Non-surgical periodontal therapy: An update on current evidence

Abstract

Periodontal disease is an inflammatory condition that involves a complex interaction between pathogenic bacteria, environmental and acquired factors and host related factors. Till recently periodontal treatment was directed primarily towards reduction of bacterial load by subgingival debridement of root surfaces and modification of environmental risk factors. The current paradigm of periodontal disease stresses greater role of host-mediated inflammatory response in tissue destruction characteristic of periodontal disease. Various therapeutic modalities have been developed adjuvant to mechanical periodontal therapy. The use of laser and photodynamic therapy show great promise but their effectiveness has still not been conclusively proven. Chemotherapeutic agents, either systemic and local antimicrobials or host modulating drugs, played pivotal role in better and more predictable management of periodontal disease. The present review focuses on the best available evidence, for the current management of the chronic periodontal patients, gathered from systematic reviews and meta-analysis of mechanical non surgical periodontal therapy (NSPT) (subgingival debridement, laser therapy and photodynamic therapy) and the adjunctive chemotherapeutic approaches such as systematic and local antibiotics and antiseptics, subgingival pocket irrigation and host modulation therapies. The review also attempts to briefly introduce future developments in some of these modalities. At the end, the review summarizes the analysis of the current evidence that suggests that thorough subgingival debridement remains the mainstay of NSPT and that adjunct use of chemotherapeutic agents may offer better management of clinical parameters in periodontitis patients.

Key Words: Systematic reviews; Mechanical nonsurgical periodontal therapy; chemotherapeutic approaches; Host modulation therapy; Laser

Core tip: The present review focuses on the best available evidence, for the current management of the chronic periodontal patients, gathered from systematic reviews and meta-analysis of mechanical non surgical periodontal therapy (NSPT) (subgingival debridement, laser therapy and photodynamic therapy) and the adjunctive chemotherapeutic approaches such as systematic and local antibiotics and antiseptics, subgingival pocket irrigation and host modulation therapies. The review also attempts to briefly introduce future developments in some of these modalities. At the end, the review summarizes the analysis of the current evidence for mechanical and chemotherapeutic approaches of NSPT.

INTRODUCTION

Periodontal diseases are biofilm-mediated, chronic infectious diseases and are the most common cause of tooth loss in the modern world. According to data from the World Health Organization report gingival bleeding and calculus, which primarily reflects poor oral hygiene, are most prevalent in adults from all regions of the world while advanced disease with deep periodontal pockets (≥ 6 mm) affects approximately 10% to 15% of the adult population[1].

Periodontitis involves a complex interaction between environmental (such as specific bacteria) and host (genetic and immunological) factors that leads to loss of periodontal attachment apparatus. The current paradigm of etiopathogenesis for periodontitis suggests that though periodontal diseases are pathogen and site specific, the host- microbial interactions leading to overproduction of destructive enzymes and pro-inflammatory mediators determine the extent and severity of tissue destruction[2,3]. This shift in paradigm has led to better understanding of the underlying host immune responses and to development of novel treatment strategies that may improve therapeutic outcomes and overall clinical management of periodontitis patients.

Treatment of periodontitis is directed primarily towards the reduction of pathogens embedded in the subgingival biofilm[4]. Non surgical periodontal therapy (NSPT) has been shown to improve probing pocket depths (PPD) and clinical attachment levels (CAL) in mild to moderate periodontitis cases with probing pocket depths of less than 6 mm[5]. In the treatment of deep pockets (> 6 mm) surgical periodontal therapy results in greater PPD reduction and clinical attachment gain[5]. Chronic periodontal disease can be successfully treated by NSPT provided adequate plaque control is maintained throughout the supportive phase of treatment[6].

NSPT includes both mechanical and chemotherapeutic approaches to minimize or eliminate microbial plaque associated with the periodontal tissues, tooth surfaces and within other niches in the oral cavity[4,7], and to alter host immune-inflammatory response in the periodontal tissues. Mechanical therapy refers to both supragingival and subgingival scaling and debridement of the roots by use of hand or power-driven scalers to remove local deposits such as plaque, calculus, endotoxins, and other plaque-retentive local factors[8].

Chemotherapeutic approaches includes antimicrobial therapies that can be used systemically or locally to address changes in the microflora and host modulatory therapy that can be used to address altered host immune response consisting of excessive levels of pro-inflammatory enzymes, cytokines, and prostanoids and excessive osteoclast function that may be related to certain risk factors[9].

Once the active bacterial challenge and host inflammatory reactions are controlled by surgical or nonsurgical therapy, it is imperative for the patient to maintain periodontal health with daily plaque control at home and periodic professional maintenance by the dentist or dental hygienist[10,11].

Systematic reviews include a comprehensive appraisal of research using transparent methods whilst aiming to minimize bias. This present review will cover an evidence based update through recent systematic reviews on NSPT and provide an insight into current advances in both mechanical and chemotherapeutic approaches used adjunctively to treat, manage and prevent periodontal diseases.

ASSESSMENT AND MODIFICATION OF RISK FACTORS

It is a well established fact that periodontal diseases are multifactorial in nature and one or more risk factors are necessary for disease initiation and progression. These risk factors include microbial factors, host related factors and environmental and acquired factors. Presence of poor oral hygiene, poorly controlled diabetes mellitus, persistent stress, habits such as tobacco smoking, genetic susceptibility, extent of alveolar bone loss are just some of the risk factors that may influence long term outcomes periodontal therapy[1,11]. Evaluation of these risk factors is a dynamic process and therapeutic strategies to modify them become an integral part of NSPT.

