Oral enzyme combination in the comprehensive treatment of periodontal disease: a systematic review

Relevance. The rising prevalence of periodontal disease underscores the need for innovative diagnostic and therapeutic approaches. Mechanical debridement of the biofilm remains the cornerstone of periodontal treatment. However, systemic antibiotics are recommended for patients experiencing rapidly progressing periodontal attachment loss who do not respond adequately to conservative therapy. Despite their widespread application, antibiotics do not always achieve the desired outcomes. In such scenarios, adjuvant therapies that enhance the efficacy of standard treatment against infectious agents become particularly important. Oral enzyme combination (OEC) has emerged as a valuable adjunct in this context. Objective: to review the available data on oral enzyme combination (OEC) drugs and assess their potential application in clinical practice for managing periodontal disease.

Materials and methods. A total of 939 publications from 2010 to 2024 were identified through searches in PubMed and eLIBRARY. Following inclusion and exclusion criteria, 10 publications, including randomized clinical trials, were selected for analysis. The search was conducted using the following keywords: bromelain, trypsin, rutin, periodontal disease, enzyme therapy in dentistry, and systemic antibiotics: bromelain, trypsin, rutin, periodontal disease, enzyme therapy in dentistry, and systemic antibiotics.

Results. Oral enzyme combination (OEC) drugs reduce inflammatory activity, limit pathological manifestations of autoimmune and immune complex processes, decrease vascular wall permeability, and enhance antibiotic concentration at the site of inflammation. The efficacy of oral combinations of proteases, such as bromelain (a proteolytic enzyme), and other components like rutin (a glycoside combining the flavonol quercetin and the disaccharide rutinose), has been demonstrated in dental practice. These combinations have shown benefits in relieving pain, reducing swelling and inflammation, enhancing the effectiveness of antibacterial therapy, and minimizing its side effects.

Conclusion. With their potent proteolytic activity and low cytotoxicity, systemic enzyme therapy drugs have become widely accepted as adjuvants to antibiotic therapy, enhancing its effectiveness. The combination of antibiotics and systemic enzyme therapy has shown superior outcomes compared to antibiotics alone, indicating its potential efficacy in the treatment of periodontal disease.

1. Afanasyeva OYu, Grigoryan MM, Konovodov VV, Kurbanov BB. Systemic enzyme therapy in dental surgery. Аktual'nyye issledovaniya. 2021;11(38):40-44 (In Russ.). Available from: https://elibrary.ru/item.asp?id=44861872

2. Aishwarya AG, Rajanikanth K, Nitin B, Anendd J. Comparative efficacy of bromelain and aceclofenac in limiting post-operative inflammatory sequelae in surgical removal of lower impacted third molar: a randomized controlled, triple blind clinical trial. J Dent Anesth Pain Med. 2022;22(1):29-37. doi: 10.17245/jdapm.2022.22.1.29

3. Alessandro P, Martina D, Giada N, Simona S, Paolo P, Gaetano I. Drugs for the Quorum Sensing Inhibition of Oral Biofilm: New Frontiers and Insights in the Treatment of Periodontitis. Pharmaceutics. 2022;14(12):2740. doi: 10.3390/pharmaceutics14122740

4. Apanasovich M, Apanasovich V. Possibilities of using systemic enzyme therapy in dentistry. Sovremennaya stomatologia. 2018;(2):63-65 (In Russ.). Available from: https://elibrary.ru/item.asp?id=35290281

5. Varilla C, Marcone M, Paiva L, Baptista J. Bromelain, a Group of Pineapple Proteolytic Complex Enzymes (Ananas comosus) and Their Possible Therapeutic and Clinical Effects. A Summary. Foods. 2021;10(10):2249. doi: 10.3390/foods10102249

6. Bumm CV, Wölfle UC, Keßler A, Werner N, Folwaczny M. Influence of decision-making algorithms on the diagnostic accuracy using the current classification of periodontal diseases-a randomized controlled trial. Clin Oral Investig. 2023;27(11):6589-6596. doi: 10.1007/s00784-023-05264-z

7. Hammami C, Nasri W. Antibiotics in the Treatment of Periodontitis: A Systematic Review of the Literature. Int J Dent. 2021;2021:6846074. doi: 10.1155/2021/6846074.

