Step 2 for the treatment of periodontal diseases: adjunctive therapies

The desired outcome of periodontal treatment is disruption of a dysbiotic dental plaque biofilm, including bacteria and bacterial metabolites and toxins, leading to a return to healthy, non-pathogenic biofilm, and resolution of dysbiosis-induced inflammation.

Step 2 of periodontal therapy primarily aims at the non-surgical, mechanical disruption of the subgingival biofilm, as well as removal of plaque retentive factors (PRFs), allowing the shift in the microbiome–host interaction, leading to disease resolution.¹ This stage is conditional on patient engagement with improvements in oral hygiene and risk-factor control as part of the first step of periodontal therapy. There are a number of potential adjunctive therapies that can be administered, alongside mechanical plaque removal, to facilitate the disruption of the subgingival biofilm or to alter the host immune response. In this article, the present authors discuss the use of therapies adjunctive to non-surgical subgingival instrumentation, as part of step two of periodontal therapy.

The British Society of Periodontology and Implant Dentistry's (BSP) implementation of the S3-level guidelines published in 2021² evaluated the evidence surrounding adjunctive therapies and this article provides a comprehensive summary of the recommendations on the use of various treatment adjuncts in a UK healthcare setting.

Adjuncts can be categorized into four broad groups and the recommendations are summarized in Table 1:

• Physical and chemical agents
• Host modulating agents (local/systemic)
• Subgingival locally delivered antimicrobials
• Systemic antimicrobials

Physical and chemical agents

Subgingival instrumentation, through ultrasonic or hand instruments, aims to remove soft and calcified plaque deposits to re-establish a healthy biofilm and to prevent further accumulation of plaque. Various physical and chemical adjuncts have been investigated for their use in eliminating or disrupting the subgingival biofilm.

Lasers and photodynamic therapy

Lasers, an acronym for ‘light amplification by the stimulated emission of radiation’, are gaining popularity in dentistry and work by emitting focused beams of a specific wavelength of light. Within dentistry, lasers have a wide range of potential uses. Lasers in dentistry are categorized by method of laser production, for example, neodymium yttrium aluminium garnet (Nd-YAG) or erbium chromium: yttrium scandium gallium garnet (Er, Cr: YSGG) and hence the wavelength of light produced.³ Of interest, in relation to non-surgical periodontal therapy (NSPT), is the potential to break up calcified deposits and their antimicrobial activity.

While lasers act independently and directly on the target site, antimicrobial photodynamic therapy (aPDT) works by activation of a photosensitizer through a light source of a specific wavelength (including lasers), causing release of reactive oxygen species (ROS), which then act on the target, usually bacteria.⁴ Reactive oxygen species are a group of free radicals containing oxygen and capable of causing cell death through various different mechanisms. In aPDT, the plaque is first treated with a chemical photosensitizing agent, followed by exposure to light,⁵ generating the release of ROS with the aim of killing plaque bacteria.

A systematic review of five studies investigating the effects of lasers in periodontal therapy concluded that there was insufficient evidence to support the use of lasers as a periodontal adjunct. This is, in part, due to the high heterogeneity between studies, arising from the various different types of lasers available for dental treatment. Review of studies evaluating aPDT similarly identified significant heterogeneity between laser type, photosensitizer and outcome measures among other factors. Almost all studies evaluating both lasers and aPDT failed to report on residual periodontal pocket depth (PPD), an important outcome measure to consider when recommending or suggesting a change to clinical practice. Additionally, as most studies were undertaken in universities or specialist centres, it is difficult to understand the applicability of the results in general practice.⁶

Chlorhexidine mouthwash

Chlorhexidine, a bisbiguanide with a broad spectrum of activity against both bacteria and fungi, is commonly used as a 0.2% chlorhexidine digluconate prescription-free mouthwash. Although commercially available mouthwashes ordinarily have limited use in terms of plaque control owing to the lack of mechanical plaque disruption provided from a mouth rinse, chlorhexidine differs in its ability to adsorb onto various surfaces, including the salivary pellicle, and exhibit significant substantivity prolonging its antimicrobial action.⁷

A systematic review and meta-analysis of the use of chlorhexidine mouthrinse identified that there was a statistically significant, but clinically small reduction in probing depth following adjunctive use of the mouthwash alongside professional mechanical plaque removal (PMPR).⁸ Alhough there is consistency, chlorhexidine can be recommended in appropriate cases and for a limited time (1–2 weeks), to avoid staining and taste disturbance. Appropriate cases include patients where mechanical plaque control would cause discomfort, for example after surgery, acute instances of oral pain, or patients at risk of oral mucositis. It is not acceptable as a replacement for effective mechanical plaque removal and should be used in conjunction with patient education and behaviour change techniques.

