Clinical Efficacy of Repeated Applications of Local Drug Delivery and Adjunctive Agents in Nonsurgical Periodontal Therapy: A Systematic Review
Abstract
:1. Introduction
2. Methods
2.1. Review Protocol and Registration
2.2. Inclusion and Exclusion Criteria
2.2.1. Population
2.2.2. Interventions
2.2.3. Comparisons
2.2.4. Outcomes
2.3. Search Methods
2.4. Study Selection and Data Extraction
2.5. Assessment of the Risk of Bias of Selected Studies
2.6. Data Analyses
3. Results
3.1. Study Characteristics
3.2. Risk of Bias within the Selected Studies
3.3. Primary Outcomes
PPD and CAL Changes
3.4. Secondary Outcomes
BOP, Patient-Related Outcome Measures, and Postoperative Adverse Effects Associated with LDA
4. Discussion
4.1. Summary of Findings
4.2. Comparison of Findings to Other Reviews
5. Conclusions
- Repeated LDA application has an observed mean range of 0.27–3.82 mm PD reduction and −0.09–2.82 mm CAL gain.
- LDAs had limited clinical improvements compared with SMD alone whereby the majority of the studies exhibited no significant differences between SMD alone and SMD with an adjunct.
- Different LDAs have different clinical efficacy, even with the use of similar device such as aPDT. LDAs are considered safe for their intended use in clinical practice with minor to moderate post-treatment adverse events reported.
- The repeated use of LDAs lack statistical and clinical significance with all included studies demonstrating some concerns and high risk of bias. Although some studies have a purportedly minimum mean 2 mm change in attachment level post-treatment, most of the studies were single-blinded and did not utilize intention-to-treat analysis.
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Adjunct Used. | Study Citation | Trial Design, Country | Centre, Setting | Disease Severity, Definition | Number of Smokers (%) | Age Mean ± SD (Range) | Sex Male/Female | ||
---|---|---|---|---|---|---|---|---|---|
Test | Control | Test | Control | ||||||
Chlorhexidine chip | Carvalho et al., 2007 [48] | Split-mouth, USA | 1, university | mild to moderate CP, Nonmolar sites with PD > 4 mm and BoP | 9/26 (35) | 54.5 (35–81) | 11/15 | ||
Grisi et al., 2002 [46] | Parallel, Brazil | 1, university | CP, PD ≥ 5 mm and BoP | 20, NS | 43.3 ± 5.9 (35–56) | 41.1 ± 5.4 (37–54) | 5/5 | 3/6 | |
Kasaj et al., 2007 [49] | Split-mouth, Germany | 1, university | moderate to severe CP, PD ≥ 5 mm and BoP | 20, NS | 42.0 ± 5.6 (20–60) | 7/13 | |||