MECHANICAL NON-SURGICAL PERIODONTAL THERAPY

Mechanical periodontal therapy is usually the first line treatment for most periodontal infections and includes subgingival scaling and root debridement procedures. Previously aggressive root planing was thought to be required to remove bacterial endotoxin bound to the contaminated root surface[12]. Listgarten et al[13] in an electron-microscope study observed that the epithelial attachment on calculus that had been treated with chlorhexidine gluconate (CHX) has the same ultrastructure as normal epithelial attachment on various tooth surfaces. Current evidence suggests that bacterial endotoxins are weakly adherent to root surfaces and therefore intentional removal of root substance and contaminated cementum is not required for successful periodontal healing as it occurs even in the presence of calculus, provided that the subgingival bacterial plaque had been meticulously removed[14,15]. Hence the term debridement is now frequently used instead of root planing (Table 1).

Table 1 Summary of the systematic reviews for mechanical non surgical periodontal therapy.

Systematic review	No. of studies	Treatment modalities	Tested clinical parameters	Conclusion
Mechanical therapy
Tunkel et al[17]	27	Machine driven vs subgingival debridement	Tooth loss, CAL, PPD, BOP	No difference between ultrasonic/sonic and manual debridement in the treatment of chronic periodontitis for single-rooted teeth. Ultrasonic/sonic subgingival debridement requires less time than hand instrumentation
Van der Weijden et al[25]	26	Subginigval debridement + supragingival plaque control	BOP, PPD, CAL	Improvement in PPD and CAL by subgingival debridement (with supragingival plaque control)
Slots et al[19]	15	Vector® ultrasonic scaler vs conventional ultrasonic instruments and/or hand instrumentation	Calculus removal, time of instrumentation, root surface aspects, patients' perception, BOP, PPD, CAL and microbiological effects	Comparable clinical and microbiological effect of all 3 modalities. Vector® ultrasonic system is more time consuming
Laser therapy
Schwarz et al[29]	11	Laser monotherapy vs mechanical debidement	Clinical data Laser safety data	Er:YAG laser monotherapy resulted in similar clinical outcomes, both in the short and long term compared with mechanical debridement. Insufficient evidence to support the clinical application of either CO(2), Nd:YAG, Nd:YAP, or different diode lasers
Karlsson et al[32]	4	Laser therapy + SRP	BOP, PPD, CAL	No consistent evidence for efficacy of laser as an adjunct to NSPT in adults with chronic periodontitis
Slots et al[30]	8	Nd:YAG Laser monotherapy vs Laser + SRP	Plaque, BOP, gingivitis, PPD, CAL, and GR	No beneficial effect of a pulsed Nd:YAG laser compared to ultrasonics and/or hand instrumentation in the initial periodontitis
Sgolastra et al[31]	5	Er:YAG laser vs SRP	CAL, PPD and GR	No evidence of effectiveness of Er:YAG laser compared to SRP
Photodynamic therapy
Azarpazhooh et al[40]	5	Monotherapy or adjunctive PDT	PPD, CAL, GR, Full mouth plaque and bleeding scores	Routine use of PDT for clinical management of periodontitis cannot be recommended
Sgolastra et al[39]	4	PDT used alone or adjunctive to scaling root planning	CAL, PPD, GR	PDT adjunctive to conventional treatment provides short-term benefits, but microbiological outcomes are contradictory. No evidence of effectiveness for the use of PDT as alternative to SRP

CA: Clinical attachment level; PPD: Probing pocket depth; BOP: Bleeding on probing; SRP: Scaling and root planing; GR: Gingival recession; PDT: Photodynamic therapy; Er:YAG: Erbium-doped: yttrium-aluminum garnet; Nd:YAG: Neodinium doped: yttrium-aluminum garnet.

Manual vs sonic or ultrasonic instrumentation

Manual instrumentation and sonic or ultrasonic scalers have been shown to be very effective in reducing the risk of tooth loss, slow down the rate of periodontal disease progression, reduce bleeding on probing and probing pocket depths and improve gingival health[6,10]. Use of hand scalers has been referred to as “gold standard” in mechanical periodontal therapy[16] but it is more time consuming, requires more skill, and is tiring for dentist and patients alike. On contrary, ultrasonic instrumentation improves patient compliance and requires less time for thorough debridement.

A systematic review of efficacy of machine-driven and manual subgingival debridement in chronic periodontitis concluded that ultrasonic/sonic subgingival debridement can be completed in less time compared to hand instruments, though the clinical efficacy remained similar. It further reported no major difference in the frequency and severity of adverse effects following the two treatment modalities[17]. Ultrasonic instrumentation when used on medium power settings has shown comparatively lesser root surface alteration and found to be more effective in furcation areas[18]. A new pain free ultrasonic system, Vector^®, has been introduced few years back. It’s a linear oscillating device that result in the parallel movement of the instrument tip to the root surface[19]. A systematic review concluded that clinical and microbiological effects of the Vector^® system is comparable to power-driven and manual instrumentation in moderately deep pockets. However the system was found to be is less effective in deep pockets and was considerably more time consuming[19].

Several other comparison studies have observed that both manual and ultrasonic instrumentation were equally effective in removal of plaque, calculus and endotoxins[18] and resulted in changes in the composition of the microbial flora in deep periodontal pockets such as reduction of spirochetes and motile rods[20,21] and increase in gram positive rods and cocci[7,22].