Host-modulating agents

Although the defining factor in the development of periodontal diseases is the composition of the dental plaque biofilm,⁹ the progression of the disease is driven by the complex host immune response to the biofilm microbiota.¹⁰ The increased genetic susceptibility to periodontal diseases is associated in part with the variation in expression of genes associated with host inflammatory pathways¹¹ and perhaps, it is this subgroup of patients who would benefit the most from immune modulation in addition to biofilm removal for treatment or prevention of periodontitis.

Various host-modulating agents have been researched for use in periodontology, usually agents that already have a clearly defined use for other inflammatory conditions in the human body. The aim of these agents is to reduce the host inflammatory response that is key to the tissue destruction observed in periodontitis.

Statins

Statins are a group of medications used primarily for hypercholesterolaemia. The mechanism of action of statins against cholesterol is through inhibition of the synthesis of cholesterol,¹² although statins have been discovered to have multiple functions at various sites of the human body, including anti-inflammatory effects, effects on bone formation and even potential tumour cell growth reduction.¹² Within periodontology, localized use of statin gels within periodontal pockets has been investigated as an adjunct to non-surgical therapy, primarily for its anti-inflammatory effects.

A meta-analysis of the literature revealed that the topical application of 1.2% statin gels (atorvastatin, rosuvastatin and simvastatin) to infrabony defects and furcation defects resulted in improved PPD reduction compared to placebo, when used in combination with NSPT.¹³ However, all the studies evaluated originated from the same research group and thus, further research is required to confirm the results before the use of adjunctive topical statin gels can be widely recommended. Additionally, all formulations evaluated were used ‘off label’. Further understanding of the potential side effects or health risks of topical statin gels is required.

Probiotics

Probiotics are gaining interest as modulators of human health as more understanding of the wide ranging impact of the human microbiome on health and disease is gained. Probiotics are, in the most basic terms, live bacteria with an anticipated beneficial action on health. The proposed mechanism of action of probiotics as a periodontal adjunct are wide ranging, but include encouraging the formation of a healthy biofilm through competition with pathogenic species, and immune modulation through interactions with the host.¹⁴ The most widely researched probiotic strain, Lactocaseibacillus rhamnosus GG (LGG), although primarily investigated for its effects on gastrointestinal health, has been researched to see whether it has any effect on periodontal health.¹⁵

A meta-analysis of five RCTs investigating different probiotic preparations showed that only studies evaluating Lactobacillis reuteri in combination with NSPT resulted in improved clinical outcomes. There were no improvements observed in any of the other probiotic preparations (Lactobacillus rhamnosus SP1, or a combined preparation of Streptococcus oralis KJ3, Streptococcus uberis KJ3 and Streptococcus rattus JH145).¹³ The BSP's implementation guidelines also considered a double-blind, placebo-controlled RCT evaluating the effects of L. reuteri or placebo lozenges as an adjunct to NSPT, concluding that there was no benefit for the addition of probiotic consumption on periodontal treatment outcomes.¹⁶ Overall, the current literature does not support the use of probiotics as an adjunct to NSPT.

Systemic sub-antimicrobial doxycycline

Doxycycline, a tetracycline antibiotic, when used at sub-antimicrobial doses can illicit an anti-inflammatory response in the body. The background behind sub-antimicrobial dose doxycycline (SDD) is based on studies demonstrating matrix metalloproteinase (MMP) inhibition observed following SDD.¹⁷ MMPs have a significant role in periodontitis, activating an immune response that results in localized tissue destruction.¹⁸

Of the studies evaluated, following use of systemic SDD, a greater reduction in pocket depths was observed compared with placebo, with a greater effect seen in deeper pockets, with a mean reduction of 0.68 mm at 6 months.¹³ This effect, although consistent throughout studies, is small and its relevance needs to be considered. The available literature does not support the recommendation to use SDD as an adjunct to subgingival instrumentation.