Mizrak et al., 2006 [47] | Parallel, Turkey | 1, university | CP, PD 5–8 mm and radiographic bone loss | 34, NS | 35 ± 8.5 (20 to 55) | 22/12 | |||
Doxycycline hyclate gel | Bogren et al., 2008 [44] | Parallel, Sweden and USA | 3, university and private practice | moderate to advanced periodontitis, PD ≥ 5 mm | 38/128 (29.7) | 58 (34–77) | 60 (35–82) | 44/19 | 42/23 |
Minocycline gel/ointment | Shalev 2019 [45] | Parallel, USA | 1, university | moderate to severe periodontitis, PD 5–9 mm and BoP | 22/59 (37.3), Ex-users: 19/59 (32.2) | 53.8 ± 11.3 (NR) | Sham: 53.8 ± 11.3 (NR) Vehicle: 50.8 ± 0.5 (NR) | 10/10 | 24/15 |
van Steenberghe et al., 1999 [43] | Parallel, Belgium, Sweden, UK, Netherlands | 6, university | moderate to severe CP, Interproximal sites with PD ≥ 5 mm, CAL ≥ 3 mm and radiographic bone loss | 104, NR | 48 ± 7 (35–64) | 44 ± 7 (34–61) | 43/50 | ||
Minocycline microspheres | Killeen et al., 2018 [42] | Parallel, USA | 1, university | moderate to severe CP, Interproximal posterior sites with PD ≥ 5 mm and BoP | 12/55 (21.8) | 67.3 ± 10.5 (NR) | 66.8 ± 12.1 (NR) | 22/5 | 16/12 |
Chloramine gel | Megally et al., 2020 [41] | Parallel, Switzerland | 1, university | CP, Distal site of first incisor or mesial site of second molar with PD ≥ 5 mm | 7/32 (21.9) | 61.7 ± 9.8 (NR) | 62.1 ± 8.8 (NR) | 11/5 | 10/6 |
Antimicrobial photodynamic therapy (Methylene blue 0.005%) | Müller Campanile et al., 2015 [50] | Split-mouth, Switzerland | 1, private practice | CP, PD > 4 mm, CAL > 1 mm and BoP | 12/27 (44.4) | 62.8 (37–77) | 14/13 | ||
(Methylene blue 1%) | Katsikanis et al., 2020 [51] | Split-mouth, Greece | 1, university | moderate to severe CP, PD ≥ 5 mm | 7/21 (33.3) | 48.2 ± 8.2 (NR) | 8/13 | ||
(Indocyanine green) | Sukumar et al., 2020 [52] | Split-mouth, India | 1, university | CP, Min 3 bilateral mandibular posteriors with PD 4–6 mm and CAL | 33, NS | 38.6 ± 6.8 (NR) | 22/8 | ||
(Phenothiazine chloride) | Lulic et al., 2009 [40] | Parallel, Switzerland | 1, university | CP, PD ≥ 5 mm ± BoP | 2/10 (20) | 56 (44–74) | 52 (40–57) | 3/2 | 4/1 |
Petelin et al., 2015 [39] | Parallel, Slovenia | 1, university | CP, Minimum 4 teeth with PD ≥ 4 mm per quadrant | 27, NS | 47 (36–59) | 51 (42–64) | 5/4 | 4/5 | |
(Toluidine blue O) | Harmouche et al., 2019 [53] | Split-mouth, France | 1, university | generalized severe CP, PD ≥ 5 mm, CAL > 5 mm and BoP | 11/36 (30.6) | 50.25 ± 5.98 (NR) | 14/22 | ||