A thorough review of nonsurgical periodontal therapy by Cobb et al[23] reported mean PPD reductions of 1.29 mm to 2.16 mm and CAL gains of 0.55 mm to 1.19 mm for initial probing depths of 4 mm to 6 mm or more than 6 mm before treatment in chronic periodontitis patients receiving sungingival debridement[23,24]. Another systematic review[25] reported weighted mean of attachment gain of subgingival debridement in deep pockets (≥ 5 mm) was 0.64 mm while PPD reduction was 1.18 mm and clinical attachment gain was 0.74 mm. The author concluded that subgingival debridement in conjunction with supragingival plaque control is an effective treatment in reducing probing pocket depth and improving the clinical attachment level.

Mechanical instrumentation alone has shown limited ability in areas with deeper pockets, underlying bony defects and also found to be ineffective in reducing levels of tissue penetrating bacteria, such as Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans)[26,27]. Therefore use of chemotherapeutic agents as adjuncts to mechanical therapy has been strongly suggested along with regular maintenance visits[9].

Laser (Light amplification by stimulated emission of radiation)

The use of lasers has been advocated for past few years within the periodontal pocket for subginigival debridement, reduction of subgingival bacterial loads and scaling and root planing (SRP). But its clinical effectiveness in the treatment of periodontal diseases remains debatable among clinicians and there is dearth of clinical evidence for their benefit over traditional mechanical therapy[28].

Among the different wavelengths of lasers compared with traditional mechanical therapy involving manual and sonic and ultrasonic instrumentation, the erbium-doped: yttrium-aluminum garnet (Er:YAG) laser is reported to be the most effective[29]. However, current evidence suggests that the clinical effectiveness of the Neodinium doped: yttrium-aluminum garnet (Nd:YAG)[30] or Er:YAG[31] laser was comparable to SRP in terms of clinical attachment gain, PPD reduction or change in gingival recession and that there was no added advantage of using lasers as a standalone therapy in treatment of chronic periodontitis[30-32]. Even in terms of reduction in subgingival putative pathogens use of the Nd:YAG or Er:YAG wavelengths was found to be equivalent and not superior to SRP[33].

Photodynamic therapy

Antimicrobial photodynamic therapy (PDT) is a non-invasive therapeutic modality, which relies upon an oxygen-dependent photochemical reaction that occurs upon light mediated activation of a photosensitizing compound bound to the target cell. This reaction leads to the generation of cytotoxic reactive oxygen species, predominantly singlet oxygen[34,35] and hence can be very effective in anaerobic infections like periodontitis. The light source could be a low-power laser[36,37] or light emitting diodes[38].

There are very few systematic reviews and well designed research published on clinical effectiveness of PDT over conventional periodontal therapy. A recent systematic review of seven randomized controlled trials (RCTs)[39] and another with five trials[40] concluded that the use of photodynamic therapy as a standalone therapy does not produce any beneficial clinical effect as compared to SRP. The review further noted that PDT as an adjunctive to SRP provides only short-term benefits. Finally both reviews recommended well-designed, long term RCTs as currently there is an insufficient evidence to suggest that PDT is superior to the conventional periodontal therapy.

CHEMOTHERAPEUTIC APPROACHES IN NON-SURGICAL PERIODONTAL THERAPY

Although mechanical non-surgical and surgical therapy continues to dominate other treatment approaches in the treatment of periodontal disease, its inability to completely eliminate periodontal pathogens from the soft tissues and hard tissue surfaces and within other niches in the oral cavity may cause recolonization of these pathogens leading to reinfection[1,2]. To overcome these deficiencies in traditional periodontal therapy, adjunctive use of chemotherapeutic agents either systemically, locally or topically becomes an indispensible treatment modality[2,8,9].

As the current paradigms in the etiopathogenesis of periodontal disease suggests greater role of host immune reaction to bacterial challenge in the ensuing periodontal tissue destruction, the newer chemotherapeutic approaches are focused on how to effectively modulate these host responses and lessen the degree of tissue destruction as well as help periodontal tissue regenerate and repair to a healthy state[41].

Various chemotherapeutic approaches include use of antimicrobials and antiseptics via topical application, subgingival pocket irrigation, local delivery into the periodontal pocket and systemic administration.

Systemic antibiotic therapy

Systemic antimicrobials therapy as an adjunct to mechanical debridement has been advocated in past few decades, the rationale for their use being the suppression of periodontal pathogens persisting in biofilms in deep pockets, root furcations and concavities or residing within the periodontal tissues or other oral niches where mechanical therapy alone may prove to be ineffective. In particular the periodontal pathogen A. Actinomycetemcomitans, Porphyromonas gingivalis (P. gingivalis), Prevotella intermedia (P. intermedia), Bacteroides forsythus (B. forsythus), staphylococci and enteric rods has been reported to be difficult to eradicate with nonsurgical therapy alone[42]. While more than 500 bacterial species may be present in the gingival sulcus[43], it is clear that only a subset of bacterial species are consistently found to be associated with diseased sites[44]. These findings suggest that systemic antimicrobial therapy may prove an indispensible adjunct to mechanical therapy for efficient management of periodontal conditions that cannot be managed with mechanical therapy alone. These conditions may include severe or acute infections, aggressive periodontitis, and recurrent or refractory cases[45], (Table 2).

Table 2 Summary of systematic reviews on adjunctive chemothrerapeutic agents.