Locally delivered bisphosponates

Bisphosphonates (BP) will be familiar for their role in the modulation of bone remodelling when used for the management of osteoporosis at low doses, and reduction of cancer metastasis at high doses. All use is, however, associated with various levels of risk with medication-related osteonecrosis of the jaw (MRONJ). BPs, like many of the drugs discussed in this article, have pleotropic effects. Of most interest in periodontology is the potential for bisphosphonates to reduce inflammation.¹⁹

Most studies investigating the use of BPs evaluate the use of locally administered topical BP gel. Although some effects in reducing PPD have been observed, these were all observed by the same study group.¹³ More research is required, including multi-centre studies, to fully understand the potential benefits of topical BPs in periodontal treatment, particularly with an understanding of the risks of MRONJ, which cannot be understated for its potentially significant and severe negative effects on quality of life.²⁰ Additionally, the BP gel preparations were used ‘off label’, thus a full understanding of potential side effects and harms to health is not known.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Both systemic and topical NSAIDs have been investigated for their effects on periodontitis, including a flurbiprofen toothpaste, irrigation with acetylsalicylic acid and systemic administration of celecoxib and diclofenac.

Studies evaluating the effectiveness of an NSAID toothpaste or NSAID daily supragingival irrigation identified no improvement in PPD compared to a placebo. Systemic administration, investigated in two studies, revealed a greater PPD reduction in the NSAID groups compared with placebo at 6 months.¹³

Topical NSAIDs are not recommended because there is no clear clinical evidence for their use. While systemic NSAIDs may have a benefit evident at 6 months, longer-term studies have not been completed. Additionally, administration of systemic NSAIDs is associated with unwanted side effects.²¹ Thus, NSAIDs are not recommended for use as an adjunct to subgingival instrumentation.

Omega-3 polyunsaturated fatty acids (PUFAs)

Polyunsaturated fatty acids (PUFAs) encompass a number of types of molecules, some of which are essential to human health. The most common of these molecules are omega-3 (n-3) and omega-6 (n-6) PUFAs. These molecules are obtained by the human body through dietary sources because they cannot be made intrinsically. Omega-3 PUFAs have been suggested to have numerous beneficial effects on the human body.²² There are numerous studies investigating the effects of omega-3 PUFAs in vitro, but systematic reviews evaluating the clinical effects of PUFAs on cardiovascular disease,²³ dementia,²⁴ depression²⁵ and cystic fibrosis²⁶ fail to identify evidence at a high enough quality to indicate clinical significance.

Similarly, although PUFAs appear promising in their anti-inflammatory activity in vitro,²⁷ there are limited studies investigating the effects of PUFAs on periodontal disease in humans. Of these studies, low-dose supplementation of omega-3 PUFAs showed no difference in PPD reduction compared with placebo.²⁸ Although higher doses (1000 mg twice daily)²⁹ and doses of omega-3 PUFAs in combination with aspirin³⁰ did show statistically significant improvements in PPD compared to placebo, full understanding of the size and clinical relevance of the effect requires further studies.

Metformin

Metformin, the first-line medication for type II diabetes mellitus has also been found to improve bone quality through stimulation of osteoblast differentiation,³¹ and has therefore gained interest in periodontology, with the drug being seen as a potential topical adjunct to periodontal therapy.^32–34 It has also known to have direct anti-inflammatory effects through numerous mechanisms.³⁵

Formulations of metformin as a topical 1% gel have been developed and investigated for their use as a periodontal adjunct, both for its anti-inflammatory effects and modulation of bone remodelling. In a systematic review and meta analysis,¹³ studies identified that the use of metformin gel as an adjunct to non-surgical periodontal treatment in infrabony defects resulted in an increased PPD reduction and infrabony defect depth compared with placebo,^33,34,36,37 although further studies from different research groups would be required before wide recommendation of metformin gel as a topical adjunct. As with other drugs discussed in this article, the metformin gel preparation used in the studies evaluated was ‘off label’, hence a full understanding of the safety of its use in this preparation is not available.

Subgingival locally delivered antimicrobials

Locally administered sustained-release chlorhexidine

Certain antimicrobial agents have been developed as preparations that permit a sustained release acting in a localized area, i.e. a periodontal pocket. The most common of these is either a chlorhexidine or doxycycline preparation.