Povidone- Iodine subgingival irrigation | Kessler et al., 2021 [54] | Split-mouth, Belgium | 1, university | stage II to III, grade A to B periodontitis, PD ≥ 4 mm, CAL ≥ 3 mm and BoP | NR | 51.8 (34–62) | 9/8 |
Study Citation, Follow-Up | Interventions | Area, Frequency of Application | Test Group | Control Group | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Sample Size BL/End of Study | Pre-Intervention Clinical Parameters Mean ± SD | Post-Intervention Clinical Parameters Mean ± SD | Change in Clinical Parameters Mean ± SD | Sample Size BL/End of Study | Pre-Intervention Clinical Parameters Mean ± SD | Post-Intervention Clinical Parameters Mean ± SD | Change in Clinical Parameters Mean ± SD | |||
Carvalho et al., 2007 [48], 9 m | Test: CHX chip (Periochip®) + SRP Control: SRP | PM, 3× (BL, 3 m, 6 m) | 28/26 | PPD: 5.90 ± 1.30 CAL: 6.10 ± 2.10 BOP: 96% | PPD: 4.70 ± 1.30 CAL: 5.20 ± 1.90 BOP: 54% | PPD: 1.20 ± 1.59 CAL: 0.90 ± 2.39 BOP: 42% | 28/26 | PPD: 5.60 ± 1.10 CAL: 5.30 ± 1.40 BOP: 100% | PPD: 4.50 ± 1.40 CAL: 4.40 ± 1.90 BOP: 46% | PPD: 1.10 ± 1.55 CAL: 0.90 ± 2.06 BOP: 54% |
Grisi et al., 2002 [46], 9 m | Test: CHX chip (Periochip®) + SRP Control: SRP | PM, 3× (BL, 3 m, 6 m) | 10/10 | PPD: 5.20 ± 0.60 CAL: NR BOP: 87.8% | PPD: 3.00 0.80 CAL: NR BOP: 65.9% | PPD: 2.20 ± 0.70 CAL: 0.60 ± 0.70 * BOP: 22% | 10/9 | PPD: 5.20 ± 0.50 CAL: NR BOP: 79.1% | PPD: 2.90 ± 0.60 CAL: NR BOP: 43.6% | PPD: 2.40 ± 0.70 CAL: 1.00 ± 0.40 * BOP: 36% * |
Kasaj et al., 2007 [49], 6 m | Test: CHX chip (Periochip®) + U/S Control: U/S | PM, 2× (BL, 3 m) | 20/20 | PPD: 6.20 ± 1.00 CAL: 6.90 ± 1.60 BOP: 71% | PPD: NR CAL: NR BOP: 29% | PPD: 2.20 ± 0.80 CAL: 1.90 ± 1.10 BOP: 42% | 20/20 | PPD: 6.30 ± 0.90 CAL: 7.20 ± 1.40 BOP: 67% | PPD: NR CAL: NR BOP: 58% | PPD: 0.70 ± 0.60 CAL: 0.60 ± 0.70 BOP: 9% |
Mizrak et al., 2006 [47], 6 m | Test: CHX chip (Periochip®) + SRP Control: SRP | PM, 2× (BL, 3 m) | 17/17 | PPD: 6.94 ± 0.74 CAL: 7.50 ± 0.80 BOP: 1.70 ± 0.46 | PPD: NR CAL: NR BOP: NR | PPD: 3.82 * CAL: 2.82 * BOP: 1.05 | 17/17 | PPD: 6.05 ± 0.89 CAL: 7.00 ± 1.10 BOP: 1.74 ± 0.43 | PPD: NR CAL: NR BOP: NR | PPD: 2.35 CAL: 1.64 BOP: 0.88 |
Bogren et al., 2008 [44], 36 m | Test: DH gel (Atridox®) + SRP Control: SRP | FM, 3× (BL, 1y, 2y) | 63/60 | PPD: 5.40 (95% CI 5.33–5.57) CAL: NR BOP: 51% | PPD: 4.20 (95% CI 4.04–4.45) CAL: NR BOP: 50% | PPD: 1.20 ± 1.67 CAL: 0.90 ± 2.26 BOP: 1% | 65/64 | PPD: 5.60 (95% CI 5.44–5.77) CAL: NR BOP: 56% | PPD: 4.50 (95% CI 4.29–4.74) CAL: NR BOP: 38% | PPD: 1.10 ± 1.97 CAL: 0.70 ± 2.10 BOP: 18% |