Systematic review	No. of studies	Treatment modalities	Tested clinical parameters	Conclusion
Systemic antimicrobial therapy
Herrera et al[50]	25	SRP + systemic antibiotics vs SRP alone or SRP + placebo	PPD, CAL	Systemic antimicrobials in conjunction with SRP can offer an additional benefit over SRP alone in the treatment of periodontitis
Haffajee et al[51]	29	SRP + systemic antibiotics vs SRP alone or SRP+ placebo	CAL	The use of systemically administered adjunctive antibiotics with and without SRP and/or surgery appeared to provide a greater clinical improvement in CAL
Goodson et al[52]	RCT# (187 Patients)	SRP + systemic antibiotics vs SRP + local antibiotic therapy and/or periodontal surgery	CAL, PPD	Adjunctive therapies generally exhibited improved CAL gain and/or PPD reduction when compared with SRP alone
Sgolastra et al[54]	6	AMX/MET + SRP vs full mouth SRP alone	CAL, PPD, secondary outcomes, and adverse events	Significant CAL gain and PPD reduction in favor of full mouth SRP + AMX/MET; no significant risk difference in the occurrence of adverse events
Sgolastra et al[55]	4	AMX/MET + SRP vs SRP alone	CAL, PPD, secondary outcomes, and adverse events	Significant CAL gain and PPD reduction in favor of SRP + AMX/MET; no significant difference in BOP or suppuration. Supports effectiveness of SRP with AMX/MET in chronic periodontitis
Zandbergen et al[53]	28	Adjuvant AMX/MET + SRP	CAL, PPD, plaque index, BOP	AMX/MET as an adjunct to SRP can enhance the clinical benefits of non-surgical periodontal therapy in adults who are otherwise healthy
Keestra et al[56]	43	Different systemic antibiotics + SRP vs SRP alone	BOP, CAL, PPD	Systemic antibiotics combined with SRP offer additional clinical improvements compared to SRP alone. For initially moderate and deep pockets, MET or MET + AMX, resulted in clinical improvements that were more pronounced over doxycycline or azithromycin. Clinical benefit became smaller over time (1 yr)
Local antimicrobial therapy
Hanes et al[60]	32	Local controlled-release anti-infective drug therapy with or without SRP vs SRP alone	PPD, CAL	Local anti-infective agents resulted in significant adjunctive PPD reduction or CAL gain for minocycline gel, microencapsulated minocycline, CHX chip and doxycycline gel during SRP compared to SRP alone. The decision to use local anti-infective adjunctive therapy remains a matter of individual clinical judgment, the phase of treatment, and the patient’s status and preferences
Bonito et al[61]	3	Local antimicrobials with SRP vs SRP alone	CAL, PPD	Only modest improvements in PPD reductions
Matesanz-Pérez et al[62]	52	Local antimicrobials with SRP vs SRP alone	CAL, PPD, plaque index, BOP	Scientific evidence supports the adjunctive use of local antimicrobials to debridement in deep or recurrent periodontal sites, mostly when using vehicles with proven sustained release of the antimicrobial
Full mouth disinfection
Eberhard et al[78]	7	FMD with or without antiseptics vs quadrant scaling	Tooth loss, BOP, PPD, CAL	Only minor differences in treatment effects between the treatment strategies
Eberhard et al[79]	7	FMD with or without antiseptics vs quadrant scaling	Tooth loss, BOP, PPD, CAL	Slightly more favourable, but modest outcomes were found following FMD in moderately deep pockets. Very limited number of studies available for comparison, thus limiting general conclusions about the clinical benefit of full-mouth disinfection
Lang et al[80]	12	FMD with or without antiseptics vs conventional staged debridement	BOP, PPD, CAL microbial changes	Despite the significant differences of modest magnitude, FMD with or without antiseptics do not provide clinically relevant advantages over conventional staged debridement. Hence, all three treatment modalities may be recommended for debridement in the initial treatment of chronic periodontitis
Farman et al[81]	7	Full mouth debridement vs FMD with antiseptics vs quadrant scaling	BOP, PPD, CAL	Traditional quadrant approach and full-mouth debridement could be equally effective

CAL: Clinical attachment level; PPD: Probing pocket depth; SRP: Scaling and root planing; BOP: Bleeding on probing; RCT: Randomized controlled clinical trial; AMX/MET: Amoxicillin plus metronidazole; FMD: Full mouth disinfection.

Common antibiotic regimens for the treatment of periodontitis are included in Table 3. Early approaches to systemic antibiotic therapy for periodontal treatment involved monotherapy with metronidazole, tetracyclines, doxycycline, amoxicillin (with or without clavulanic acid), spiramycin, clindamycin, and azithromycin[45,46].

Table 3 Recommended systemic antibiotic dosing regimens.

Single agent regimen dosage/duration
Amoxicillin	500 mg, three times per day × 8 d
Azithromycin	500 mg, once daily × 4-7 d
Ciprofloxacin	500 mg, twice daily × 8 d
Clindamycin	300 mg, three times daily × 10 d
Doxycycline or minocycline	100-200 mg, once daily × 21 d
Metronidazole	500 mg, three times daily × 8 d
Combination therapy
Metronidazole + amoxicillin	250 mg, of each three times daily × 8 d
Metronidazole + ciprofloxacin	500 mg of each twice daily × 8 d

Adapted from Krayer et al[41].

Since periodontitis is a polymicrobial infection, the heterogeneity of pathogenic bacteria necessitates use of drug combination therapies that can also be effective to overcome drug protective effects of biofilm[47]. Combination therapy should involve drugs with complementary but different mechanisms of action and synergistic or additive effect[45]. In-vitro experiments have reported synergistic effect of amoxicillin with metronidazole and ciprofloxacin with metronidazole against A. actinomycetemcomitans and other periodontal pathogens[48,49]. Combination therapy of amoxicillin with metronidazole has been the most well documented for adjunctive treatment of chronic and aggressive periodontitis.

