C111 special considerations for managing patients with diabetes
C111 SPECIAL CONSIDERATIONS FOR MANAGING PATIENTS WITH DIABETES MARIA EMANUEL RYAN, DDS, PHD THURSDAY, FEBRUARY 21DISCLAIMER: This work, audio recordings and the accompanying handout, are the intellectual property of the clinician, and permission hasbeen granted to the Chicago Dental Society, its members, successors and assigns, for the unrestricted, absolute, perpetual, worldwide rightto distribute solely as an educational material at the scientific program being presented at the 2011 Midwinter Meeting. Permission has beengranted for this work to be shared for non-commercial education purposes only. No other use, including reproduction, retransmission in anyform or by any means or editing of the information may be made without the written permission of the author. The Chicago Dental Societydoes not assume any responsibility or liability for the content, accuracy, or compliance with applicable laws, and the Chicago Dental Societyshall not be sued for any claim involving the distribution of this work.
Chicago Dental Society MWM & REGIONAL MEETING COURSE EVALUATIONSpeaker: Date:Subject: Number of attendees:PLEASE RATE YOUR SPEAKER AS TO: Excellent Good Fair Poor N/A • Subject selected................................. 4 3 2 1 0 • Timeliness of subject ......................... 4 3 2 1 0 • Comprehensiveness........................... 4 3 2 1 0 • Meeting your expectations ................ 4 3 2 1 0 • Content level...................................... 4 3 2 1 0 • Delivery .............................................. 4 3 2 1 0 • Voice quality....................................... 4 3 2 1 0 • Holding your interest ......................... 4 3 2 1 0 • Appropriate audiovisuals ................... 4 3 2 1 0 • Effective audiovisuals ........................ 4 3 2 1 0 • Overall evaluation of speaker ............ 4 3 2 1 0 • Overall evaluation of program........... 4 3 2 1 0Should this speaker be invited for future meetings? Yes q No qWhat topics of interest would you like to see covered in the future?Comments (use reverse if you need additional space):Name (requested but not required—please print):RETURN EVALUATION CARD TO: DO NOT FOLD CARD. FOR CDS PERMANENT FILES.Chicago Dental SocietyAloysius F. Kleszynski, DDS401 N. Michigan Ave., Suite 200, Chicago, IL 60611-5585
en •U ,....c = Q.) ~ in the ~Trea nt ,.p Perio _,~ Treatment strategies combining the use of mechanical therapies and adjunctive chemotherapeutics enable clinicians to better manage periodontal diseases. Q) By Rebecca S. Wilder, RDH, MS, and Maria Emanuel Ryan, DDS, PhD ,..C Oral healthcare professionals continually that clinicians rarely if ever achieve complete removal of the seek ways to address the plaque biofilm and putative pathogens that reside in the biofilm from the surface. excessive host response that are responsible What scientists do know is that the plaque biofilm is composed ~_-::::; __ ~:::-_ for e-breakdown of connective tissue and bone associated with of a complex group of bacteria living together in a multispecies -~~ =e= While mechanical therapy (such as scaling, community. The microbes in the biofilm are stable, and tightly root planiQg-and"p,ower instrumentation) is considered the gold adhere to each other and to an oral substrate by means of an standard ~~fil;ri,disruPtion , and removal, the data tell us extracellular matrix.,3 Bacteria in biofilms are much more resist- ant to antimicrobial agents than those dispersed as single cells of the same species. Knowing this helps us to understand why antibiotics uti- lized to address the biofilm, either locally applied or systemi- cally administered, are considered adjuncts to mechanical therapy instead of monotherapies. What this means to dental clinicians is that an optimal therapeutic approach may include adjunctive therapies such as antiseptics and/or antibiotics, as well as host modulation (in addition to mechanical therapy) to best address a complex disease process. Devising a suitable treatment plan would also depend, of course, on the patients host response and oral healthcare habits. Chemotherapeutic agents are used to eliminate, reduce or alter the effect of microorganisms in the oral cavity and~~iOns ~~£IIE www.dimensionsofdentalhygiene.com JUNE 2010
elevated levels of pro-inflammatory media- Allare safe when used as directed. Chemother- dentifrices. Previous reports showed a reduc-tors. The term antimicrobial refers to agents apeutic dentifrices in the U.S. primarily contain tion in plaque biofilm and gingivitis for shortthat kill microbes or affect the growth and triclosan or stannous fluoride. periods after use. A possible downside is thatmultiplication of microorganisms.· Several Here is a brief description of the active formulations have received mixed reviews inchemotherapeutic agents are available to oral ingredients in common chemotherapeutic the past due to the instability of stannous fluo-healthcare providers to assist in the control and mouthrinses and dentifrices used in the con- ride (although new, more stable formulationsreduction of supragingival plaque and associ- trol of plaque and gingivitis: are available). Reported side effects includeated gingivitis. These typically take the form of Chlorhexidine (CHX): The antiseptic CHX staining and altered taste.mouth rinses or dentifrices. Other agents avail- is one of the most effective antiplaque/antigin- Triclosan: This is a broad spectrum anti-able for the control and treatment of chronic givitis agents available to clinidans. It is sold in bacterial agent. In the U.S., triclosan (0.03%)periodontitis, such as locally applied antimicro- the U.S. as a prescription mouthrinse at 0.12 is only available in a dentifrice with thebials/antibiotics and systemically administered percent concentration. Most products contain copolymer Gantrez (2.0%), which improvesantimicrobials, are reserved for more aggres- 11 .6 percent alcohol, although products with- its efficacy. With the addition of 0.243 sodiumsive cases. out alcohol are also available. The mechanism fluoride in a silica base, it has demonstrated As noted in Table 1, a valuable quality in of action is related to an alteration of bacterial efficacy in reducing plaque, gingivitis calculusantimicrobial agents is substantiveness, or the adsorption, a reduction in pellicle formation and dental caries. Reductions in plaque and gingivitis ranging from 12 to 59% and 22 to A valuable quality in antimicrobial 250/0, respectively, have been reported.? Tri- closan has been used safely for many years. agents is substantiveness CHEMOTHERAPEUTIC AGENTSability of an agent to remain in an area or site and an alteration of the bacterial cell wall caus- FOR CHRONIC PERIODONTITISand resist being diluted or washed away by gin- ing lysisto occur. A major advantage of CHX is Although many patients will respond togival crevicular fluid or salivary action. In addi- that it is a very substantive agent that brings thorough debridement and self-care thera-tion, a systemically administered sub-antimicro- reductions in plaque biofilm and gingivitis pies such as described above, for patientsbial dose of doxycycline (20 mg) has been ranging from 22 to 61 % and 18 to 44%, who do not improve or for whom their peri-approved by the United States Food and Drug respectively," The disadvantages of CHX are odontal health continues to decline,Administration (FDA) as an adjunctive host teeth staining, alteration of taste and an stronger adjunctive therapies may be neces-modulatory therapy to reduce levels of enzymes increase in calcified deposits. sary. Since the 1980s, locally applied antimi-ami cytokines known to drive the breakdown of Essential Oils: The three essential oils are a crobials/antibiotics (lAAs) have been avail- onnective tissue and bone metabolism mixture of thymol, menthol and eucalyptol able to dental professionals. (See Table 2.)dTanges associated with periodontitis. combined with methyl salicylate. The alcohol content is 21.0 to 26.9%. The mechanism of Ol7HRINSES AND action is related to alteration of the bacterial ;:...;npRICES cell wall. Studies have reported plaque and gin- rinses designed to reduce plaque and givitis reductions ranging from 14 to 56% andgingivitis contain antiseptic agent:s--<:hemical 14 to 39%, respectively," The adverse effect is aantimicrobial agents that are applied topically buming sensation during use with certain for-or subgingiva/ly to mucous membranes, mulations.wounds or intact dermal surfaces to destroy Cetylpyridinium Chloride (CPC): CPC ismicroorganisms, inhibit their reproduction or classified as a quaternary ammonium com-inhibit their metabolism. While most antiseptics pound. The mechanisms of action include: rup-are bactericidal (meaning, kills bacteria), some ture of cell walls; the promotion of cell lysis; Currently, three resorbable, site-specificare bacteriostatic (that is, they inhibit growth decreased cell metabolism; and the ability for locally administered antimicrobial/antibi-and reproduction of bacteria without killing bacteria to attach to tooth surfaces. Studies otics products approved by the FDA for thethem). The most common active ingredients have reported plaque and gingivitis reductions treatment of chronic periodontitis arein mouth rinses are essential oils of dentifrice: of 15% and 24%, respectively!-· Reported side available. They are: Arestin" (OraPharma,chlorhexidine gluconate (CHX-available by effects include staining, increased calculus for- Inc. Warminster, Penn.), minocydine micros-prescription only); cetylpyridinium chloride mation and occasional buming. pheres; AtridoxTM (Tolrnar Inc. Ft. Collins,(CPC) and stannous fluoride. These agents Stannous Fluoride (SnF2): SnF2 products Colo.), a doxycycline gel; and PerioChip" have been evaluated in the laboratory (pre-clin- are available in rinses and dentifrices. Formula- (Dexcel Pharma, Alzenau, Germany), a ically)and in clinical trials for efficacy and safety. tions vary from 0.63% in rinses to 0.045% in chlorhexidine based chip. PerioChip is theJUNE 2010 www.dimensionsofdentalhygiene.com Dimensions OF DENTAL HYGIENE 45