Shalev 2019 [45], 9 m | Test: MINO gel (Periocline ®) + SRP Control: Placebo + SRP | FM, 4× (BL, 2 w, 1 m, 3 m, 6 m) | 20/20 | PPD: 5.68 ± SE 0.09 CAL: 4.87 ± SE 0.26 BOP: 95.46% ± SE 1.48% | PPD: 3.91 ± SE 0.13 CAL: 3.32 ± SE 0.26 BOP: 32.50% ± SE 3.71% | PPD: 1.76 ± 0.63 CAL: 1.56 ± 0.54 BOP: 63% ± 3.94% * | 39/39 | Sham: PPD: 5.82 ± SE 0.13 CAL: 5.33 ± 0.25 BOP: 92.51% ± SE 2.57% Vehicle: PPD: 5.65 ± SE 0.08 CAL: 4.79 ± SE 0.22 BOP: 95.71% ± SE 1.31% | Sham: PPD: 4.29 ± SE 0.18 CAL: 3.94 ± SE 0.31 BOP: 40.84% ± SE 5.28 Vehicle: PPD: 3.96 ± SE 0.16 CAL: 3.18 SE 0.30 BOP: 49.63% ± SE 4.57% | PPD: 1.59 ± 0.61 CAL: 1.42 ± 0.53 BOP: 49% ± 5.36% * |
van Steenberghe et al., 1999 [43], 15 m | Test: MINO gel (Dentomycin®) + SRP Control: Placebo + SRP | PM, 7× (BL, 2 w, 1 m, 3 m, 6 m, 9 m, 12 m) | 52/45 | PPD: 6.50 CAL: NR BOP: 2.50 | PPD: 4.60 CAL: NR BOP: 1.40 | PPD: 1.90 ± 0.32 CAL: 0.90 ± 0.39 BOP: 1.1 ± 0.85 | 52/45 | PPD: 6.30 CAL: NR BOP: 2.50 | PPD: 5.10 CAL: NR BOP: 1.70 | PPD: 1.20 ± 0.31 CAL: 0.50 ± 0.37 BOP: 0.8 ± 0.82 |
Killeen et al., 2018 [42], 24 m | Test: MINO microspheres (Arestin®) + SRP Control: SRP | PM, 4× (BL, 6 m, 12 m, 18 m) | 27/23 | PPD: 5.29 ± 0.62 CAL: 5.42 ± 0.65 BOP: NR | PPD: 4.14 ± 0.89 CAL: 4.36 ± 1.05 BOP: NR | PPD: 0.80 ± 0.90 CAL: 0.80 ± 0.90 BOP: NR | 28/25 | PPD: 5.48 ± 0.75 CAL: 5.81 ± 0.92 BOP: NR | PPD: 3.96 ± 0.73 CAL: 4.24 ± 0.66 BOP: NR | PPD: 1.00 ± 0.60 CAL: 1.00 ± 0.70 BOP: NR |
Megally et al., 2020 [41], 12 m | Test: Chloramine gel (Perisolv®) + U/S Control: U/S | PM, 3× (BL, 4 m, 8 m) | 16/16 | PPD: 5.39 ± 0.62 CAL: NR BOP: 89% | PPD: 4.43 ± 1.07 CAL: NR BOP: 83% | PPD: 0.97 ± 1.09 * CAL: 1.02 ± 1.49 * BOP: 6% | 16/16 | PPD: 5.31 ± 0.58 CAL: NR BOP: 88% | PPD: 4.46 ± 1.19 CAL: NR BOP: 73% | PPD: 0.85 ± 1.13 * CAL: 0.82 ± 1.33 * BOP: 15% |
Müller Campanile et al., 2015 [50], 6 m | Test: aPDT MB 0.005% (PeriowaveTM) + U/S Control: Sham + U/S Laser: 280 mW and 670 nm | PM, 2× (BL, 1 w) | 28/27 | PPD: 5.90 ± 0.90 CAL: 7.00 ± 1.60 BOP: 59.26% | PPD: 3.10 ± 1.00 CAL: 4.10 ± 1.60 BOP: 37.04% | PPD: 2.80 ± 1.17 CAL: 2.90 ± 1.96 BOP: 22% | 28/27 | PPD: 6.30 ± 1.50 CAL: 7.60 ± 2.00 BOP: 55.56% | PPD: 3.40 ± 1.50 CAL: 4.60 ± 2.20 BOP: 37.04% | PPD: 2.90 ± 1.84 CAL: 3.00 ± 2.58 BOP: 19% |
Katsikanis et al., 2020 [51], 6 m | Test: aPDT MB 1% + SRP Control: SRP Laser: 350 mW and 670 nm | PM, 3× (48 h, 1 w, 2 w) | 21/21 | PPD: 4.76 ± 0.79 CAL: 5.49 ± 1.52 BOP: 79% | PPD: NR CAL: NR BOP: 15.9 | PPD: 1.66 ± 1.02 CAL: 1.04 ± 1.19 BOP: 63% | 21/21 | PPD: 4.80 ± 0.76 CAL: 5.29 ± 1.17 BOP: 81.9% | PPD: NR CAL: NR BOP: 13.3% | PPD: 1.66 ± 1.14 CAL: 1.24 ± 1.35 BOP: 69% |