Herrera et al[50] in a systemic review of 25 studies concluded that systemic antimicrobials in conjunction with SRP, can offer an additional benefit over SRP alone in the treatment of periodontitis, in terms of CAL and PPD change, and reduced risk of additional CAL loss. They further noted that patients with deep pockets, progressive or active disease, or specific microbiological profile, can benefit more from this adjunctive therapy. Haffaji et al[51] in a systematic review of 29 studies concluded that systemically administered antimicrobials were uniformly beneficial in providing an improvement in clinical attachment gain when used as adjuncts to scaling and root planing.

In a large multicenter randomized controlled trial, Goodson et al[52] reported that adjunctive systemic antimicrobial therapy with amoxicillin and metronidazole resulted in significantly more clinical attachment gain and PPD reduction in deep periodontal pockets (probing depth ≥ 5 mm) compared to SRP alone in chronic periodontitis patients. The results of recent systematic reviews involving aggressive periodontitis[53,54] and chronic periodontitis[53,55,56] also corroborate earlier findings of significant clinical attachment gain and reduction in PPD when systemic amoxicillin with metronidazole was administered with conventional periodontal therapy. Another recent systematic review of 43 studies utilizing different antibiotic regimens concluded that systemic antibiotics combined with SRP resulted in significant PPD reduction for initially moderate pockets at 3 mo (0.27 ± 0.09 mm), at 6 mo (0.23 ± 0.10 mm) and at 12 mo (0.25 ± 0.27 mm ) and deep pockets at 3 mo (0.62 ± 0.17 mm), at 6 mo (0.58 ± 0.16 mm) and at 12 mo (0.74 ± 0.30 mm) though there was a trend that the magnitude of the clinical benefit became smaller over period of time (1 year)[56]. The authors further conclude that clinical effects of metronidazole or metronidazole combined with amoxicillin resulted in clinical improvements that were more pronounced over doxycycline or azithromycin, though the difference was not statistically significant[56].

The best available evidence indicates that systemic antimicrobials used in conjunction with SRP, can offer an additional benefit over SRP alone, in terms of CAL, and PPD change, especially in deep periodontal pockets. However it should be remembered that systemic antibiotics are an adjunct to mechanical periodontal therapy and should not be used as monotherapy. Their use should be restricted in severe or acute infections, aggressive periodontitis, and recurrent or refractory cases that cannot be managed with other therapeutic modalities. The indiscriminate use of systemic antimicrobials can lead to development of antibiotic resistance among human pathogens. To reduce this risk, microbiological analysis and antimicrobial susceptibility testing is suggested for selecting the optimal antimicrobial therapy[47].

Local antimicrobial delivery

Limited indications of systemic antimicrobial therapy and the risk-benefit ratio of their use led to development of local delivery of antimicrobial and antiseptics (LAD) directly in the periodontal pocket. The rationale of using LAD in periodontal disease is to chemically kill or reduce the plaques within the biofilm in the pocket by placing high concentrations of an antibiotic or antiseptic in direct contact with the root surface without noticeable systemic effect, which may not be always possible with systemic antibiotics. Sakellari et al[57] reported that gingival crevice fluid concentration of systemically administered antimicrobials tetracyclines was less than that of plasma concentration and vary widely among individuals (between 0 and 8 Lg/mL), with approximately 50% of samples not achieving a level of 1 Lg/mL. This possibly explains variable clinical response to systemic tetracyclines observed in clinical practice.

Various non-resorbable and resorbable intrapocket delivery systems have been developed. The first LAD agent developed for periodontitis was Actisite™, supplied as hollow, non-resorbable fibers filled with tetracycline (12.7 mg/9 inch fiber)[58]. Though very effective, the non-absorbable fibers were tedious to insert in the deep pockets and required a second visit for retrieval from pocket. These deficiencies fuelled the development of absorbable systems for LAD.

Among the first absorbable system to be developed was Atridox^TM, which is a 10% formulation of doxycycline (50 mg in a bioresorbable gel system).The polymer gel fills and conforms to pocket morphology, then solidifies to a wax-like consistency upon contact with gingival crevicular fluid. Doxycycline is released at effective concentrations over 7 d, and significant reductions (60%) in anaerobic pathogens are sustained for up to 6 mo post treatment[59].

The early success of Atridox™ led to development of other absorbable LAD systems such as minocycline microspheres (Arestin™), chlorhexidine gluconate chips (PerioChip™) and gel (Chlosite™), and metronidazol gel (Elyzol™).

Hanes et al[60] in a meta-analysis of 19 studies compared SRP and adjunctive local sustained-release agents with SRP alone. The authors concluded that local anti-infective agents resulted in significant adjunctive PPD reduction or CAL gain for minocycline gel, microencapsulated minocycline, CHX chip and doxycycline gel during SRP compared to SRP alone.

Bonito et al[61] in a subsequent systematic review, reported most positive results for tetracycline, minocycline, metronidazole, and CHX with modest but statistically significant improvements in PPD reductions compared with scaling and root planing alone. The authors did not report any significant changes in clinical attachment gain and questioned the clinical significance of these small improvements though they were statistically significant.

In a recent systematic review of 52 studies, Matesanz-Pérez et al[62] observed that subgingival application of tetracycline fibers, sustained released doxycycline and minocycline resulted in statistically significant benefit in PPD reduction (WMD between 0.5 and 0.7 mm) while that for CHX and metronidazole showed a minimal effect (WMD between 0.1 and 0.4 mm) when compared with placebo. The authors concluded that the scientific evidence supports the adjunctive use of local antimicrobials to debridement in deep or recurrent periodontal sites, mostly when using vehicles with proven sustained release of the antimicrobials.