8. Shah D, Mital K. The Role of Trypsin:Chymotrypsin in Tissue Repair. Adv Ther. 2018;35(1):31-42. doi: 10.1007/s12325-017-0648-y.

9. Hajishengallis G, Lamont RJ. Beyond the red complex and into more complexity: the polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol Oral Microbiol. 2012;27(6):409-419. doi: 10.1111/j.2041-1014.2012.00663.x

10. Hajishengallis G, Chavakis T, Lambris JD. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol 2000. 2020;84(1):14-34. doi: 10.1111/prd.12331

11. Chisci G, Fredianelli L. Therapeutic Efficacy of Bromelain in Alveolar Ridge Preservation. Antibiotics (Basel). 2022;11(11):1542. doi: 10.3390/antibiotics11111542

12. Vijayakumar G, Sundaram GA, Kumar SP, Krishnan M, Krishna VK, Lakshmanan S. Comparison of the Efficacy of Corticosteroids With Enzymatic Agents in the Postoperative Sequelae for Lower Third Molar Surgery: A Prospective Study. Cureus. 2024;16(3):e55397. doi: 10.7759/cureus.55397

13. Inchingolo F, Tatullo M, Marrelli M, Inchingolo AM, Picciariello V, Inchingolo AD, et al. Clinical trial with bromelain in third molar exodontia. Eur Rev Med Pharmacol Sci. 2010;14(9):771-774. Available from: https://pubmed.ncbi.nlm.nih.gov/21061836/

14. Caton JG, Armitage G, Berglundh T, Chapple ILC, Jepsen S, Kornman KS, et al. A new classification scheme for periodontal and peri-implant diseases and conditions – Introduction and key changes from the 1999 classification. J Clin Periodontol. 2018;45 Suppl 20:S1-S8. doi: 10.1111/jcpe.12935

15. Vosáhlo J, Salus A, Smolko M, Němcová B, Nordmeyer V, Mikles M, et al. Oral enzyme combination with bromelain, trypsin and the flavonoid rutoside reduces systemic inflammation and pain when used pre- and post-operatively in elective total hip replacement: a randomized exploratory placebo-controlled trial. Ther Adv Musculoskelet Dis. 2023:15:1759720X231186875. doi: 10.1177/1759720X231186875

16. Dmitrieva LA, Atrushkevich VG, Gerasimova EV, Knorring GYu. The experience and perspectives of systemic enzyme therapy application in periodontology. Stomatologija dlja vseh. 2010;(3):52-56 (In Russ.). Available from: https://elibrary.ru/item.asp?id=15416050

17. Dmitrieva LA, Nemeryuk DA, Gerasimova EV, Glibina NA. Possibility of combined system enzyme therapy and antioxidants in treatment of periodontal and oral mucosa diseases. Stomatologiia (Moskva). 2015;94(2):69-72 (In Russ.). doi: 10.17116/stomat201594269-72

18. Heitz-Mayfield LJA. Systemic antibiotics in periodontal therapy. Aust Dent J. 2009:54(1):S96-101. doi: 10.1111/j.1834-7819.2009.01147.x

19. de la Barrera-Núñez MC, Yáñez-Vico RM, Batista-Cruzado A, Heurtebise-Saavedra JM, Castillo-de Oyagüe R, Torres-Lagares D. Prospective double-blind clinical trial evaluating the effectiveness of Bromelain in the third molar extraction postoperative period. Med Oral Patol Oral Cir Bucal. 2014;19(2):e157-162. doi: 10.4317/medoral.19105

20. Sanz M, Herrera D, Kebschull M, Chapple I, Jepsen S, Beglundh T, et al. Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline. J Clin Periodontol. 2020;47(22):4-60. doi: 10.1111/jcpe.13290

21. Faramarzi M, Sadighi M, Shirmohamadi A, Kazemi R, Zohdi M. Effectiveness of Bromelain in the control of postoperative pain after periodontal surgery: A crossover randomized clinical trial. J Adv Periodontol Implant Dent. 2023;15(1):22-27. doi: 10.34172/japid.2023.002