Sukumar et al., 2020 [52], 6 m | Test: aPDT ICG 0.1% + SRP Control: SRP Laser: 800 mW and 810 nm | PM, 4× (BL, 1 w, 2w, 4w) | 33/30 | PPD: 5.93 ± 0.82 CAL: 5.73 ± 0.69 BOP: 2.0 | PPD: 3.40 ± 0.56 CAL: 3.00 ± 0.91 BOP: 0.17 ± 0.37 | PPD: 2.53 ± 0.87 * CAL: 2.73 ± 1.00 * BOP: 1.8 ± 0.37 * | 33/30 | PPD: 5.83 ± 0.64 CAL: 5.60 ± 0.72 BOP: 2.0 | PPD: 3.80 ± 0.40 CAL: 3.70 ± 0.91 BOP: 0.6 ± 0.35 | PPD: 2.03 ± 0.66 * CAL: 1.90 ± 1.01 * BOP: 1.4 ± 0.35 * |
Lulic et al., 2009 [40], 12 m | Test: aPDT PC (HELBO®) + SRP Control: Sham + SRP Laser: 75 mW and 670 nm | FM, 5× (BL, 1 d, 2 d, 7 d, 14 d) | 5/5 | PPD: 6.08 ± 1.19 CAL: 6.70 ± 2.17 BOP: 97% | PPD: 5.81 ± 1.33 CAL: 6.79 ± 2.37 BOP: 77% | PPD: 0.27 ± 0.43 CAL: −0.09 ± 0.41 BOP: 20% * | 5/5 | PPD: 5.90 ± 0.71 CAL: 7.55 ± 1.73 BOP: 84% | PPD: 5.93 ± 0.49 CAL: 7.76 ± 1.66 BOP: 87% | PPD: 0.07 ± 0.61 CAL: −0.20 ± 0.61 BOP: −3% |
Petelin et al., 2015 [39], 12 m | Test: aPDT PC (HELBO®) + U/S Control: U/S Laser: 60 mW and 660 nm | FM, 3× (BL, 3 d, 7 d) | 9/9 | PPD: 3.40 ± 0.20 CAL: 4.20 ± 0.30 BOP: 24.9% ± 2.8% | PPD: 2.90 ± 0.20 CAL: 3.70 ± 0.20 BOP: 9.4% ± 1.4% | PPD: 0.50 ± 0.24 CAL: 0.50 ± 0.32 BOP: 16% ± 2.8% * | 9/9 | PPD: 3.60 ± 0.20 CAL: 4.30 ± 0.30 BOP: 23% ± 2.8% | PPD: 3.00 ± 0.20 CAL: 3.70 ± 0.20 BOP: 12.2% ± 1.4% | PPD: 0.60 ± 0.24 CAL: 0.60 ± 0.32 BOP: 11% ± 2.8% * |
Harmouche et al., 2019 [53], 6 m | Test: aPDT TBO (FotoSan®) + SRP Control: Sham + SRP Laser: 2 W and 628 nm | PM, 3× (BL, 1 w, 3 m) | 36/28 | PPD: 4.06 ± 1.71 CAL: 4.79 ± 2.07 BOP: 64.89% | PPD: 2.93 ± 1.42 CAL: 3.94 ± 1.99 BOP: 32.48% | PPD: 1.13 ± 1.93 CAL: 0.85 ± 2.49 BOP: 32% | 36/28 | PPD: 4.10 ± 1.72 CAL: 4.77 ± 2.06 BOP: 64.64% | PPD: 2.94 ± 1.43 CAL: 3.92 ± 1.93 BOP: 33.12% | PPD: 1.16 ± 1.94 CAL: 0.85 ± 2.45 BOP: 32% |
Kessler et al., 2021 [54], 6 m | Test: PVP-I 10% (iso-Betadine, Dermal) + SRP Control: 0.9% NaCl + SRP | FM, 3× (BL, 3 m, 6 m) | 17/22 | PPD: 3.70 ± 0.90 CAL: 3.90 ± 0.90 BOP: 64% 26.9% | PPD: 2.50 ± 0.60 CAL: 3.00 ± 0.80 BOP: NR | PPD: 1.20 ± 0.95 CAL: 0.80 ± 1.04 BOP: NR | 17/22 | PPD: 3.70 ± 0.70 CAL: 3.90 ± 0.80 BOP: 56% 29.3% | PPD: 2.60 ± 50 CAL: 3.20 ± 0.70 BOP: NR | PPD: 1.10 ± 0.75 CAL: 0.70 ± 0.92 BOP: NR |
Study Citation | Blinding | Examiners | Calibration | Probing Type | Use of Stent | Gingival Bleeding Indices | Plaque Indices | Adverse Events |
---|---|---|---|---|---|---|---|---|