w Chemotherapeutics only antiseptic LAA; it is not an antibiotic. in the periodontal condition after single or mul- OTHER WCALLY APPLIED Patients who have an allergy to the tetracy- tiple applications. PRODUCTS cline class of drugs or who are pregnant While all of the agents were studied in PeriowaveTM (Periowave Dental Technologies, should have PerioChip placed if an LAA is nine-month clinical trials for the improvement Ine. Toronto, Ontario, Canada), currently not indicated. of chronic periodontitis, more recent investi- approved for use in the U.S., is a non-antibi- These agents, used as an adjunct to scaling gations continue to show benefits for high- otic therapy intended to destroy gram nega- and root planing, deliver an antiseptic or antibi- risk patients. For example, Goodson et al tive bacteria without promoting the devel- otic to the base of the periodontal pocket with demonstrated that Arestin ™ significantly opment of bacterial resistance." Used in the the goal of improving pocket depth reductions, reduces periodontal pathogens comprising the treatment of chronic periodontitis, it utilizes clinical attachment level gains and reductions "red complex" (i.e., P gingivalis, T. forsythia and a cold (non-thermal), low-power diode laser in bleeding on probing. The substantivity of T. denticola), compared to scaling and root as the activating light. Indications for use are the agents vary (seven days for chlorhexidine planing alone by one month, particularly in for patients with 4 to 9 mm pockets that glucontate" and doxycycline;" 14 to 21 days smokers." A two-year follow-up of Atridox™ bleed on probing. for minocycllne"). However, all have greater and scaling and root planing in smokers Marketed as a method to treat chronic peri- substantivity than mouth rinses used subgingi- demonstrated sustained improvements in odontitis, Perio Protect" (Perio Protect LLC, SL vally as irrigants. The added benefit of the probing depth reductions and relative attach- Louis, Mo.) relies on a custom-made tray to agents is the slow release of the active ingredi- ment level gains beyond what was achieved deliver a solution (selected by the dentist) to ents at a higher minimal inhibitory concentra- with scaling and root planing alone." These chemically alter the biofilm in the periodontal tion (MIC) level than can be achieved by any findings are important for clinicians who strive pocket and change the pockets microbiologi- other application. The MIC represents the con- to improve the periodontal condition of cal environment to disrupt biofilm growth. In centration of antibiotic required to inhibit patients who do not respond to mechanical November 2009, the American Academy of growth of a planktonic bacterial population. therapy. Recent studies have demonstrated Periodontology (AAP) published a fact sheet on Locally delivered, site-specific agents have a the intensive periodontal therapy with locally its consumer website to educate the public higher and longer substantivity and maintain applied antimicrobials also results in significant about Perio Protect.? The AAP reported that it MIC long enough to significantly reduce the reduction in the overall inflammatory burden, was not aware of any randomized, controlled level of pathogens, leading to improvements with reduced risk for cardiovascular events.6.17 clinical trials published in peer-reviewed sclen- Product !fame! . Active Method of Delivery Mechanism of Action Indications Manufacturer Ingredient Contra indications ARESTIN· Minocycline Loc;ally delivered Contains the antibiotic minocycline, a As an adjunctive therapy to seal- Should not be(minocycline Hel microspheres pack- member of the tetracycline class of ing and root planing procedures used on patients HCI1mg) aged in a specially antibiotics; minocydine exerts its for reduction of pocket depth with known sen- Microspheres designee unit-dose antimicrobial activity by inhibiting pro- and bleeding on probing in sitivitv to cartridge, which is tein synthesis and has been shown to patients with adult periodontitis minocycline or inserted into a car- be effective against the pathogens tetracyclines, inOraPharma children, or in tridge handle to associated with periodontal diseaseInc administer the prod- pregnant or uet into the pocket nursing women , Single patient use; Subgingival controlled-release product For use in the treatment of Should not be syringe suspended composed of a two-syringe mixing sys- chronic adult periodontitis for used in patients in 450 mg of tern; one syringe contains 450 mg of the a gain in clinical attachment, who are hyper- .. ATRIGEL * [poly(DL- ATRIGEL delivery system, which is a bioab- reduction in probing depth, sensitive to Lactide):NMP] sorbable, flowable polymeric formulation and reduction in bleeding on doxycycline or composed of 36.7"10 poly(DL-lactide) dis- probing any other drug solved in 633% N-methyl-2-pyrrolidone; in the tetracy- the second syringe contains doxycycline cline class ~~V·~ hyclate, which is equivalent to 42.5 mg of doxycycline; the constituted product is a pale yellow to yellow viscous liquid with a com:entration of 10% of doxycycline hvdate: upon contact with the crevicular fluid, the liquid product solidifies and then allows for controlled release of the drug for a period of seven days ~ Chlorhexi- Gelatin chip; no spe- Bactericidal: the chlorhexidine mole- Adjunctive to scaling~ and root Should notbe dine glu- dal instrument is cule reacts with the microbial cell sur- planing procedures for reduction used in anyManufactured conate needed for insertion; face, destroys the integrity of the cell of pocket depth in patients with patient who (2.5 mg) standard cotton for- membrane, penetrates in the cell, adult periodontitis; PerioChip has a knownby DexcelPharrna, Dis- ceps are suggested; precipitates the cytoplasm, and the may be used as part of a peri- sensitivity totributed by tissue should be cell dies odontal maintenance program, chlorhexidineMIS Implants driea before the (hip which includes good oral hygieneTechnologies is inserted and scaling and root planing46 Dimensions OF DENTAL HYGIENE www.dimensionsofdentalhygiene.com JUNE 2010
Chemotherapeutics tiftc journals on the efficacy of this therapy. FDA tion and treatment of periodontitis. Treatment dition of patients, but may also have a positive approval relative to this product is for the tray strategies combining the use of mechanical impact on their overall health. Re-evaluation as a device only. therapies and adjunctive chemotherapeutics and constant monitoring of patients is essential In the 1980s it was recognized that al- enable us to better manage both gingivitis and when managing a chronic progressive disease, though bacteria may initiate the periodontal periodontitis. The use of antiseptics, antibiotics and clinicians must recognize that when non- disease process, they were insufficient by them- and host modulatory therapy as adjuncts to surgical therapy is not enough, they must con- selves to cause peridontitis. Research supported brushing, ultrasonics, scaling and root planing sider surgical approaches to manage periodontal the fact that a persons response to the perio- have made non-surgical therapies more pre- diseases. We are fortunate to be practicing in dontal pathogens, known as the host response, dictable, resulting in improvements in plaque an era where we have the tools to treat a wide was key to the development and progression of control, pocket depth reductions, clinical array of patients with varying riskfor the devel- the disease. Elevations in pro-inflammatory attachment levels and bleeding. opment and progression of peridontitis. It is up mediators (such as cytokines, prostanoids and The implementation of intensive periodon- to us to plan treatment strategies that address enzymes known as matrix metalloproteinases) tal therapy may not only improve the oral con- the unique needs of each patient e were driving the disease process, leading to the connective tissue breakdown and bone metab- REFERENCES 1. KepicTj,Oleary TJ,KafrawyAH.Total calculus removal: an attainable objective? Periodontol. 1990; olism changes patho-gnomonic of periodonti- 61:16-20. tis. These findings resulted in the development 2. Ustgarten MA Structure of the microbial flora associated with periodontal health and diseases in m~·n. } Periodontol. 1976;47:1-18. .1N of an FDA-approved host modulatory therapy 3. Cobb CM,Killoy Wj.Microbialcolonization in human periodontal disease: an illustrated tutorial on known as Periostat. This therapy evolved as a selected ultrastructural and ecologicconsiderations. Scan Microsc. 1990;4:675-691. 