liquid crystals. Mean GCF concentration, after a single application of Elyzol®, is 461 micrograms per ml. When metronidazole is delivered systemically it has a GCF concentration of 8–10 micrograms per ml.19 Efficacy of Elyzol® is reported in Table 2.
Metronidazole in nanofibres
Metronidazole has also been incorporated into nanofibres.20 The concentration of metronidazole within the fibres was 25–35% w/w. A recent clinical trial showed additional benefits of the metronidazole nanofibres when used as an adjunct to RSI.20 Whilst the authors reported significant benefits (p < 0.01) in terms of reduction in probing pocket depths, plaque and gingival indices, the benefits were most obvious at 30 days after treatment. Again the long-term value of such a metronidazole preparation needs to be determined.
Azithromycin (AZM) and clarithromycin (CLM)
Both azithromycin and clarithromycin are macrolide antibiotics. AZM is a semi-synthetic, acid stable antibiotic. It has a long half-life and good tissue penetration and it is well tolerated. AZM acts on a wide number of bacteria, including anaerobic bacteria, as well as Gram Negative bacilli. It is therefore effective against periodontal pathogens. It has significantly less bacterial resistance to the subgingival microflora of chronic periodontitis compared to other commonly prescribed antibiotics. AZM is characterized by its significantly higher uptake by fibroblasts and various acute phase reactant cells. Only one clinical trial has been completed with this product and results showed that a gel containing 0.5% AZM with poly(lactic-co-glycolic acid) when used as an adjunct to RSI was superior to RSI alone.21
Clarithromycin has been incorporated into a 0.5% gel and evaluated as an adjunct to RSI in a group of smokers.22 In this placebo-controlled trial, the authors reported some benefit of the adjunctive use of the gel in this group of patients. The benefit was still present at 6 months after application. Interestingly, clarithromycin was still detected in GCF at 6 weeks after application. A similar gel was used in non-smokers23 and the findings showed that the clinical outcome was enhanced at 3 months.
The new macrolide antibiotics are relatively new in terms of local application in the management of periodontal disease. These recent studies do show promise and indicate that further studies with longer follow-up periods would be helpful.
Moxifloxacin
This is a fourth generation fluoroquinolone antibiotic with a broad antibacterial activity against aerobic and anaerobic bacteria. This antibiotic has also been incorporated into a gel for local application into periodontal pockets.24 Three concentrations of the drug (0.125, 0.4 and 1.25%) were evaluated as an adjunct to RSI in patients with chronic periodontitis. Patients were evaluated 3 months after treatment. Most favourable results were obtained with the 0.4% gel, with a significant improvement in probing pocket depths when compared to RSI alone. This compound is worthy of further evaluations.
Non-antimicrobial agents
There has been an interest in the application of non-antimicrobial agents as local drug delivery devices for adjunctive use in the management of periodontal diseases. Three compounds have been used to date and include:
The anti-diabetic drug, metformin;
The bisphosphonate, alendronate; and
The cholesterol lowering drug, simvastatin.
Metformin
Metformin, at a concentration of 0.5, 1.0 and 1.5%, was evaluated in the management of patients with infrabony defects.25 The results showed that those patients treated with the metformin gel exhibited greater probing depth reductions and attachment gain than the placebo-treated group. Likewise, the metformin gel appeared to bring about a reduction (bony infill) in the infrabony defect. The best outcome was achieved with the 1% gel.
Alendronate
Bisphosphonates inhibit osteoclast-mediated bone resorption. It has been demonstrated that those patients who take the drug systemically for the management of their osteoporosis show a greater response to periodontal therapy than control patients.26
Two studies27,28 have demonstrated the efficacy of a 1% alendronate gel when used as an adjunct to RSI in the management of chronic periodontitis and aggressive periodontitis. Both studies evaluated patients at 6 months post-treatment and showed that those treated with the 1% gel had a significant increase in probing pocket depth reduction, attachment gain and improved bony infill when compared to the placebo gel.
Simvastatin
Statins are known to assist in bone regeneration as well as showing anti-inflammatory actions.29 The efficacy of a 1.2 mg simvastatin gel has been investigated in a cohort of patients with chronic periodontitis who also exhibited infrabony defects.30 The results showed that, at 6 months post-treatment, those patients treated with the adjunctive simvastatin gel showed a significantly greater decrease in gingival inflammation, probing pocket depths and greater attachment gain than the placebo-treated group. Furthermore, simvastatin gel also appeared to enhance bony infill in the infrabony pockets.
Conclusions
Local drug delivery seems to be a logical step in the management of periodontal disease. It was not surprising that the first agents employed for such usage were those that possessed antibacterial actions. Whilst the early studies showed some benefit when used as adjuncts to RSI, the benefits were small in terms of clinical outcomes.31 Those systems which allowed for slow, sustained release of the active ingredient appeared to be the most efficacious.
Recently, interest in the application of local drug delivery has come from non-antibacterial compounds. The early clinical trials show promise and perhaps indicate the multi-factorial pathogenesis of plaque-induced periodontal breakdown. It is likely that further agents which impact upon the periodontal breakdown process will emerge and be investigated. Perhaps even combination therapies will be explored.
Local drug delivery systems may still further have a place in the management of periodontal diseases. However, they should only be considered as an adjunct and not a replacement for conventional non-surgical techniques.
Summary
Overall the efficacy of local antibiotic therapies has been evaluated using meta-analysis of over 50 articles, with each study demonstrating at least a 6 months' follow-up.34 The meta-analysis considered studies of the local adjunctive use of LDD and found such additions provide generally favourable, but minimal differences compared with RSI alone. Additional statistically significant probing pocket depth reductions of 0.1–0.5 mm may be possible and smaller, less frequently statistically significant improvement in attachment levels were noted.31 The overall treatment effect is somewhat variable and, although found to be statistically significant, has not resulted in the widespread use of these systems by the clinical community. New products with better release characteristics of the active ingredients may provide further opportunities for the use of LDD systems in the management of periodontal diseases.
