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Drug-Induced Gingival Overgrowth
Drug-Induced Gingival Overgrowth Nuha Nakib, DDS, MS, and Seema S. Ashrafi, DDS, MS An increasing number of dental patients are being treated with multiple medications; some of these medications have an adverse reaction on the mouth and periodontal tissues. One of the unwanted side effects of these drugs is gingival overgrowth. Gingival overgrowth is associated mainly with 3 types of drugs: 1. Antiepileptic drugs, especially Phenytion (Dilantin) 2. Calcium channel blockers, such as nifedipine 3. Immunosuppressant drugs, mainly cyclosporine Although these drugs have different pharmacologic effects on the body, they seem to influence the same tissues in the periodontium, mainly the gingival connective tissues, causing common clinical and histopathological findings.1
Prevalence The prevalence of gingival overgrowth is difficult to determine accurately in each drug category, because studies and reports used dissimilar parameters, such as contrasting populations (institutionalized vs outpatients), age of the patient, underlying medical conditions, periodontal assessments, combined medications, severity of the condition, and others.2 Bearing this difficulty in mind, it has been reported that the prevalence of gingival overgrowth in patients taking phenytoin ranges from 0% to 84% with an average effect of around 50%, with an increased prevalence in children and institutionalized people reported.3 Drug-induced gingival overgrowth was found to be rare in patients taking other antiepileptic drugs, such as valproic acid, (Depacon) Phenobarbiton (⬍5%) (phenobarbital, Donnatal), and carbamazepine (Tegretol) (number 3). The prevalence of calcium channel blockers has been reported to be 15-85% with an average composite of around 42%, in patients taking nifedipine (adalat, procardia),4 while the prevalence with other calcium Dis Mon 2011;57:225-230 0011-5029/2011 $36.00 ⫹ 0 doi:10.1016/j.disamonth.2011.03.010 DM, April 2011
225
channel blockers, such as varapamil, dilatiazem, felodipine, or amlodipine, is significantly less and reported to be around 5%.5,6 Multiple studies on the prevalence of the immunosuppressant drug cyclosporine have reported an average of 25%-50% in adults and significantly higher prevalence being reported in children, with more than 70-97%.7 These differences in the prevalence of drug-induced gingival enlargement may be related to multiple parameters used in the studies, such as drug dosage, plasma concentration and duration of drug use, periodontal health, and other factors.8
Risk Factors A variety of risk factors for drug-induced gingival overgrowth have been identified. Some of these factors are as follows.
Plaque According to the Academy of Periodontology report, the patient’s oral hygiene represents a significant risk factor for drug-induced gingival overgrowth. Plaque-induced inflammation can exacerbate the effect of medications, leading to a combined effect on the gingival tissues and leading to excessive gingival enlargement. Some investigators believe that inflammation is a prerequisite for gingival enlargement that could be prevented by proper plaque removal, thus highlighting the importance of plaque control in these patients.9 The role of plaque as an important cofactor has been recognized in the classification of periodontal diseases. One of the categories of this classification is “plaque-induced gingival diseases modified by medications,” thus acknowledging the important role of plaque and its effect on gingival overgrowth.1 Despite this association, it has been reported that drug-induced gingival enlargement can occur in mouths with good oral hygiene and minimum plaque and can be absent in mouths that have poor oral hygiene and heavy amounts of plaque, which might be explained by genetic and susceptibility factors.10 However, there is an agreement in the literature that improving patient oral hygiene and reducing inflammation will have a positive impact on reducing gingival overgrowth.