4. American Academy of Periodontology:AAPguidelines for periodontal therapy.} Periodontol. new use for an old drug, doxycycline, which 2001;72:1624-1628. when used at a sub-antimicrobial dose (20mg) 5. E1wortby Greenman J, Doherty FMet al. Thesubstantivity of a number of oral hygiene products A, determined by the duration of effects on salivary bacteria.} Periodontal. 1996;76;572-576. could inhibit the destructive enzymes and 6. Addy M.Chlorhexidinecornpared with other locallydelivered antimicrobials.j Gin Periodontol. reduce the excessive levels of cytokines associ- 1986;13:957-964. " ated with active disease. 7. t.obene RR.Lobene S, Soparkar PM.The effect of a cetylpyridiniumchloride mouthwash on plaque and gingivitis.}Dent Res. 1977;56:595. When administered at this sub-antimicro- 8. Allen DR,DaviesR, Bradshaw B et al. Efficacy a mouth rinse containing 0.05% cetylpyridinium of bial dose, doxycycline does not cause the chloride for the control of plaque and gingivitis:a six-month study in adults. Compend Contin Educ Dent 1998;19:20·26. long-term side effects seen with high doses 9. Volpe AR.Petrone ME,DeVizioW et al. A review of plaque, -gingiVitis, calculus and caries clinicalefficacy with a dentifrice containingtriclosan and PVM/MA Copolymer.} Clin Dent 1993;4:31-41. of antibiotics such as gastrointestinal upset, 10. CubellsAB,Dalrnau LB,Petrone MEet al. The effect of a tritlosan111opolymer/flu0ride entifrice on, d the overgrowth of yeast and the de- plaque formation and gingivitis:a six-month study.} Gin Dent 1991;2:63-69. velopment of bacterial resistance. Periostat 11. Jeffcoat MK,Bray KS,CiancioSGet al. Adjunctive use of a a subgingivalcontrolled-release chlorhexidine chip reduces probing depth and improves attachment level compared with scalingand was tested in multiple randomized double root planing along.} PeriodontoI1998;69:989-997. blind placebo controlled clinical trials and 12 StollerNH,johnson LR,Trapnell S et al. The pharrnacokinetic profile of a biodegradable controlled release deliverysystem containing doxycyclinecompared to ~emically delivered doxycyclinein gingival found to be an effective adjunct to scaiing crevicularfluid, saliva,and serum.} Periodontal. 1998;69:1085-91. - and root planing, contributing to significant 13. Christersson LA. TISSUeesponse and release of minocycline after subgingivaldeposition by use of a r resorbable polymer. Warminster,Pa: OraPharma Ine; 1988. improvements in probing depth reductions, 14. Goodson jM, GunsolleyjC, GrossiSGet al, MinocyclineHCImicrospheres reduce red-complex bacteria clinical attachment level gains, and reduc- in periodontal disease therapv j Periodontol. 2007;78:1568-79. . 15. Machion L, Andia DC, Leeio Get al, locally delivered doxvcvclineas an adjunctive therapy to SEaling tions in bleeding on probing with no adverse and root planing in the treatment of smokers: a two-year follow-up.} Periodontol. 2006 Apr,77(4):606-13. effects.2o It has been shown to boost the 16. OAiutoF, Parkar M, Nibali Let al. Periodontal infections cause changes in traditional and novel cardiovascular riskfactors: results from a randomized controlled clinicaltrial. Am Heart j. 2006 May; effects of locally applied antimicrobials such 151(5):977-84. as Atridox." Recent clinical studies have sup- 17. Tonetti MS,DAiuto1", ibaliLet al. Treatm~nt of periodontitis and endothelial function. N Engl} Med. N 2007 Mar 1;356(9):911-20. ported its use in high-risk patients who are 18. http://www.periOvave.com.AccessedApriI16.2010. more difficult to manage, such as smokers," 19. http://www.perioprotectcorn/whatls.asp. AccessedApril16,2010 .. people with diabetes-> and women with 20. CiancioS,AshleyR.Safetyand efficacyof sub-antimicrobial-dose doxycyclinetherapy in patients with adult periodontitis. Adv. Dent Res. 1998 NOV;12(2):27-31. osteoporosis/ osteopenia, 24 as well as those 21. Novak MJ,Dawson DR3rd, Magnusson I et al. Combining host modulatiori and topical antimicroBial at risk for cardiovascular disease.2S It is avail- therapy in the management of moderate to severe periodontitis: a randomized multicenter trial. } Periodontol. 2008jan;79(1):3341. able in a generic form by prescription only 22 Preshaw PM,HeftiAF,Bradshaw MHet at. Adjunctivesubantimicrobial dose doxycyclinein smokers and should be used for a minimum of three and non-smokers with chronic periodontitis.} Gin Periodontol. 2005 jun;32(6):61<F6. 23. Martorellide LimaAF,CUryCCet al. Jherapy with adjunctive doxyt;:Ycline deliverv in patients with local months. type 1 diabetes mellitus and periodontitis.} Gin Periodontol. 2004 Aug;31(8):648-53. 24. Reinhardt RA,Stoner JA,Golub LMet al. Efficac;yf sub-antimicrobial dose doxycyclinein post- o menopausal women: clinicaloutcomes.] Gin Periodontol. 2007 Sep;34(9):768-75. CONCLUSION 29. Brown Dl, Desai KK, VakiliSA.El(II. Oinicaland Biochemical Resultsof the Metalloproteinase Dental professionals have come a long way in Inhibition with Subantimicrobial Doses of 00xycydine to Prevent Acute Coronary Svndromes (MIDAS) Pilot Trial.Afterioscfer Thromb Va¥, ~iol. 2004;24:733·738. developing strategies that help in the preven-48 Dimensions OF DENTAL HYGIENE www.dimensionsotdentalhygiene.com JUNE 2010
Dent Clin N Am 49 (2005) 611–636 Nonsurgical Approaches for the Treatment of Periodontal Diseases Maria Emanuel Ryan, DDS, PhD Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, State University of New York, South Campus, Stony Brook, NY 11794-8702, USA Periodontal diseases are the most common dental conditions. Gingivitisis gingival inﬂammation associated with plaque and calculus accumulation.Gingivitis may or may not progress to more advanced forms of the diseaseknown as periodontitis, which is associated with alveolar bone loss anddiagnosed by increases in probing depths, loss of clinical attachment, andradiographic evidence of bone loss. Periodontitis is chronic and progressiveand there is no known cure. Periodontal disease, however, is treatable andmay even be prevented. Risk for periodontal disease and lack of treatmentof periodontitis have been linked to the systemic health of the patient.Periodontitis is a complex interaction between an infection and a susceptiblehost. Periodontal disease is initiated by an infection; however, it appears tobehave not like a classic infection but more like an opportunistic infection.As a bioﬁlm-mediated disease, periodontal disease is inherently diﬃcult totreat. One of the greatest challenges in treatment arises from the fact thatthere is no way to eliminate bacteria from the oral cavity, so bacteria willalways be present in the periodontal milieu. In addition, the bacteria withinthe bioﬁlm are more resistant to antimicrobial agents and variouscomponents of the host response. When certain, more virulent species existin an environment that allows them to be present in greater proportions,there is the opportunity for periodontal destruction to occur. Although it isapparent that plaque is essential for the development of the disease, the The author is a consultant, serves on a number of advisory boards, and is named on pa-tents as an inventor of therapeutic applications of tetracyclines discussed in this article.These patents have been fully assigned to the research foundation of Stony BrookUniversity, State University of New York, Stony Brook, New York, and have been licensedexclusively to CollaGenex Pharmaceuticals, Newtown, Pennsylvania. E-mail address: firstname.lastname@example.org/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.doi:10.1016/j.cden.2005.03.010 dental.theclinics.com
612 RYANseverity and pattern of the disease are not explained solely by the amount ofplaque present. In the 1980s, research began to focus on the relationship between thebacteria in the oral cavity and the response of the individual challenged bythese bacteria or the bacterial host . As a result of multiple studies, it wasrecognized that although there is evidence that speciﬁc bacterial pathogensinitiate the pathogenesis of periodontal disease, the host response to thesepathogens is equally if not more important in mediating connective tissuebreakdown including bone loss. It has become clear that certain host-derived enzymes known as the matrix metalloproteinases (MMPs) andchanges in bone resorptive osteoclast cell activity driven by factors known ascytokines and other inﬂammatory mediators such as prostanoids cause mostof the tissue destruction in the periodontium (Fig. 1) .Risk factors It has been recognized that the severity of periodontal disease, its rate ofprogression, and its response to therapy vary from patient to patient.Bacteria are essential for the initiation of the disease but insuﬃcient bythemselves to cause the disease. The host must be susceptible, and it is thepatient’s risk factors that determine susceptibility to the disease. Risk factorsare patient characteristics associated with the development of a disease. Genetic Risk Factors Antibody PMNs Cytokines Antigens Host Connective Clinical Microbial Immune- Prostanoids tissue and signs of challenge Inflammatory LPS bone disease Response metabolism MMPs Other Virulence Factors Environmental & Acquired Risk Factors Tissue breakdown products and ecological changesFig. 1. The pathogenesis of periodontitis. LPS, lipopolysaccharide; PMNs, polymorphonuclearneutrophils. (Adapted from Page RC, Kornman KS. The pathogenesis of human periodontitis:an introduction. Periodontol 2000 1997;14:10; with permission.)