The advent of newer formulations, such as sub-gingival delivery of statins and azithromycin, have shown promise in improving clinical parameters in chronic periodontitis patients when used along with SRP[63,64].

Current evidence seems to suggest that site-specific delivery of drug can overcome the disadvantages with systemic administration of antimicrobials for periodontitis and may prove to be a viable adjunct to conventional periodontal therapy.

Subgingival pocket irrigation

Sub gingival irrigation of agents such as chlorhexidine digluconate, 10% povidone iodine (PI), and 0.1% sodium hypochlorite has been advocated in periodontal disease as they show excellent antibacterial and antiviral properties and are readily available[65,66]. They are also more effective in flushing out the bacteria and reducing gingivitis scores as it penetrates much deeper in to the pocket when compared to mouth rinses or suprgingival irrigation[67].

Systematic reviews analysing the effect of subgingival irrigation with CHX[51] and PI[68] observed no additional clinical benefit to mechanical debridement for CHX irrigation[51] and a small but statistically significant effect of PI in probing depth reduction[68]. Consensus report of 6^th European workshop on periodontal disease also concluded that the use of antiseptic irrigants has not shown any advantage over conventional periodontal therapy in periodontal diseases[69]. Current evidence suggests that subgingival irrigation is never intended to be used as a standalone therapy; rather it is meant to be used as an adjunct to professional debridement, but one that simplifies home-care oral hygiene for the patient[70].

Topical antiseptic application

Topical application of antiseptics such CHX, povidone iodoine, phenolic compounds and sodium hypochlorite, with anti-plaque or anti-gingivitis action, has been suggested as useful oral hygiene aids to complement mechanical periodontal therapy. Though topical application seems to be of limited value, since it does not appreciably penetrate into the gingival crevice, they are useful adjuncts to control gingival inflammation, especially in acute conditions, post-surgically and during periods of interrupted hygiene[71].

A recently published meta-analysis of 50 studies, of atleast 6 mo duration, reported clinically and statistically significant antiplaque and antigingivitis effect of dentrifices containing triclosan/copolymer formulations and mouthrinses with 0.12% CHX and essential oils-containing formulations [menthol (0.042%), thymol (0.064%), methyl salicylate (0.060%), and eucalyptol (0.092%)]. Statistically and clinically significant antigingivitis effect was reported with dentifrices containing stannous fluoride. The author concluded that the meta-analysis provided strong evidence in favor of the use of antimicrobial agents as adjuncts to mechanical plaque control[72].

Certain disadvantages associated with long term use of mouthrinses include staining of teeth, mucositis and reversible epithelial desquamation, alteration of taste, and increased supragingival calculus[73]. Another important aspect of using topical antiseptics is that drugs should be in contact with periodontal pathogens at optimal concentration for optimal time period to exert bactericidal activity. For example, CHX must be in contact with P. gingivalis for 10 min at concentrations of 0.5% to 2%[74]. While povidone iodine, active against most bacteria, viruses, fungi and some spores, must be in contact with these pathogens for at least 5 min at concentrations between 0.5% and 10% to reach bactericidal activity[75].

Full mouth disinfection

The full mouth disinfection (FMD) protocol was first proposed by Quirynen et al[76] in 1995 as a new therapeutic approach to eradicate or at least suppress all periodontal pathogens in a short time not only from the periodontal pockets but also the entire oropharyngeal cavity so that the recolonization of the pockets by bacteria residing at non-treated pockets and other oral sites is prevented. The purported advantages of the FMD approach include significant additional clinical and microbiological improvements, better outcome of the mechanical debridement, reduced need for surgery and more efficient treatment and time management with less overall chair-side time and less travelling or absence from work for the patient[77].

Full-mouth disinfection involves removal of all plaque and calculus in two visits within 24 h. In addition, at each of these visits, the tongue was brushed with a 1% CHX gel for one minute, CHX spraying on tonsils and the mouth rinsed with a 0.2% CHX solution for two minutes. Furthermore, subgingival CHX (1%) irrigation was performed in all pockets. The recolonization of the pockets was retarded by oral hygiene and 0.2% CHX rinses during two weeks[76].

Two systematic reviews of 7 studies each, comparing full-mouth scaling and root planing within 24 h with antiseptics (FMD) or without (FMS) the adjunctive use of an antiseptic (chlorhexidine) with conventional quadrant scaling and root planning as control, concluded that in patients with chronic periodontitis, only minor differences in reduction in PD and CAL were observed in moderately deep pockets between the treatment strategies[78,79]. The authors further concluded that there were very limited number of studies available for comparison, thus limiting general conclusions about the clinical benefit of full-mouth disinfection[79]. Lang et al[80] in a systematic review of 12 trials and Farman and Joshi[81] in a systematic review of 7 trials concluded that FMD or full mouth scaling do not provide clinically relevant advantages over conventional staged debridement and recommended all three treatment modalities for debridement in the initial treatment of patients with chronic periodontitis.

HOST MODULATION THERAPY

As the role of host immune reactions to the bacterial challenges is being established in the etiopathogenesis of periodontal disease, modulation of these reactions provides for very promising and exciting therapeutic options to manage periodontal disease. Host modulation therapy has witnessed rapid advances in recent years and newer therapeutic modalities are being developed to restrain or inhibit release of proteolytic enzymes, pro-inflammatory mediators and osteoclast activity that occur as a result of host-microbial interactions. Different agents currently being investigated as an adjunct to mechanical NSPT are anti-proteinases, anti-inflammatory agents, and anti-resorptive agents (Table 4)[9,41].

