From Volume 41, Issue 8, October 2014 | Pages 732-736
Periodontal pockets provide an ideal environment for the application of local drug delivery for the management of periodontitis. In this first article, consideration is given to the principles that underlie local drug delivery and the pharmacological challenges. It is essential that such systems are compatible with the periodontal tissues. Potential unwanted effects that can arise from both drug and delivery vehicle are also appraised.
A local drug delivery device consists of a drug reservoir and a limiting element that has a control over the amount of active ingredient released. This can be divided into two classes:
The sustained release devices release a drug over a period of 24 hours, whereas the controlled delivery device has duration of drug release greater than 1 day.
Several areas are targeted by locally delivered pharmacological agents in the treatment of periodontal disease. These include the bacteria which reside in the periodontal pocket, the soft tissue walls of the pocket itself and exposed cementum or radicular dentine. The periodontal pocket provides a natural environment which is easily accessible for the positioning of a drug delivery device and offers theoretical benefits to local drug delivery technology, such as:
The delivery device should be able to expand into the volume of the periodontal pocket and remain dimensionally stable.
A local drug delivery device is designed to deliver a pre-determined amount of drug to a specific anatomical site for an extended period of time.1
While local antimicrobial therapy for periodontitis is not widespread, many dentists use this form of therapy and most believe it is more effective than root surface instrumentation (RSI) alone.2
The aim of this paper is to review the local drug delivery systems in the management of periodontal disease.
Systemic antibiotic use for the treatment of periodontitis has shown some beneficial effects.3,4 In recent years, systemic antimicrobials are mainly recommended for the treatment of aggressive periodontitis.5,6 Multiple systemic doses of these drugs have several drawbacks.7 These include:
Local drug delivery can avoid most of the problems associated with systemic drug delivery by limiting the amount of drug to its target site with little or no systemic uptake. The local concentration achieved can be much higher (100 x) than is possible via the systemic route. Safe and intrinsically efficacious medications can be delivered into periodontal pockets to suppress or eradicate the pathogenic microbiota or modulate the inflammatory response, thereby limiting tissue destruction. As described by Greenstein and Tonetti,8 local application of pharmacological agents must fulfil three criteria; the medication must:
The main challenge is the ability to maintain effective concentrations of chemotherapeutic agents at the site of action for long periods, despite drug loss from crevicular fluid clearance.8
The gingival crevicular fluid (GCF) provides a leaching medium for the release of a drug and for its distribution throughout the pocket. The characteristics of GCF have been reviewed by Cimasoni.10 Healthy sites are associated with small volumes (0.04 microlitres) and low flow rates (0.03 microlitres per minute). It has been calculated that the turnover rate of gingival fluid is 40 fold per hour.9 Thus, if an antibacterial agent is placed subgingivally, its local concentration rapidly declines. The expected half-life of a pharmacological agent in the gingival crevice is about 1 minute.9 The high rate of clearance is the major obstacle to maintaining effective concentrations of an antimicrobial agent within the pocket. To counteract the continuous loss of drug in the crevicular fluid, a subgingival drug reservoir is required to release the active ingredient at a rate which will counteract its continuous loss due to crevicular fluid flow.8
Intrapocket drug delivery systems are desirable due to the potentially lower incidence of unwanted effects, improved efficacy and enhanced patient compliance. The advantages of treating periodontal disease by the intrapocket drug delivery system are based on the fact that high levels of drug can be maintained in the GCF for a prolonged period of time to produce the desirable clinical benefits. LDD devices do not produce fluctuating concentrations typically seen with multiple dose regimens. This is depicted in Figure 1, which compares drug concentrations after systemic dosing when compared to local delivery.11 The transient spikes in drug concentration are not present, therefore the risk of unwanted effects is decreased. The ideal properties of a local drug delivery system are listed in Table 1.
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The indications for the use of controlled drug delivery are shown in Table 2. For the most part, these drugs are used as an adjunct to root surface instrumentation (RSI), and this is indicated in the number of studies completed to evaluate efficacy. RSI is necessary for success long term because:
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Local delivered antimicrobial application into periodontal pockets as a monotherapy offers no advantage over root surface instrumentation.13,14
Concern with respect to the possibility local drug delivery with antibiotics might induce resistant strains of bacteria have been addressed in several studies.15,16,17,18,19 Investigators noted a transient increase in resistant bacteria after administration of local drug delivery. However, after 6 months, there was bacterial repopulation of sites and no detectable increase in the number of resistant strains.
In a systematic review of local adjuncts to RSI in periodontal therapy, it was shown that adjunctive antimicrobial drugs appear to be efficacious.20 The most positive results occurred with tetracycline, minocycline, metronidazole and chlorhexidine(CHX). The systematic review also showed that the adjunctive benefits of LDD increased pocket depth reductions in the range 0.25–0.50 mm.
However, even though the differences were statistically significant, the additional improvement in pocket depth (PD) was a fraction of the reported mean of 1.45 mm after RSI alone. Major clinical attachment level (CAL) gains were in the range 0.10–0.50 mm. These gains were smaller and statistical significance was less common.
Combining PD and CAL results suggests that minocycline might be the most promising adjunctive therapy, followed by tetracycline.20 The effectiveness of adjunctive treatment was greatest in patients with advanced disease.
Bleeding has an adverse affect on local drug delivery systems. If an LDD device is placed in a periodontal pocket immediately after root surface instrumentation, its efficacy is reduced. This is because the drug binds to the protein in blood hence reducing its activity. A prime example is chlorhexidine, whose activity is reduced in the presence of organic matter such as blood.21 A further unwanted effect can arise if the vehicle degrades into materials which interfere with repair and regeneration of the periodontal tissues.
A possible barrier to the use of LDD in the management of periodontal disease is cost.2 Several LDD agents are now available. The various products together with their active ingredients and cost are shown in Table 3.
| Active Ingredient | Chlorhexidine | Tetracycline | Minocycline | Doxycycline | Metronidazole | Azithromycin |
| Commercial products | PerioChip® £12.50 per chip | Periodontal Plus AB® Cost N/A | Periocline® or Dentomycin® £114 | Atridox® £45.50 per syringe | Elyzol® £42.50 (2x 1g applicators) | AZM gel Cost N/A |
| Chlo-site® £40 per syringe | Arestin® £19.50 per dose |
Antimicrobial agents have shown to be of benefit in the management of periodontal diseases. Systemic antimicrobials have numerous drawbacks. Local drug delivery can overcome most of these drawbacks by limiting the drug to its target site with little or no systemic uptake. The high turnover rate of gingival crevicular fluid results in a high rate of clearance, which presents an obstacle to maintaining effective concentrations of an antimicrobial agent within the periodontal pocket. Use of a subgingival drug reservoir releases the antimicrobial to counteract its continuous loss due to GCF flow. Use of locally delivered antimicrobials as a monotherapy provides no benefit over RSI alone. It is important for the clinician to use RSI at the infected pocket sites before administering a local drug delivery device. Local drug delivery is expensive and its benefits have to be weighed against the cost.
Although LDD devices have restricted use in general practice, they may have more indication in specialist periodontal practices. As new drug reservoirs become available, with improved drug release characteristics, the use of local drug delivery in the management of periodontal diseases may become more widespread.