NONSURGICAL APPROACHES 613Risk assessment in the patient with periodontitis There are a number of environmental and acquired risk factors that playa major role in the host response and can increase a patient’s susceptibilityto periodontitis. Listed in Box 1 [3–5] are the risk factors that should be Box 1. Risk assessment for periodontitis 1. Heredity as determined by genetic testing and family history 2. Smoking including frequency, current use, and history 3. Hormonal variations such as those seen in a. pregnancy in which there are increased levels of estradiol and progesterone that may change the environment and permit the virulent organisms to become more destructive b. menopause in which the reductions in estrogen levels lead to osteopenia and eventually osteoporosis 4. Systemic diseases such as a. diabetes (the duration and level of control are important) b. osteoporosis c. immune system disorders such as HIV d. hematologic disorders such as neutropenias e. connective tissue disorders such as Marfan’s and Ehlers-Danlos syndromes 5. Stress as reported by the patient 6. Nutritional deﬁciencies that may require a dietary analysis 7. Medications such as a. calcium channel blockers b. immunomodulatory agents c. anticonvulsants d. those known to cause dry mouth or xerostomia 8. Faulty dentistry such as overhangs and subgingival margins 9. Excessive occlusal loads 10. Poor oral hygiene resulting in excessive plaque and calculus 11. History of periodontal disease 12. Additional risk factors including hyperlipidemia and possibly arthritis Data from Refs. [3–5].
614 RYANassessed because they can aﬀect the onset, rate of progression, and severityof periodontal disease and response to therapy. It is important to document and determine the patient’s risk and toconvey to the patient that these risk factors can be more than additive. Thevalue of risk assessment is that it can help the practitioner to establish anaccurate diagnosis, provide an optimal treatment plan, and determineappropriate maintenance programs. Risk assessment may help to explainvariability in treatment responses. In patients with multiple risk factors, thepractitioner may proceed with caution with regard to invasive surgicalprocedures and may aggressively use pharmacologic adjuncts such asantimicrobials and host modulatory therapy in addition to mechanicaltherapy. When considering a risk-based approach to therapy, there is lesswatching and waiting to see what will happen and more frequent activetreatment and maintenance therapy. It is also important to note that riskassessment is an ongoing process because a patient’s risk changesthroughout his or her life.Risk modiﬁcation Some of these risk factors can be modiﬁed to reduce a patient’ssusceptibility to periodontitis. In addition to more frequent dental visits,including active treatment and maintenance visits, risk reduction may includethe strategies listed in Box 2. The ﬁeld of ‘‘perioceutics,’’ or the use ofpharmacologic agents speciﬁcally developed to better manage periodontitis,is emerging to aid in the management of susceptible patients who developperiodontal disease. When patients are unable to eﬀectively reduceriskdsuch as the risk presented by the patient’s genetics, smokers who areunable to kick the habit, patients who are unable to maintain adequate oralhygiene, the inability to reduce stress, diabetics who are poorly controlleddespite the physician’s best eﬀorts, and the inability or unwillingness of thephysician to alter medicationsdpatients may require the use of perioceutics.Perioceutics includes antimicrobial therapies that can be used to addresschanges in the microﬂora and host modulatory therapy that can be used toaddress a host response consisting of excessive levels of enzymes, cytokines,and prostanoids and excessive osteoclast function that may be related tocertain risk factors.The antimicrobial approach The antimicrobial approach to periodontal therapy has been used formany years, recognizing that the prevalence and severity of these diseasescan be reduced by mechanical plaque removal or by the use of a variety ofsystemic or topically applied antimicrobial agents aimed at inhibitingpathogenic bacteria.
NONSURGICAL APPROACHES 615 Box 2. Risk reduction strategies 1. More frequent visits for those with a genetic predisposition and the use of perioceutics (use of pharmacotherapeutics for the management of periodontitis) 2. Smoking cessation using one or more of the six approved regimens; these regimens rarely are successful as sole therapies (multiple forms of therapy often are used in combination with counseling to achieve success) 3. Hormonal variations such as those seen in a. pregnancy require good oral care before pregnancy to prevent complications during pregnancy; treatment of women during pregnancy may be necessary to prevent adverse pregnancy outcomes b. menopause may require hormonal supplements, calcium, and other medications and supplements prescribed by the physician to prevent osteopenia 4. Systemic diseases that require consultation with the physician include a. diabetes (for improved glycemic control) b. osteoporosis (requiring calcium supplements, bisphosphonates) c. immune system and hematologic disorders d. connective tissue disorders 5. Stress management; possible referral to a psychologist or psychiatrist 6. Nutritional supplementation; possible referral to a nutritionist 7. Medications can be changed in consultation with the physician 8. Corrective dentistry 9. Occlusal adjustments 10. Improved oral hygieneMechanical therapy Brushing and ﬂossing, as part of an oral hygiene routine, is the ﬁrst-lineapproach to microbial reduction. The American Dental Association (ADA)recommends brushing for 2 minutes twice a day and ﬂossing once a day.Many patients also use interproximal brushes, stimudents, and othermechanical aids to reduce plaque levels. Proper oral hygiene can eﬀectivelyreduce gingivitis and aid in the treatment of periodontitis. Oral hygieneinstructions should be given to all patients undergoing periodontal therapy.The unfortunate reality is that despite clinicians’ best eﬀorts, many patients
616 RYANdo not spend a suﬃcient amount of time brushing and most cannot or will notﬂoss on a daily basis . These circumstances result in a population in whichmore than 50% of adults have gingivitis . Studies have demonstrated thatpowered toothbrushes, particularly those that work with rotation oscillationaction, are safe and often more eﬀective than manual toothbrushes atreducing plaque and gingivitis in the long- and short-term . Poweredbrushes with timers help patients to comply with the recommended30 seconds per quadrant of toothbrushing twice a day. Despite attempts toencourage plaque removal solely by mechanical means, adjuncts to existinghome care routines have been developed to aid in the removal of plaque. Tooth scaling by the dental care provider is also a key component intreating and preventing gingivitis. Aggressive subgingival debridementincludes scaling and root planing (SRP) by manual instrumentation orwith sonic or ultrasonic scalers. SRP has become the ‘‘gold standard’’nonsurgical treatment of periodontitis, with multiple clinical studiesdemonstrating that it eﬀectively reduces the microbial load and leads toreductions in bleeding on probing and probing depths and allows for gainsin clinical attachment. A review of nonsurgical mechanical pocket therapyby Cobb  reveals mean probing depth reductions and clinical attachmentlevel gains of 1.29 mm and 0.55 mm, respectively, for initial probing depthsof 4 to 6 mm before treatment and 2.16 mm and 1.19 mm, respectively, forinitial probing depths of O6 mm before treatment. Conventional non-surgical periodontal therapy involves performing SRP in single or multiplequadrants or sextants per visit and is usually completed in 2 to 6 weeks. Thenew concept of full-mouth disinfection for the prevention of reinfectionfrom bacterial reservoirs has recently been introduced and shows promisingresults but requires further investigation . In addition, the use of laserswithin the periodontal pocket is being investigated and may emerge as a newtechnical modality for nonsurgical therapy in the near future . Mechanical removal of plaque and calculus (nonsurgical and withsurgical access) is time-consuming, operator and patient dependent, anddiﬃcult to master . Although mechanical and surgical interventionscontinue to be the most widely used methods of controlling diseaseprogression, instrumentation inevitably leaves behind signiﬁcant numbers ofmicroorganisms, including putative pathogens. Recolonization of thesepathogens can occur within 60 days of SRP, resulting in the need for regularmaintenance visits. The need for chemotherapeutic agents as adjuncts tomechanical and surgical debridement is compelling.Antiseptics Antiseptics can be used topically or subgingivally. They are agents thatkill oral microorganisms that cause gingivitis, periodontitis, and caries.Antiseptics are not antibiotics or disinfectants and do not cause bacterialresistance.