While chlorhexidine mouthwash has good evidence to support its use in oral disinfection, localized, sustained delivery of chlorhexidine at specific sites has the advantage of targeting persistent deep pockets where it is difficult to maintain a high concentration of an antimicrobial through other means, such as irrigation or mouthrinsing. PerioChip (Dexcel Pharma Ltd, Daventry) is a preparation of chlorhexidine digluconate within a gelatin matrix, facilitating placement in a subgingival pocket. It has demonstrated a statistically significant reduction in PPD as an adjunct to non-surgical therapy with an effect size of about 10%, but there is no available evidence on its long-term effects.³⁸ Locally administered sustained-release chlorhexidine may be considered in specific cases on the basis that there are reports of improvement in PPD and the lack of reported adverse effects, but further evidence, including more studies with more detailed data on its effects, including long-term results are required.

Locally administered sustained-release antibiotics

Locally administered sustained-release antibiotics include 10% and 14% doxycycline gels and minocycline ‘microspheres’. These are all in the tetracycline class of antibiotics and are effective at reducing bacteria associated with periodontal disease.³⁹ The topical method of administration reduces or eliminates the risk of unwanted side effects of tetracyclines, including tetracycline staining.

A systematic review evaluating studies using locally administered sustained-release antibiotics of the tetracycline class identified that topical application of such products resulted in an increased reduction of PPD with the greatest difference seen with the 10% gel, Atridox (doxycycline hyclate; Tolmar Inc, Fort Collins, CO, USA). The effects observed with locally administered antibiotics were greater than that seen for locally administered chlorhexidine. Long-term effects are less clear.³⁸

The S3-level guidelines suggest that locally administered sustained-release antibiotics may be considered as an adjunct to subgingival instrumentation. The decision to use these must be considered very carefully in the context of antimicrobial resistance.

Systemic antimicrobials

The two most commonly prescribed systemic antibiotics for periodontal conditions are metronidazole and amoxicillin. Studies evaluated in the development of the S3 guidelines show significant reductions in PPD following use of either metronidazole or amoxicillin alone, or both metronidazole and amoxicillin used concurrently.⁴⁰

A significant and incredibly important disadvantage to the use of systemic antimicrobials is the worldwide threat to human health of antimicrobial resistance. The use of systemic antimicrobials in periodontitis must be considered carefully in balance with side effects and antimicrobial resistance. Although systemic antibiotics can effectively reduce or eliminate the pathogenic microbiota in the periodontal pocket, resulting in improved clinical outcomes, antibiotic resistance is rapidly increasing and is a significant threat to global public health.

Clear differences have been observed in antimicrobial resistance of the subgingival microflora of periodontitis patients when comparing patients from a country of low antibiotic use to one of high antibiotic use.⁴¹ Further, systemic administration of antibiotics clearly has systemic effects, including significant disturbance of the gut microbiome.⁴² The impact of disturbance of the gut microbiome is wide ranging, including associations with inflammatory conditions⁴³ and cancer.⁴⁴

For public health concerns and concerns of lasting and potentially significant detrimental effects for individuals, systemic antibiotics cannot be recommended as an adjunct to non-surgical therapy in routine use. Where there is severe and rapidly progressing disease, antibiotics may be considered.

Conclusion

The majority of patients with gingivitis and periodontitis can be successfully treated by standard methods of plaque removal, involving primarily patient-focused oral health interventions and behaviour change, accompanied by professional mechanical plaque removal.⁴⁵ Adjunctive therapies have been researched generating various degrees of quality of evidence. Although based on a sound theoretical base and supported by in vitro and animal studies, evidential outcomes of certain adjuncts do not currently translate into sufficient clinical improvement, in balance with any unwanted outcomes, to justify their use.

Certain cases may justify the use of adjuncts with a strong evidence base, including patients with rapidly progressing disease despite maintenance of excellent oral hygiene, or patients who are temporarily unable to maintain mechanical plaque removal. The S3 guidelines limit these adjuncts to chlorhexidine mouthwash and systemic antibiotics in carefully selected cases. A summary of recommendations is illustrated in Figure 1.

While some adjuncts have been shown to be effective in selected individual studies, larger, multi-centre trials are required to fully understand the overall treatment effect for wide recommendation of use.

Many of the potential adjuncts discussed in this article have a common theme: reducing the risk of antimicrobial resistance, either through means of eliminating bacteria without the use of antimicrobials, or through modulation of the host response to bacteria, reducing the potential need for antimicrobial use. With antimicrobial resistance becoming an increasing risk to the persistence of human life on our planet, careful consideration of the use of antimicrobials, and further research into alternative methods for bacterial elimination or host modulation in relation to the progression of periodontal disease, are essential.