22. de la Fuente M, Lombardero L, Gómez-González A, Solari C, Angulo-Barturen I, Acera A, et al. Enzyme Therapy: Current Challenges and Future Perspectives. Int J Mol Sci. 2021;22(17):9181. doi: 10.3390/ijms22179181

23. Nazir M, Al-Ansari A, Al-Khalifa K, Alhareky M, Gaffar B, Almas K. Global Prevalence of Periodontal Disease and Lack of Its Surveillance. ScientificWorldJournal. 2020:2146160. doi: 10.1155/2020/2146160.

24. Hikisz P, Bernasinska-Slomczewska J. Beneficial Properties of Bromelain. Nutrients. 2021;13(12):4313. doi: 10.3390/nu13124313

25. Jayachandran S, Khobre P. Efficacy of Bromelain along with Trypsin, Rutoside Trihydrate Enzymes and Diclofenac Sodium Combination Therapy for the treatment of TMJ Osteoarthritis - A Randomised Clinical Trial. J Clin Diagn Res. 2017;11(6):ZC09-ZC11. doi: 10.7860/JCDR/2017/25771.9964

26. Tharani Kumar S, Ashok Prasanna R, Kirubanandan JR, Elaveyini U, Prasanna Devi S, Balasubramaniam M. Postoperative Healing after Surgical Removal of Mandibular Third Molar: A Comparative Study between Two Proteolytic Enzymes. J Pharm Bioallied Sci. 2020;12(1):S289-S294. doi: 10.4103/jpbs.JPBS_87_20

27. Soheilifar S, Bidgoli M, Hooshyarfard A, Shahbazi A, Vahdatinia F, Khoshkhooie F. Effect of Oral Bromelain on Wound Healing, Pain, and Bleeding at Donor Site Following Free Gingival Grafting: A Clinical Trial. J Dent (Tehran). 2018;15(5):309-316. Available from: https://pubmed.ncbi.nlm.nih.gov/30833977/

28. Lorenzo-Erro SM, Andrade E, Massa F, Colistro V, Asquino N, Moliterno P. Periodontitis prevalence and associated factors: a comparison of two examination protocols. Acta Odontol Latinoam. 2022; 35(3):178-187. doi: 10.54589/aol.35/3/178

29. Singh T, More V, Fatima U, Karpe T, Aleem MA, Prameela J. Effect of proteolytic enzyme bromelain on pain and swelling after removal of third molars. J Int Soc Prev Community Dent. 2016;6(3):S197-S204. doi: 10.4103/2231-0762.197192

30. Marzin T, Lorkowski G, Reule C, Rau S, Pabst E, Vester JC, et al. Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial. BMJ Open Sport Exerc Med. 2016;2(1):e000191. doi: 10.1136/bmjsem-2016-000191

31. Rathnavelu V, Alitheen NB, Sohila S, Kanagesan S, Ramesh R. Potential role of bromelain in clinical and therapeutic applications. Biomed Rep. 2016;5(3):283–288. doi: 10.3892/br.2016.720

32. Grabs V, Nieman DC, Haller B, Halle M, Scherr J. The effects of oral hydrolytic enzymes and flavonoids on inflammatory markers and coagulation after marathon running: study protocol for a randomized, double-blind, placebocontrolled trial. BMC Sports Sci Med Rehabil. 2014;6(1):8. doi: 10.1186/2052-1847-6-8

33. Yuan X, Zhou F, Wang H, Xu X, Xu S, Zhang C, et al. Systemic antibiotics increase microbiota pathogenicity and oral bone loss. Int J Oral Sci. 2023;15(1):4. doi: 10.1038/s41368-022-00212-1

34. Henrotin YE, Michlmayr C, Rau SM, Quirke AM, Bigoni M, Ueberall MA. Combination of Enzymes and Rutin to Manage Osteoarthritis Symptoms: Lessons from a Narrative. Review of the Literature. 2022;9(5):1305-1327. doi: 10.1007/s40744-022-00472-7