NONSURGICAL APPROACHES 617Rinses and irrigation Antiseptic mouthrinses have been used to aid in controlling plaque build-up. They have been used to complement, not replace mechanical therapy.Two clinically proven ADA-accepted antiseptic mouthrinses are Peridex(Zila, Inc., Phoenix, Arizona; chlorhexidine gluconate) and ListerineAntiseptic Mouthrinse (four essential oils; Pﬁzer, Inc., Morris Plains, NewJersey), studied in clinical trials of at least 6 months’ duration. Both of theserinses have demonstrated an extremely broad spectrum of kill in vitro andin vivo. In a number of randomized, double-blinded, controlled 6-monthclinical studies, these two agents demonstrated comparable eﬃcacy forimproving reductions in plaque and gingivitis compared with brushing alone[13,14]. Clinical studies have demonstrated additional beneﬁts with the useof these antiseptic mouthrinses, such as control of oral malodor [15,16],enhancement of the beneﬁts of oral irrigation [17,18], improvement in thegingival health around dental implants , reductions in plaque andgingivitis in orthodontic patients , reductions in bacteria in saliva anddental aerosols when used preprocedurally , and support of early healingafter gingival ﬂap surgery [22,23].Chlorhexidine gluconate. Chlorhexidine gluconate is available at 0.12% inthe United States and has strong substantivity . Chlorhexidine isavailable only by prescription and is partly to fully covered by someprescription plans. Chorhexidine can stain teeth, the tongue, and aestheticrestorations. It can promote supragingival calculus formation and may altertaste perception . When prescribed, it is recommended that patients rinsetwice a day for 30 seconds with 15 mL after brushing and ﬂossing and aftertoothpaste has been completely rinsed out of the mouth.Listerine. Listerine is available over-the-counter and is composed of a ﬁxedcombination of essential oils: thymol (0.064%), eucalyptol (0.092%), methylsalicylate (0.060%), and menthol (0.042%). Some patients complain of atransient tingling sensation. Listerine’s comparable eﬃcacy in reducinginterproximal plaque and gingivitis to the ‘‘gold standard’’ of ﬂossing wasdemonstrated in a recent study in which 611 subjects rinsed twice daily orﬂossed once daily as an adjunct to brushing for 6 months [26,27]. In addition,the incremental beneﬁt (with regard to plaque and gingivitis reduction) ofListerine in patients who were already brushing and ﬂossing was demon-strated in a brush, ﬂoss, and rinse study . The recommendation for use isrinse twice a day for 30 seconds with 20 mL after brushing and ﬂossing.ToothpasteTriclosan. Triclosan is present in a toothpaste (Colgate Total; ColgatePalmolive, Piscataway, New Jersey) currently available in the United States.Triclosan is a substantive antibacterial agent that adheres to the oral mucosa,hard, and soft tissues for up to 12 hours. Colgate Total is approved by the
618 RYANFood and Drug Administration (FDA) and accepted by the ADA fortreatment of gingivitis, plaque, caries, calculus, and oral malodor. Placebo-controlled studies in smokers  and in subjects with recurrent periodontitis suggest that an oral hygiene regimen including a triclosan/copolymerdentriﬁce may sustain the short-term eﬀect of nonsurgical therapy in smokersand improve on healing after nonsurgical treatment of recurrent peri-odontitis as measured by improvements in gingival inﬂammation, probingdepths, and probing attachment levels. Triclosan in vitro has anti-inﬂammatory eﬀects, inhibiting cytokine-stimulated (interleukin 1b andtumor necrosis factor a) production of prostanoids (prostaglandin E2) frommonocytes, reducing the activity of the enzyme cyclooxygenase 2 responsiblefor the production of prostanoids in culture, and inhibiting bone resorptionin a parathyroid hormone–induced release of calcium from bone cultures.Locally applied antisepticPeriochip. Periochip (Dexcel Pharmaceuticals, Israel) is an orange-brown,biodegradable, rectangular chip rounded at one end that has an activeingredient of chlorhexidine gluconate (2.5 mg) that is released into thepocket over a period of 7 to 10 days. It has been found to suppress thepocket ﬂora for up to 11 weeks post application . In a 9-monthrandomized, blinded, and controlled parallel arm study, Periochip, as anadjunct to SRP, signiﬁcantly reduced probing depths and maintainedclinical attachment levels relative to baseline at 9 months compared withcontrols with repeated application of the Periochip up to three applicationsper site over 9 months . Periochip eﬀects on alveolar bone weredemonstrated in a 9-month randomized, blinded, and placebo-controlledstudy. After 9 months of adjunctive treatment with Periochip, no sitesexhibited bone loss and 25% of the sites experienced bone gain as measuredthrough subtraction radiography . In contrast, 15% of periodontal sitestreated with SRP alone experienced bone loss. Periochip has a documentedsafety proﬁle and does not cause any visible staining. The most frequentlyobserved adverse event in the clinical trials was mild to moderate toothache,which often resolved spontaneously and required no further treatment. Thisadverse event occurred less frequently with subsequent Periochip place-ments. Periochip is the only locally applied nonantibiotic antimicrobialapproved by the FDA as an adjunct to SRP procedures for the reduction ofprobing pocket depth or as part of a routine periodontal maintenanceprogram. The recommendation for use adjunctive to SRP involves isolationof the periodontal pocket of 5 mm or more, drying the surrounding area,and grasping the Periochip with a forceps and inserting the chip, curvedend ﬁrst, into the pocket to its maximum depth. The chip can be maneu-vered further into position with a plastic instrument. One site can be treatedper chip.
NONSURGICAL APPROACHES 619AntibioticsLocally applied antimicrobials To have a therapeutic eﬀect on the microﬂora, antimicrobial agents mustreach adequate concentrations to kill or inhibit the growth of targetorganisms. The drug of choice has to reach the site where the organisms exist,stay there long enough to get the job done, and not cause harm. Mouthrinsesdo not reach the depths of periodontal pockets, whereas irrigation can deliverdrugs to the base of the pocket. Because the gingival crevicular ﬂuid (GCF)in the pocket is replaced about every 90 seconds, the duration of exposureduring subgingival irrigation is short, and topically applied subgingivalagents are rapidly washed out. With regard to the systemic administration ofantibiotics to patients with periodontitis, early research suggested thatdoxycycline administered systemically [35,36] was highly concentrated in theGCF at levels 5 to 10 times greater than found in serum. Furthermore,tetracyclines show substantivity because they bind to the tooth structure andare slowly released as still-active agents. Even this supposed hyperconcen-tration of the drug in the GCF resulted in a level of antibiotic to which manyorganisms were not susceptible. More recent work has challenged earlierﬁndings of hyperconcentration of tetracyclines in the GCF. In the 2 hoursafter the administration of a single dose of tetracycline (250 mg), minocycline(100 mg), or doxycycline (100 mg), the concentration of these tetracyclineswas found to be highest in the plasma, intermediate in the GCF (doxycyclineachieving the highest levels), and lowest in the saliva . Furtherexperimentation may be required to resolve this issue because there wasa great deal of variability in the average GCF concentrations (0–8 mg/mL) inthis study, and steady-state levels of the drug were never achieved. To addressthe issue of reaching adequate concentrations at the base of the pocketwith adequate duration, controlled local delivery of antimicrobials wasdeveloped (Table 1). Dental research has provided us with a better understanding of themicrobial etiology and the nature of periodontitis. Periodontitis, initiated bybacteria, frequently appears in localized areas in the patient’s mouth or isconﬁned to localized areas by treatment. These infected localized areas lendthemselves well to treatment with a controlled local delivery system using anantimicrobial . Antimicrobial agents may be applied directly to thepocket, thereby eliminating many of the adverse side eﬀects associated withTable 1Periodontal antimicrobial delivery systems Mouthrinse or Local Systemic ControlledObjective toothpaste irrigation delivery deliveryReach the pocket O4 mm Poor Good Good ExcellentAdequate concentration Poor Good Fair ExcellentAdequate duration Poor Poor Fair Good
620 RYANsystemic delivery of antibiotics. Nonresorbable and resorbable intrapocketdelivery systems have been used. There is evidence that local delivery ofsustained-release antimicrobials may lead to improvements in periodontalhealth, although a few side eﬀects such as transient discomfort, erythema,recession, transient resistance, and allergy have been reported. Oral can-didiasis has been reported in a small number of cases with local tetracyclinedelivery. Systems have been developed for the release of all three commerciallyavailable tetracyclines at high doses and at a regular rate over a 10- to 14-dayperiod. The ﬁrst such FDA-approved system, Actisite, was developed by Dr.Max Goodson in 1983 . Actisite consisted of a nonresorbable polymerﬁber of ethyl vinyl acetate, 25% saturated with tetracycline hydrochloride.Use of this product resulted in substantially higher doses of tetracycline in thepocket (1590 mg/mL in the GCF and 43 mg/mL in the tissue) than could beachieved by systemic dosing (2–8 mg/mL). A local concentration of 30 mg/mLeliminates most pathogenic bacteria associated with periodontal diseases.When using locally applied antimicrobials, the area being treated is saturatedwith doses of the therapeutic agent that can be sustained for prolongedperiods. Despite the high doses of drug that are achieved locally, serum levelsof the drug do not exceed 0.1 mg/mL. The use of a singly applied tetracyclineﬁber as an adjunct to SRP proved to be more eﬀective than scaling alone atreducing bleeding on probing, pocket depth, and achieving attachment gainas early as 60 days after placement, with additional improvements at 6months. At 6 months after a single application of Actisite, the respectiveaverage results for SRP plus tetracycline ﬁber therapy versus SRP only were1.81 mm versus 1.08 mm for pocket depth, 1.56 mm versus 1.08 mm forattachment gain, and 63% versus 50% for bleeding on probing reductions. Subsequent studies concluded that SRP combined with full-mouthActisite therapy versus SRP alone resulted in increased bone density (þ2.43computer-assisted densitometric image analysis [CADIA] versus ÿ2.13CADIA) and increased alveolar bone height (þ0.24 mm versus ÿ0.29 mm)at 6 months after therapy . Despite its demonstrated eﬃcacy, this productis no longer marketed to the dental community. Actisite was diﬃcult to use,requiring considerable operator skill, and because it was not resorbed,a second visit had to be scheduled to remove it. In attempts to improve on easeof placement of local antimicrobials into the pocket and to obviate the needfor a second visit to remove the product, bioabsorbable delivery systems weredeveloped.Atridox. The second FDA-approved locally delivered tetracycline to bedeveloped was Atridox (Atrix Laboratories, Inc., Fort Collins, Colorado),a 10% formulation of doxycycline in a bioabsorbable, ‘‘ﬂowable’’ poly-DL-lactide and N-methyl-2-pyrrolidone mixture delivery system that allows forcontrolled release over 7 days. This system is supplied in two preﬁlledsyringes to be mixed at chairside and applied subgingivally to the base of the