Age Reports showed that age is a risk factor in patients who are taking dilantin and cyclosporine, but not an important factor in patients who are 226
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using calcium channel blockers because most of the patients on calcium channel blockers are middle aged or older.2 Children and teenagers are more susceptible to gingival overgrowth, suggesting a hormonal component.11 It has been theorized that with high levels of circulating androgens, this can have a stimulating effect on gingival fibroblasts to increase collagen synthesis, thus increasing the risk for gingival overgrowth in this age group.12
Gender Ellis et al5 reported that males are 3 times more likely to develop overgrowth than females in patients taking nifedipine. Other reports showed this to be true of patients receiving cyclosporine but not in patients who are on dilantin.1
Drug Variables The daily dose, blood level, salivary levels, and gingival crevicular levels of the drugs have been related to the presence of gingival overgrowth. This effect is dose-related, with minimum baseline and threshold level required to induce gingival changes. In the case of patients taking phenytoin, the plasma level of phenytoin necessary to maintain seizure control is 10-20 g/mL and this plasma level exceeds the minimal threshold dose needed to induce gingival enlargement.2 In the case of calcium channel blockers, Ellis et al assayed nifedipine levels in the plasma and gingival crevicular fluid and found that patients with high drug concentration in the crevicular fluid (gingival crevicular fluid) developed gingival enlargement, in contrast to patients where the drug could not be detected in the gingival crevicular fluid and the patients failed to develop gingival overgrowth.9 Gingival overgrowth was reported on a patient taking a dose of 500 mgd⫺1 of cyclosporine.12 The effect of these drugs on the gingiva was found to be reversible when the medications were discontinued. Other risk factors that can be important in drug-induced gingival overgrowth are multiple medications, genetics, and others.
Clinical Manifestations The onset of drug-induced gingival overgrowth appears within the first 3 months of drug administration.3 The growth starts in the interdental papillae and extends to the facial and lingual aspects of the gingival margin and may involve the attached gingival, as seen in Figure 1.4 This enlargement may continue to grow and develop to become a massive amount of tissue that covers the crowns of the teeth and can interfere with DM, April 2011
227
FIG 1. A case of drug induced gingival overgrowth. (Courtesy of the Periodontal Department, College of Dentistry, University of Illinois.) (Color version of figure is available online.)
mastication, speech, and esthetics and can lead to shifting of teeth and malocclusion. Gingival enlargement can also complicate the patient’s oral hygiene and the patient ability to clean the teeth, thus increasing the inflammatory process and in return further increasing gingival overgrowth. The appearance of gingival overgrowth in patients on cyclosporine varies slightly and presents with a more vascularized, lobulated, inflamed gingiva that bleeds easily in comparison with a more fibrotic and uniform growth in patients with dilantin medications.7
Histopathology The main histologic features of gingival overgrowth were the predominant fibrotic changes in the connective tissue, especially the collagenous component with an increase in fibroblasts, an accumulation of extracellular matrix, and various levels of inflammation (more pronounced in cyclosporine-induced enlargements), thickening of the epithelium with proliferation, and elongation of rete ridges.3 It has been hypothesized that the mechanism through which these medications trigger the connective tissue response could be that individuals who develop gingival overgrowth may have fibroblasts with an abnormal susceptibility to these medications.1
Prevention and Treatment Because plaque has been identified to be an important risk factor for gingival overgrowth, meticulous plaque control measures, combined with strict maintenance therapy, will be one of the essential methods of 228
DM, April 2011
prevention for patients receiving these drugs. Patients who are taking these medications should be informed about the importance of these measures. The resultant effect of a rigorous plaque control habit for these patients will be reduction of inflammation and the risk of gingival overgrowth. The most effective treatment for patients who present with gingival enlargement is the possibility of withdrawal of the medication and substitution with others. It has been found that it takes 1-8 weeks for resolution of gingival enlargement after discontinuing or switching these medications.13 Professional debridement with scaling and root planing combined using antimicrobials, such as mouthwashes and antibiotics (azithromycin or metronidazole), can reduce the gingival enlargements in patients receiving these drugs.1 Finally surgical treatment of gingival enlargement is also indicated for some patients, especially in patients with severe fibrotic growths that are compromising esthetics and function.
REFERENCES 1. 2. 3.
4. 5.
6. 7. 8.
9.
10.