Table 4 Summary of systematic reviews on host modulation therapy.

Systematic review	No. of studies	Treatment modalities	Tested clinical parameters	Conclusion
Reddy et al[89]	7 (SDD), 10 (NSAIDs), 3 (BPs)	Adjuntive efficacy of anti-proteinases, anti-inflammatory agents, and anti-resorptive	Bone changes, CAL, PPD, plaque index, gingivitis	Use of SDD+ SRP‡ is statistically more effective than SRP alone in reducing PPD and achieving CAL gain Insufficient data for NSAIDs and BPs may have potential adjunctive role in periodontal therapy
Preshaw et al[92]	2	SDD + SRP vs SRP + placebo	CAL, PPD	Adjunctive SDD enhances therapeutic outcomes compared with SRP alone, resulting in clinical benefit in both smokers and non-smokers with chronic periodontitis
Sgolastra et al[91]	3	SDD + SRP vs SRP + placebo	CAL, PPD, Plaque Index, Gingival Index, and gingival crevicular fluid levels	Supports long-term effectiveness of adjunctive SDD therapy
Moreno Villagrana et al[90]	9	SDD + SRP vs SRP + placebo	CAL, PPD	Statistically significant results in patients with aggressive or chronic periodontitis under periodontal treatment

SDD: Subantimicrobial dose doxycycline; NSAID: Non steroidal antiinflammatory drug; BP: Bisphosphonates; CAL: Clinical attachment level; PPD: Probing pocket depth; SRP: Scaling and root planing.

Anti proteinase agents

Current research postulates that host cells, when stimulated directly or indirectly by bacterial endotoxins, secrete tissue-destructive enzymes known as the matrix metalloproteinases (MMPs). Although several periodontal pathogens produce MMPs, including collagenase, host derived proteinases are considered to be the major destructive enzymes associated with periodontal disease progression[82]. Golub et al[83] first reported that the semisynthetic analogs of tetracyclines, like doxycycline, were more effective in reducing excessive collagenase activity in the gingival crevicular fluid of adult periodontitis patients. This is accomplished through the non-antimicrobial activities of low-dose doxycycline via the inhibition of MMP-8 and 13 protease mechanisms[84] and downregulation of key inflammatory cytokines (interleukin-1,6; tumor necrosis factor-α)[85].

Currently doxycycline hyclate (Periostat^®) is the only collagenase inhibitor available for use specifically in periodontal disease, the recommended dosage being 20 mg tablet two times daily for a minimum of 3 mo to achieve long-term benefit without a rebound[86]. More recent trials recommend a 6 to 9 mo regime of Subantimicrobial dose doxycycline (SDD) to prevent a rapid rebound in collagen-destructive enzyme activity and to enhance clinical efficacy[87,88]. Since their introduction, the beneficial effects of SDD in improving CAL, reducing PPD, and clinical attachment gain when used as an adjunct to SRP have been established through many systematic reviews[89-92]. A recent meta-analysis[90] of 9 randomized controlled double-blind clinical trials reported that the host modulating agent such as SDD was effective in improving CAL and reducing PPD when administered as an adjuvant in the nonsurgical management of chronic and aggressive periodontitis. Another meta-analysis of 3 trials by Sgolastra et al[91] supported the long term effectiveness of the adjunctive SDD treatment. Preshaw et al[92] in a meta-analyses of 2 trials reported significant PPD reduction and clinical attachment gain in smokers with chronic periodontitis when SDD was used as an adjunct to SRP.

Anti-inflammatory agents

In periodontal inflammation, significantly high levels of prostaglandin E₂ (PGE2) has been reported in gingival tissues and gingival crevicular fluid (GCF)[93,94]. The tissue damage resulting from host-microbial interactions allows production of free arachidonic acid (AA) from phospholipids in plasma membranes of cells by action by phospholipase A2 via the cyclooxygenase (CO) or lipoxygenase (LO) pathways. The final products of the CO pathway include prostaglandins, prostacyclin, and thromboxane, whereas the end results of the LO pathway include leukotrienes and other hydroxyeicosatetraenoic acids.

Non-steroidal anti-inflammatory drugs (NSAIDs) have the ability to block the enzyme CO and reduce prostaglandin synthesis and rate of alveolar bone resorption. A recent systematic review[89] of ten trials compared various NSAIDs such as indomethacin, flurbiprofen, ibuprofen, naproxen, meclofenamic acid, piroxicam and Ketoprofen in periodontal disease treatment. Although the heterogeneity of data did not allow a meta-analysis, limited quantitative analysis suggested a significant benefit related to alveolar bone height maintenance when NSAIDs were combined with mechanical periodontal therapy. Though theses agents are found to be useful in chronic[95] and aggressive periodontitis[96], they require prolonged administration to prevent recurrence of infection and to maintain healthy periodontal status[97]. The adverse effects associated with prolonged systemic administration of non-selective NSAIDs[98] such as gastrointestinal, renal, and hepatic impairment has curtailed their application in management of chronic conditions like periodontitis. To counter these adverse effects of non selective NSAIDs, selective COX-2 inhibitors were developed but they were subsequently withdrawn because of increased incidence of thrombosis and myocardial infarcts associated with their long term administration[98].