NONSURGICAL APPROACHES 621pocket through a cannula. The ﬂowable polymer gel of Atridox ﬁlls andconforms to pocket morphology, then solidiﬁes to a waxlike substance aftercontact with GCF. Signiﬁcant reductions (60%) in anaerobic pathogens aresustained for up to 6 months after placement of Atridox . In subjectswith chronic adult periodontitis, the application of this doxycycline gel atbaseline and 4 months later resulted in reductions in probing depths (1.3mm) and gains in clinical attachment (0.8 mm) equivalent to SRP alone at 9months after baseline . An important ﬁnding of these studies was thatfor the Atridox treatment group, smoking status did not seem to aﬀect theoutcome of clinical parameters such as probing depth reductions and clinicalattachment level gains, whereas smokers and even former smokers did notrespond as well to mechanical therapy alone . A recent study supportsthese ﬁndings, indicating that locally applied Atridox improves the healingfollowing nonsurgical therapy in smokers . The side eﬀect proﬁle wasequivalent to placebo. Despite the results of the initial phase III studies, it islikely that this agent will be used not as a monotherapy for the managementof periodontal disease but as an adjunct to mechanical therapy. Removal of the oﬀending plaque and calculus deposits by SRP hasproved to be eﬀective. Disruption of the bioﬁlm improves on the eﬃcacy ofantimicrobial agents. Phase IV studies conducted to support improvedoutcomes by using Atridox as an adjunct to scaling have demonstratedincremental beneﬁts of use . One arm of a 6-month study involvedinitiating therapy with ultrasonic scaling combined with Atridox, followedat 3 months by SRP alone in those sites with pocket depths that remainedO5 mm. Results showed that this approach was at least as eﬀective inimproving probing depths and clinical attachment levels as the second armof the study that involved SRP alone followed at 3 months by ultrasonicscaling and Atridox in those sites with pocket depths that remained O5 mm.The main diﬀerence between the two arms of this study was that theresponse was far more dramatic at 3 months for the combination therapythan the SRP alone, but the addition of either therapy at the 3-monthinterval allowed for equivalence to be achieved by 6 months. Atridox is the only resorbable site-speciﬁc locally applied antibioticproven to promote clinical attachment gains and reduce pocket depths,bleeding on probing, and levels of pathogenic bacteria. Clinical use of theproduct involves twisting and locking together two syringesdone witha purple stripe containing Atrigel and the second containing 50 mg ofdoxycycline hyclatedand pushing the contents of one into the other, backand forth, mixing for about 90 seconds (or about 100 times). Aftercompletion of mixing, all contents are placed into the syringe with thepurple stripe and a blunt metal or plastic cannula is screwed on to the endand bent to resemble a periodontal probe. The cannula tip is placed into thebase of the pocket and the Atridox is expressed, withdrawing the syringe asthe pocket begins to ﬁll. When the pocket is ﬁlled, the product is separatedfrom the cannula by pressing the tip up against the tooth. A wet plastic
622 RYANinstrument may be used to tap the product lightly into the pocket if it isdesirable to place additional Atridox into the site. A single syringe ofAtridox can be used to treat multiple sites (approximately 8–12), the numberof sites depending on the severity of the disease.Arestin. With regard to minocycline, there is a non–FDA-cleared ointmentproduct of 2% (wt/wt) minocycline hydrochloride known as Dentamycine(Wyeth, United Kingdom) or PerioCline (Sunstar, Japan) and marketed ina number of countries. In a four-center double-blinded randomized trialconducted in Belgium, the minocycline ointment was applied once every 2weeks for four applications due to insuﬃcient sustained-release properties.Probing depth reductions were signiﬁcantly greater in the SRP plusminocycline group versus SRP alone, whereas there was only a trendtoward improvement in clinical attachment levels and bleeding indices in theSRP plus minocycline treatment group . In a long-term 15-month study,after placement of the gel subgingivally at baseline, at 2 weeks, and at 1, 3, 6,9, and 12 months, results showed a statistically signiﬁcant improvement forall clinical and microbiologic parameters for adjunctive minocyclineointment . A minocycline microsphere system (Arestin; Johnson and Johnson, NewBrunswick, New Jersey) has been approved by the FDA. The Arestinmicrospheres are bioadhesive, bioresorbable, allow for sustained release, andare administered as a powder with a proven safety record. Arestin is indicatedas an adjunct to SRP procedures for reduction of pocket depth in patientswith adult periodontitis. Arestin may be used as part of a periodontalmaintenance program, which includes good oral hygiene and SRP. Insubjects with chronic adult periodontitis, the application of minocyclinemicrospheres three times over the course of 9 months (at baseline and at 3 and6 months) resulted in an average of 0.25 mm improvement above averageprobing depth reductions seen with SRP alone at month 9 . When the dataare stratiﬁed in accordance with severity of baseline probing depths, there are20% improvements in mild sites, 40% in moderately diseased sites, and 100%in severely diseased sites compared with SRP alone. SRP plus Arestin resultedin a greater percentage of pockets showing a change of pocket depth R2 mmand R3 mm compared with SRP alone at 9 months. The data also show thatfor pockets of 5 to 7 mm at baseline, greater reductions in pocket depthsoccurred in pockets that were deeper at baseline. In smokers, the meanreduction in pocket depths at 9 months was less in all treatment groups thanin nonsmokers; however, SRP plus Arestin produced signiﬁcantly greaterpocket depth reductions than SRP alone at 6 and 9 months . Arestin is delivered to sites of 5 mm or greater through a cartridge(containing 1 mg of minocycline hydrochloride) attached to a handle. Thetip is removed from the cartridge and placed subgingivally, and the handle isdepressed to express the Arestin from the cartridge. A single site can betreated with a single cartridge.
NONSURGICAL APPROACHES 623Periochip. For information on Periochip, see the section ‘‘Locally appliedantiseptic.’’Systemic antimicrobials For the most part, systemic antimicrobial therapy has been reserved foradvanced cases of periodontitis: (1) for sites that have not responded asexpected to debridement with or without locally applied chemotherapeuticagents and/or host modulatory agents, and (2) for patients diagnosed withaggressive forms of periodontitis that demonstrate progressive periodontaldestruction. Systemic antibiotics may be recommended as adjuncts toconventional mechanical therapy, but strong evidence for their use as amonotherapy has not been developed. There appears to be a consensus thatsystemic antimicrobial therapy should be reserved for situations that cannotbe managed with mechanical therapy alone (with or without locally appliedantimicrobials or antiseptics), such as severe or acute infections, early-onsetperiodontal diseases, aggressive types of periodontitis, and recurrent orrefractory cases . For these special situations, randomized double-blindedclinical trials and longitudinal assessments of patients indicate that systemicantimicrobials may be useful in slowing disease progression . Acutenecrotizing ulcerative gingivitis can be cured with metronidazole , andaggressive adolescent periodontitis associated with Actinobacillus actino-mycetemcomitans can be controlled or eradicated with metronidazole-amoxicillin combination therapy . Systemic antibiotic therapy has the advantage of simple, easy adminis-tration of a drug or combination of drugs to multiple periodontal sites andextradental oral sites that may harbor periodontal pathogens. Thedisadvantages include uncertain patient compliance, the inability of thedrugs to achieve adequate concentration at the site of infection, increased riskof adverse drug reactions, the potential for the selection of multipleantibiotic-resistant organisms, and the overgrowth of opportunistic patho-gens . Microbial analysis can be used to determine the speciﬁcantimicrobial susceptibility pattern of the suspected pathogens, can help tochoose the appropriate antibiotics, and may be followed-up with additionaltesting to verify the elimination or suppression of the putative pathogens. Forsome clinicians, microbial analysis may be reserved for cases that arerefractory to an initial course of antimicrobial therapy. Common antibiotictherapies for the treatment of periodontitis include metronidazole, 500 mg,three times a day for 8 days; clindamycin, 300 mg, three times a day for8 days; doxycycline or minocycline, 100 to 200 mg, every day for 21 days;ciproﬂoxacin, 500 mg, twice a day for 8 days; azithromycin, 500 mg, everyday for 4 to 7 days; metronidazole and amoxicillin, 250 mg of each drug, threetimes a day for 8 days; and metronidazole and ciproﬂoxacin, 500 mg of eachdrug, twice a day for 8 days . For adult patients with acute periodontalabscesses, an antibiotic regimen as an adjunct to incision and drainage isamoxicillin (1 g loading dose followed by 500 mg, three times a day for