Dongari-Bagtzoglou A. Academy report. Informational paper. Drug-induced gingival enlargement. J Periodontol 2004;75:1424-31. Seymour RA. Effects of medications on the periodontal tissues in health and disease. Periodontol 2000 2006;40:120-9. Hallmon WW, Rossman JA. The role of drugs in the pathogenis of gingival overgrowth. A collective review of current concepts. Periodontol 2000 1999;21: 176-96. Barclay S, Thompson JM, Idle JR, et al. The incidence and severity of nifidipineinduced gingival overgrowth. J Clin Periodontol 1992;19:311-4. Ellis JS, Seymore RA, Steele JG et al. Prevalence of gingival overgrowth induced by calcium channel blockers: A community based study. J Periodontol 1999;70: 63-7. Kaur G, Verhamme KMC, Dieleman JP, et al. Association between calcium channel blockers and gingival hyperplasia. J Clin Periodontal 2010;37:625-30. Seymore R, Heasman P. Drugs and the periodontium. J Clin Periodontal 1988; 15:1-16. King GN, Fullinfaw R, Higgins TJ, et al. Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists. J Clin Periodontol 1993;20:286-93. Nuki K, Cooper SH. The role of inflammation in the pathogenesis of gingival enlargement during the administration of diphenylhydantion sodium in cats. J Periodontal Res 1972;7:91. Carranza FA, Hogan E. Gingival enlargement chapter 23; Philaelphia PA: WB Saunders company, 2002. p. 281-85.
DM, April 2011
229
11.
12. 13.
230
Ellis JS, Seymore RA, Monkman SC, et al. Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug-induced gingival overgrowth. J Periodontal Res 1993;28:373-8. Seymore RA, Jacobs DJ. Cyclosporine and gingival tissues. J Clin Periodontol 1992;19:1-11. Khocht A, Schneider LC. Periodontal management of gingival overgrowth in the heart transplant patient: A case report. J Periodontol 1997;68:1140-6.
DM, April 2011
Prevalence The prevalence of gingival overgrowth is difficult to determine accurately in each drug category, because studies and reports used dissimilar parameters, such as contrasting populations (institutionalized vs outpatients), age of the patient, underlying medical conditions, periodontal assessments, combined medications, severity of the condition, and others.2 Bearing this difficulty in mind, it has been reported that the prevalence of gingival overgrowth in patients taking phenytoin ranges from 0% to 84% with an average effect of around 50%, with an increased prevalence in children and institutionalized people reported.3 Drug-induced gingival overgrowth was found to be rare in patients taking other antiepileptic drugs, such as valproic acid, (Depacon) Phenobarbiton (⬍5%) (phenobarbital, Donnatal), and carbamazepine (Tegretol) (number 3). The prevalence of calcium channel blockers has been reported to be 15-85% with an average composite of around 42%, in patients taking nifedipine (adalat, procardia),4 while the prevalence with other calcium Dis Mon 2011;57:225-230 0011-5029/2011 $36.00 ⫹ 0 doi:10.1016/j.disamonth.2011.03.010 DM, April 2011
225
channel blockers, such as varapamil, dilatiazem, felodipine, or amlodipine, is significantly less and reported to be around 5%.5,6 Multiple studies on the prevalence of the immunosuppressant drug cyclosporine have reported an average of 25%-50% in adults and significantly higher prevalence being reported in children, with more than 70-97%.7 These differences in the prevalence of drug-induced gingival enlargement may be related to multiple parameters used in the studies, such as drug dosage, plasma concentration and duration of drug use, periodontal health, and other factors.8
Risk Factors A variety of risk factors for drug-induced gingival overgrowth have been identified. Some of these factors are as follows.
Plaque According to the Academy of Periodontology report, the patient’s oral hygiene represents a significant risk factor for drug-induced gingival overgrowth. Plaque-induced inflammation can exacerbate the effect of medications, leading to a combined effect on the gingival tissues and leading to excessive gingival enlargement. Some investigators believe that inflammation is a prerequisite for gingival enlargement that could be prevented by proper plaque removal, thus highlighting the importance of plaque control in these patients.9 The role of plaque as an important cofactor has been recognized in the classification of periodontal diseases. One of the categories of this classification is “plaque-induced gingival diseases modified by medications,” thus acknowledging the important role of plaque and its effect on gingival overgrowth.1 Despite this association, it has been reported that drug-induced gingival enlargement can occur in mouths with good oral hygiene and minimum plaque and can be absent in mouths that have poor oral hygiene and heavy amounts of plaque, which might be explained by genetic and susceptibility factors.10 However, there is an agreement in the literature that improving patient oral hygiene and reducing inflammation will have a positive impact on reducing gingival overgrowth.