Topical application of NSAIDs has been advocated owing to lipophilic properties of these drugs. NSAIDs that have been evaluated for topical administration include ketorolac tromethamine[99], S-ketoprofen[100], and flurbiprofen[101]. Though these trials reported reductions in the rate of alveolar bone loss, no superior effect was observed for other clinical parameters when topical NSAIDs were used in conjunction with conventional periodontal treatment[97,99,101]. However, currently there is only limited evidence available and further large multi center trials are recommended to determine whether these NSAIDs provide clinically significant improvements when utilized as adjuncts to scaling and root planing[89].

Lipoxins (LX) are endogenous byproduct of AA metabolism through LO pathway and act as proresolving, anti-inflammatory molecules[101] that control the resolution phase of acute inflammation and promote healing of the lesion[102,103]. It has been demonstrated that lipoxins are produced by peripheral blood neutrophils from patients diagnosed with aggressive periodontitis and not from healthy patients[104], suggesting their immunomodulatory role in periodontal disease. LX and their more stable and bioactive form, aspirin triggered lipoxins (ATL) stimulate resolution pathways and restore tissue homeostasis through agonist actions on neutrophils. Experiments in several murine models suggest that in inflammation, stable analogs of LX inhibit P. gingivalis elicited neutrophil infiltration, reduce PGE2 levels[104] and also contain vascular permeability changes[105]. These observations suggest a promising role of lipid mediators in the regulation of local acute inflammatory responses in periodontal disease and high potential for the development of novel therapeutic regimens.

Recently, new classes of proresolving lipid mediators such as resolvins (resolution-phase interaction products) and protectin have been identified that are derived from the omega-3 fatty acids, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) rather than AA[102,103,106]. Resolvins and protectins stimulate anti-inflammatory and proresolving pathways similar to the lipoxins but their binding occurs to distinct sites on inflammatory cells[103]. In a P. gingivalis-induced experimental periodontitis, topical application of resolvins demonstrated remarkable efficacy in the reducing alveolar bone loss with complete resolution of inflammation and restoration of soft and hard tissues of periodontium[107,108]. Generation of these potent proresolving molecules may encourage integration of dietary supplementation of omega-3 fatty acids, EPA and DHA in prevention and/or adjunctive management of chronic periodontitis[109,110].

Anti resorptive agents

Bisphosphonates (BPs) are pyrophosphate analogs that suppress osteoclastic activity, prevent dissolution of hydroxyapatite crystals and promote osteoblast differentiation[111]. Mechanism of action of BPs may occur at three levels. At tissue level, they decrease bone turnover by decreasing bone resorption and by reducing the number of new bone multicellular units. At the cellular level, they decrease osteoclast and osteoblast recruitment, decrease osteoclast adhesion, increases osteoblast differentiation and number, and decrease the release of cytokines by macrophages. At molecular level, BPs inhibit mevalonate pathway that induces cell apoptosis[112].

Though use of BPs, either intravenously or orally, in conditions like osteoporosis, osteopenia, and Paget’s disease has been established[112], only limited data is available for their application in the management of periodontal diseases. Few well designed human trials have reported significant reduction in alveolar bone loss, reduction in PPD, clinical attachment gain, reduction in bleeding on probing, and gain in alveolar bone height when BPs are used as an adjunctive agent to SRP[89,113-116].

Recently, long term use of high dose intravenous BPs has been reported to be associated with osteonecrosis of the jaw(ONJ)[117] that is essentially exposed bone in the maxilla or mandible that does not heal within 8 wk of identification by health care professionals[118]. A recent report by the American Society for Bone and Mineral Research concluded that with oral bisphosphonate therapy for osteoporosis a risk for ONJ is less than one in 100000 patients while that for IV bisphosphonate therapy in patients with cancer was reported to be in the range of one to 10 per 100 patients[119]. However, scientific community is still divided on whether bisphosphonates indeed cause ONJ. Hence despite the promising therapeutic results, the data available is insufficient for use of BPs as host modulating agents in periodontal disease management. Further long-term multi center randomized controlled clinical trials are recommended to confirm the benefits of these drugs[89].

CONCLUSION

Non-surgical periodontal therapy continues to evolve and newer therapeutic modalities are being developed to make the outcomes more predictable and last longer. Past two decades have witnessed publication of some excellent systematic reviews on NSPT that has helped formulate novel treatment regimens to combat periodontal infection and restore tissue homeostasis. Current best evidence suggest that: (1) NSPT results in superior clinical outcomes as compared to surgical therapy in periodontitis patients with moderate pocket depth (≤ 5 mm); (2) Thorough mechanical periodontal therapy (manual and ultrasonic debridement) remains a gold standard resulting in significant resolution of periodontal inflammation leading to improvement in the clinical signs and symptoms of active disease. But it may be insufficient for complete elimination of putative pathogens that may cause reinfection; (3) Adjunctive use of lasers or photodynamic therapy in the treatment of periodontitis does not result in superior clinical effects compared to that achieved by conventional mechanical therapy alone; (4) Systemic and local antimicrobials used in conjunction with SRP offer additional benefits in terms of CAL and PPD change, especially in patients with deep periodontal pockets, and aggressive or refractory periodontitis. The clinical effects are modest with LAD; (5) Full mouth disinfection result in clinical benefits comparable to that achieved by full mouth scaling without antiseptics and conventional staged debridement; (6) Host modulation therapy specifically with SDD results in better clinical effects when used as an adjunct to mechanical therapy. Development of newer formulations and novel therapeutic strategies may result in faster resolution of periodontal inflammation and help in regeneration of periodontal attachment apparatus; and (7) Daily oral hygiene maintenance coupled with frequent recall visits by patients is vital for long-term success of NSPT.