Carvalho et al., 2007 [48] | single | 2 | Yes | Manual | NR | NR | NR | None, 2 chips dislodged and replaced |
Grisi et al., 2002 [46] | single | 1 | NR | Computer assisted | yes | Loesche 1979 | Loe 1967 | gingival pain, discomfort, local irritation and gingival oedema, gingival abscesses 3 sites |
Kasaj et al., 2007 [49] | single | 1 | Yes | Manual | NR | NR | NR | gingival discomfort and gingival swelling |
Mizrak et al., 2006 [47] | single | NR | NR | NR | Yes | Ainamo and Bay 1975 | Loe 1967 | NR |
Bogren et al., 2008 [44] | single | >1 | Yes | Manual | NR | NR | NR | None |
Shalev 2019 [45] | double | >1 | Yes | Manual | NR | NR | NR | NR |
van Steenberghe et al., 1999 [43] | double | 6 | NR | Manual | Yes | Muhlemann 1977 | Silness and Loe 1964 | 8 minor, 3 redness, 3 abscesses |
Killeen et al., 2018 [42] | single | 2 | Yes | Manual | NR | NR | NR | None |
Megally et al., 2020 [41] | single | 3 | Yes | Force controlled | NR | Muhlemann 1977 | Lange et al., 1977 | None |
Müller Campanile et al., 2015 [50] | single | 1 | NR | NR | NR | NR | Silness and Loe 1964 | 2–pain/discomfort |
Katsikanis et al., 2020 [51] | single | 1 | NR | NR | NR | Loe and Silness 1963 | Silness and Loe 1964 | None |
Sukumar et al., 2020 [52] | single | 1 | Yes | Manual | NR | NR | O′Leary 1972 | None |
Lulic et al., 2009 [40] | single | 1 | Yes | Manual | Yes | NR | NR | NR |
Petelin et al., 2015 [39] | double | 1 | NR | Force controlled | NR | NR | Silness and Loe 1964 | NR |
Harmouche et al., 2019 [53] | single | 1 | Yes | NR | NR | NR | NR | None |
Kessler et al., 2021 [54] | single | NR | Yes | Force controlled | Yes | Ainamo and Bay 1975 | O′Leary 1972 | None |
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Tan, O.L.; Safii, S.H.; Razali, M. Clinical Efficacy of Repeated Applications of Local Drug Delivery and Adjunctive Agents in Nonsurgical Periodontal Therapy: A Systematic Review. Antibiotics 2021, 10, 1178. https://doi.org/10.3390/antibiotics10101178
Tan OL, Safii SH, Razali M. Clinical Efficacy of Repeated Applications of Local Drug Delivery and Adjunctive Agents in Nonsurgical Periodontal Therapy: A Systematic Review. Antibiotics. 2021; 10(10):1178. https://doi.org/10.3390/antibiotics10101178
Chicago/Turabian StyleTan, Oi Leng, Syarida Hasnur Safii, and Masfueh Razali. 2021. "Clinical Efficacy of Repeated Applications of Local Drug Delivery and Adjunctive Agents in Nonsurgical Periodontal Therapy: A Systematic Review" Antibiotics 10, no. 10: 1178. https://doi.org/10.3390/antibiotics10101178