624 RYAN3 days), with patient follow-up re-evaluation. For patients with allergies tob-lactam drugs, antibiotic regimens include azithromycin (1 g loading dosefollowed by 500 mg, every day for 2 days) or clindamycin (600 mg loadingdose followed by 300 mg, four times a day for 3 days).The host modulatory approach Host modulation is a new term that has been incorporated into dentaljargon and has not been well deﬁned. The deﬁnition of host from a medicaldictionary reads ‘‘the organism from which a parasite obtains itsnourishment or in the transplantation of tissue, the individual who receivesthe graft’’ . The deﬁnition for the term modulation is ‘‘the alteration offunction or status of something in response to a stimulus or an alteredchemical or physical environment’’ . In diseases of the periodontium thatare initiated by bacteria, it is clear that the host is the individual whoharbors these pathogens; however, it was not clear for many years that itwas possible to modulate the host response to these pathogens. Hostmodulation with chemotherapeutics or drugs is an exciting new adjunctivetherapeutic option for the management of periodontal diseases. The conceptof host modulation is fairly new to the ﬁeld of dentistry but is universallyunderstood by most physicians who routinely apply the principals of hostmodulation to the management of a number of chronic progressivedisorders including arthritis and osteoporosis. A number of host modulatory agents have been investigated in clinicaltrials for their potential use as adjuncts to mechanical nonsurgicalperiodontal therapy. These agents have included the systemic (ﬂurbiprofen)and topical (ketoprofen) use of nonsteroidal anti-inﬂammatory drugs, thesystemic use of subantimicrobial-dose doxycycline (SDD; Periostat [Colla-Genex Pharmaceuticals, Newtown, Pennsylvania]), and the systemic use ofbisphosphonates (Fosamax). The only systemic host modulatory agentapproved by the FDA for adjunctive use in conjunction with nonsurgicalperiodontal procedures is Periostat. The points of intervention of theseagents in the host response can be seen in Fig. 2. In addition, a number oflocal host modulatory agents have been investigated in clinical trials fortheir potential use as adjuncts to surgical procedures not only to improve onwound healing but also to stimulate regeneration of lost bone, periodontalligament, and cementum, restoring the complete periodontal attachmentapparatus. These agents have included enamel matrix proteins (Emdogain),bone morphogenetic proteins 2 and 7, growth factors (platelet-derivedgrowth factor and insulin-like growth factor), and tetracyclines. The initiallocal host modulatory agent approved by the FDA for adjunctive use duringsurgery was Emdogain; platelet-derived growth factor combined witha resorbable synthetic bone matrix (GEM 21S) was approved recently bythe FDA. Emdogain has also been studied as an adjunct to nonsurgicaltherapy. The results of a 3-month double-blinded, split-mouth, controlled
NONSURGICAL APPROACHES 625 Bisphosphonates Mechanical Therapy NSAIDS Periostat Antimicrobials Periostat Antiseptics Osteoclasts Pockets and Prostaglandins Bone CAL Cytokines Bacterial Host Resorption (IL-1,IL-6, TNF) Products Cells Tooth Connective Mobility MMPs Tissue and Breakdown Loss Periostat Bacterial Clinical + Host Response Component = Component SequelaeFig. 2. Points of intervention for nonsurgical therapy. CAL, clinical attachment loss; IL,interleukin; NSAIDS, nonsteroidal anti-inﬂammatory drugs; TNF, tumor necrosis factor.and randomized study do not support the use of Emdogain during routinenonsurgical debridement of periodontal pockets as measured 3 months postSRP . Histologic evaluation of human intrabony defects followingnonsurgical periodontal therapy with and without application of Emdogainfailed to show periodontal regeneration with subgingival application ofEmdogain . The clinical utility of host modulation for nonsurgicalprocedures in clinical practice is limited in the remainder of this article to theuse of SDD (Periostat). SDD is a 20-mg dose of doxycycline (Periostat) that is FDA approvedand ADA accepted. It is indicated as an adjunct to SRP in the treatment ofchronic periodontitis. It has been evaluated as taken twice daily for up to9 months of continuous dosing in clinical trials. The duration of use mayvary from patient to patient. A risk factor assessment in addition to clinicalevaluation of patients can help guide the practitioner with regard to lengthof use and need for repeat use. A minimum of 3 months of host modulatorytherapy is suggested for reasons described later. Current clinical studies insusceptible patient populations such as osteopenic women are investigatingextended continuous use of up to 2 years. The 20-mg twice per day doseexerts its therapeutic eﬀect by enzyme, cytokine, and osteoclast inhibition,rather than by any antibiotic eﬀect. Research studies have found noevidence of any detectable antimicrobial eﬀect on the oral ﬂora or thebacterial ﬂora in other regions of the body and have identiﬁed clinicalbeneﬁt when SDD is used as an adjunct to SRP. At the present time, SDD isthe only FDA-approved, ADA-accepted host modulatory therapy specif-ically indicated for the treatment of chronic periodontitis. SDD works so well as a host modulatory agent because of its pleiotropiceﬀects on multiple components of the host response (see Fig. 2). The only
626 RYANenzyme (MMP) inhibitors that have been tested for the treatment ofperiodontitis are members of the tetracycline family of compounds. In anearly study using these diﬀerent tetracyclines, Golub et al  reported thatthe semisynthetic compounds (ie, doxycycline) were more eﬀective thantetracycline in reducing excessive collagenase activity in the GCF of adultperiodontitis patients. Recent clinical trials have focused on doxycyclinebecause it was found to be a more eﬀective inhibitor of collagenase thanminocycline or tetracycline [59,60] and because of its safety proﬁle,pharmacokinetic properties, and systemic absorption. In an eﬀort toeliminate the side eﬀects of long-term tetracycline therapy (especially theemergence of tetracycline-resistant organisms), SDD capsules were preparedand tested . Each capsule contained 20 mg of doxycycline compared withthe commercially available 50- and 100-mg antimicrobially eﬀective capsules.In multiple clinical studies conducted using SDD, there has not been adiﬀerence in the composition or resistance level of the oral ﬂora [62,63], andrecent studies demonstrate no appreciable diﬀerences in fecal or vaginalmicroﬂora samples . In addition, these studies have demonstrated noovergrowth of opportunistic pathogens such as Candida in the oral cavity,gastrointestinal, or genitourinary systems. With regard to MMP inhibition, Golub et al  reported that a 2-weekregimen of SDD reduced collagenase in GCF and in the adjacent gingivaltissues surgically excised for therapeutic purposes. Subsequent studies usingSDD therapy adjunctive to routine scaling and prophylaxis indicated thatafter 1 month of treatment, there were continued reductions in the excessivelevels of collagenase in the GCF but after cessation of SDD administration,there was a rapid rebound of collagenase activity to placebo levels,suggesting that a 1-month treatment regimen with this host modulatoryagent was insuﬃcient to produce a long-term beneﬁt . In contrast,during the same study, a 3-month regimen produced a prolonged drugeﬀect without a rebound in collagenase levels to baseline during the no-treatment phase of the study. The mean levels of GCF collagenase weresigniﬁcantly reduced (47.3% from baseline levels) in the SDD-treatedgroup versus the placebo group, which received scaling and prophylaxisalone (29.1% from baseline levels). Accompanying these reductions incollagenase levels were gains in the relative attachment levels in the SDD-treated group [65,66]. Continuous drug therapy over a period of severalmonths appears to be necessary for maintaining near normal collagenaselevels over prolonged periods. It is reasonable to speculate, however, thatthese MMPs will eventually reappear in susceptible patients, and thoseindividuals having the most risk factors and the greatest microbialchallenge will require more frequent host modulatory therapy than otherpatients. A series of double-blinded placebo-controlled studies of 3, 6, and 9months’ duration showed clinical eﬃcacy based on the reduction of pocketdepth, gains in clinical attachment levels, biochemical eﬃcacy based on the
NONSURGICAL APPROACHES 627inhibition of collagenase activity, and protection of serum alpha1-antitrypsin (a naturally occurring protective mediator) from collagenaseattack in the periodontal pocket [59,67,68]. Golub et al  showed that a2-month regimen of SDD signiﬁcantly decreased the level of bone-typecollagen breakdown products (pyridinoline cross-linked carboxyterminaltelopeptide of type I collagen) and MMP-8 and MMP-13 enzyme levels(neutrophil and bone-type collagenase) in adult periodontitis subjects,providing biochemical evidence of reduction of bone resorption to supportcomputer-assisted subtraction radiography data [70,71], the latter providingevidence of a reduction in the loss of alveolar bone height after 12 months oftherapy with SDD. A 9-month randomized, double-blinded placebo-controlled trial con-ducted at ﬁve dental centers demonstrated clinical eﬃcacy and safety of SDDversus placebo as an adjunct to SRP, the ‘‘gold standard’’ of periodontaltherapy. Again, the beneﬁts of host modulatory therapy in addition tomechanical therapy were seen, with statistically signiﬁcant reductions inprobing depths, bleeding on probing, gains in clinical attachment levels, andthe prevention of disease progression [72,73]. In a discontinuation study inwhich SDD administration was discontinued after 9 months of continuoustherapy, the incremental improvements demonstrated in the SDD group weremaintained for at least 3 months post treatment. There was no rebound eﬀectin pocket depth reductions or clinical attachment level gains; in fact, thereappeared to be slight continued improvements in both of these clinicalparameters [72,73], presumably due to the enhanced clinical status of thepatients who beneﬁted from adjunctive Periostat and the known persistenceof doxycycline in the bone and soft tissue of the periodontium. The clinicalrelevance of such ﬁndings conﬁrms the utility of an MMP inhibitor in themanagement of adult periodontitis. Recent phase IV clinical studies have been performed that have revealedclinical and biochemical success using SDD in diﬀerent populations ofsusceptible individuals, including subjects who are genetically susceptible; subjects who have severe generalized periodontitis , diabetes [76,77],or osteoporosis ; subjects who are institutionalized geriatric patients ;and smokers . The use of SDD in these at-risk patient populationssigniﬁcantly improved clinical response to SRP, and in the case of smokers,the subjects who were treated with SRP plus SDD experienced probing depthreductions and clinical attachment level gains equivalent to, and in somestudies superior to, the response seen in nonsmokers who were treated withSRP alone . In addition, it becomes apparent that the use of systemic hostmodulatory therapy by the dentist may not only improve the patient’speriodontal condition but also provide systemic beneﬁts for other in-ﬂammatory disorders with related tissue destruction, such as arthritis,cardiovascular disease, dermatologic conditions, diabetes, osteoporosis, andso forth. Dental studies have reported dramatic reductions in hemoglobinA1c levels (a long-term marker of glycemic control) in addition to
628 RYANimprovements in clinical parameters in diabetic subjects treated with SDDplus SRP compared with SRP alone [76,77]. Dental studies in osteoporoticwomen have reported reductions in the loss of alveolar bone height and bonedensity (as measured by computer-assisted densitometric image analyses) inaddition to clinical attachment level gains and no attachment loss in subjectstreated with SDD plus SRP compared with subjects treated with SRP alonewho experienced no attachment level gains and loss of attachment ina number of sites over the 12 months of the study . Another assumptionthat can be made is that patients who are currently being prescribed hostmodulatory agents by their physicians, such as nonsteroidal anti-inﬂamma-tory drugs, bisphosphonates, or tetracyclines, and newer agents targetingspeciﬁc cytokines for the management of medical conditions may beexperiencing periodontal beneﬁts from these systemically administeredmedications. In the clinical trials of SDD (20-mg dose), the drug was well tolerated, andthe proﬁle of unwanted eﬀects was virtually identical in the SDD and placebogroups [73,75,81,82]. SDD is indicated in the management of chronicperiodontitis [68,73,83,84]. SDD should not be used in conditions such asgingivitis or periodontal abscess, or whenever an antibiotic is indicated. SDDcan be used in aggressive periodontitis cases that are being treatednonsurgically . Furthermore, emerging studies have supported the eﬃcacyof SDD as an adjunct to periodontal surgery . SDD may also be of beneﬁtin cases that are refractory to treatment or in patients with risk factors such assmoking or diabetes in whom the treatment response might be somewhatlimited. SDD is contraindicated in anyone with a history of allergy orhypersensitivity to tetracyclines. It should not be given to pregnant orlactating females or children less than 12 years old (because of the potentialfor discoloration of the developing dentition). Doxycycline may reduce theeﬃcacy of oral contraceptives, so advice should be given to use alternativeforms of birth control, if necessary. There is a risk of increased sensitivity tosunlight (manifested by an exaggerated sunburn) seen with higher doses ofdoxycycline, but this has not been reported in any of the clinical trials at thesubantimicrobial dose. A typical prescription for Periostat (20-mg doxycy-cline tablets) is for at least 3 months (180 tablets, 1 tablet twice a day untilcomplete), and reﬁlls may be provided for longer courses of therapy. SDD treatment can also be combined with the local delivery ofantibiotics to the periodontal pocket by way of sustained delivery systems.The two treatments target diﬀerent aspects of the pathogenic process: localdelivery systems deliver antimicrobial concentrations of an antibacterialagent directly to the site of the pocket, whereas SDD is a systemic hostresponse modulator. Thus, combining these two complementary treatmentstrategies is another example of how antibacterial therapy (ie, SRP pluslocally applied antibiotics) can be combined with host modulatory therapy(SDD) to maximize the clinical beneﬁt for patients. Preliminary results froma 6-month 180-patient clinical trial designed to evaluate the safety and
NONSURGICAL APPROACHES 629eﬃcacy of SDD combined with a locally applied antimicrobial (Atridox)plus SRP versus SRP alone demonstrated that patients receiving thecombination of treatment experienced more than a 2-mm improvement inmean attachment level gain and pocket depth reduction, which was highlystatistically signiﬁcant (P!0.0001) compared with SRP alone.Clinical application The author has implemented a three-pronged approach to periodontaltherapy in her clinical practice (Fig. 3). The initial visit by a patient includesa medical and dental history, a risk assessment proﬁle, periodontal charting,and radiographic analysis. The patient must be made aware of the fact thatperiodontal disease is not curable but that it can be treated and wellcontrolled with constant monitoring by the dentist/hygienist and goodpatient compliance. The patient must also be informed of the need forperiodontal therapy, which should not be considered optional or elective butnecessary to promote not only good oral health but also good generalhealth, as recent studies have suggested. Initial therapy consists of risk reduction strategies (see Box 2). Modiﬁca-tion of any risk factors such as smoking, nutrition, stress, contributing Diagnosis of Periodontitis, Risk Factor Assessment Initial Therapy Antimicrobial Approach Risk Host Modulatory Approach OHI, Antiseptics, SRP Reduction HMT Re-Evaluation Unstable Stable Probing Depths ≥ 5 mm Probing Depths < 5 mm BOP Minimal BOP Maintenance Therapy (3 month Recall) Active Therapy Unstable Stable SPT Localized Sites Generalized Sites SRP, Local Anti-MicrobialTherapy, HMT Surgery, SRP, HMT SPT SPT Additional Maintenance Therapy Additional Therapy Re-Evaluate SPT Therapy Re-Evaluate SPTRepeat, Surgery Systemic Antibiotics Unstable Stable Unstable StableFig. 3. Periodontal therapy treatment algorithm. BOP, bleeding on probing; HMT, hostmodulatory therapy; OHI, oral hygiene instruction; SPT, supportive periodontal therapy(reinforce OHI, scaling, antiseptics).
630 RYANmedications, faulty restorations, poor oral hygiene, and poor diabetic controlshould be addressed at this time. Oral hygiene instructions are extremelyimportant and must be reinforced continuously over the course of therapy; theuse of adjunctive antiseptic agents is often employed. SRP is the core ofnonsurgical therapy, with anesthesia administered as needed. At-home oralhygiene and in-oﬃce SRP approaches are designed to reduce the bacterialload. In addition, an initial course of host modulatory therapy (Periostat) maybe prescribed to reduce excessive levels of enzymes, cytokines, andprostanoids, especially in susceptible patients as identiﬁed by risk assessment.A patient’s refusal or inability to modify contributing risk factors is animportant consideration for treatment planning and evaluation of therapeuticresponses. In the case of adjunctive chemotherapies, the more risk factors andthe poorer the hygiene, the greater the need for antiseptics, antibiotics, andhost modulation of longer duration or repeat therapy in the future. After completion of initial therapy, re-evaluation is the next step (seeFig. 3). At this point, the decision is made to continue with active(additional) therapy or to place the patient in the maintenance phase oftherapy. If all probing depths are !5 mm and there is minimal bleeding onprobing and gingival inﬂammation, then the decision is made to place thepatient in the maintenance phase of therapy. The patient is typicallymaintained on the host modulatory agent through the ﬁrst maintenancevisit. If the treated sites remain stable for this 3-month period, then thepatient is removed from the host modulatory agent and placed in the typicalmaintenance program (3- to 4-month visits) until the need for additionalactive therapy is required. If there are probing depths R5 mm at re-evaluation, then the therapeutic approach may diﬀer depending on thenumber of sites per quadrant and radiographic assessment of the sites. Typically for isolated sites with probing depths R5 mm at re-evaluation,a nonsurgical approach may include rescaling the sites and placement ofa locally applied antimicrobial agent (ie, Atridox, Arestin, or Peiochip), withthe continued adjunctive use of the host modulatory agent. Sites treatedwith locally applied antimicrobials should be re-evaluated at 3 months anda decision can be made by the clinician as to whether an additionalapplication of the same locally applied antimicrobial may be used oranother locally applied antimicrobial may be administered, and so forth.Clinicians must use their clinical judgment. If this treatment is insuﬃcient toachieve adequate pocket depth reduction or if there are multiple sites ina quadrant with probing depths R5 mm, then a surgical approach may beindicated to reduce the probing depths through resective or regenerativetechniques. After all probing depths are !5 mm, the patient is placed in themaintenance phase of therapy as described earlier. In certain patients with aggressive periodontitis or in those trulyrefractory to the therapy described previously, the use of systemicantimicrobials or additional host modulatory agents in a polypharmacologicapproach can be considered. Microbial and antibiotic susceptibility testing