Age Reports showed that age is a risk factor in patients who are taking dilantin and cyclosporine, but not an important factor in patients who are 226
DM, April 2011
using calcium channel blockers because most of the patients on calcium channel blockers are middle aged or older.2 Children and teenagers are more susceptible to gingival overgrowth, suggesting a hormonal component.11 It has been theorized that with high levels of circulating androgens, this can have a stimulating effect on gingival fibroblasts to increase collagen synthesis, thus increasing the risk for gingival overgrowth in this age group.12
Gender Ellis et al5 reported that males are 3 times more likely to develop overgrowth than females in patients taking nifedipine. Other reports showed this to be true of patients receiving cyclosporine but not in patients who are on dilantin.1
Drug Variables The daily dose, blood level, salivary levels, and gingival crevicular levels of the drugs have been related to the presence of gingival overgrowth. This effect is dose-related, with minimum baseline and threshold level required to induce gingival changes. In the case of patients taking phenytoin, the plasma level of phenytoin necessary to maintain seizure control is 10-20 g/mL and this plasma level exceeds the minimal threshold dose needed to induce gingival enlargement.2 In the case of calcium channel blockers, Ellis et al assayed nifedipine levels in the plasma and gingival crevicular fluid and found that patients with high drug concentration in the crevicular fluid (gingival crevicular fluid) developed gingival enlargement, in contrast to patients where the drug could not be detected in the gingival crevicular fluid and the patients failed to develop gingival overgrowth.9 Gingival overgrowth was reported on a patient taking a dose of 500 mgd⫺1 of cyclosporine.12 The effect of these drugs on the gingiva was found to be reversible when the medications were discontinued. Other risk factors that can be important in drug-induced gingival overgrowth are multiple medications, genetics, and others.
Clinical Manifestations The onset of drug-induced gingival overgrowth appears within the first 3 months of drug administration.3 The growth starts in the interdental papillae and extends to the facial and lingual aspects of the gingival margin and may involve the attached gingival, as seen in Figure 1.4 This enlargement may continue to grow and develop to become a massive amount of tissue that covers the crowns of the teeth and can interfere with DM, April 2011
227
FIG 1. A case of drug induced gingival overgrowth. (Courtesy of the Periodontal Department, College of Dentistry, University of Illinois.) (Color version of figure is available online.)
mastication, speech, and esthetics and can lead to shifting of teeth and malocclusion. Gingival enlargement can also complicate the patient’s oral hygiene and the patient ability to clean the teeth, thus increasing the inflammatory process and in return further increasing gingival overgrowth. The appearance of gingival overgrowth in patients on cyclosporine varies slightly and presents with a more vascularized, lobulated, inflamed gingiva that bleeds easily in comparison with a more fibrotic and uniform growth in patients with dilantin medications.7
Histopathology The main histologic features of gingival overgrowth were the predominant fibrotic changes in the connective tissue, especially the collagenous component with an increase in fibroblasts, an accumulation of extracellular matrix, and various levels of inflammation (more pronounced in cyclosporine-induced enlargements), thickening of the epithelium with proliferation, and elongation of rete ridges.3 It has been hypothesized that the mechanism through which these medications trigger the connective tissue response could be that individuals who develop gingival overgrowth may have fibroblasts with an abnormal susceptibility to these medications.1
Prevention and Treatment Because plaque has been identified to be an important risk factor for gingival overgrowth, meticulous plaque control measures, combined with strict maintenance therapy, will be one of the essential methods of 228
DM, April 2011
prevention for patients receiving these drugs. Patients who are taking these medications should be informed about the importance of these measures. The resultant effect of a rigorous plaque control habit for these patients will be reduction of inflammation and the risk of gingival overgrowth. The most effective treatment for patients who present with gingival enlargement is the possibility of withdrawal of the medication and substitution with others. It has been found that it takes 1-8 weeks for resolution of gingival enlargement after discontinuing or switching these medications.13 Professional debridement with scaling and root planing combined using antimicrobials, such as mouthwashes and antibiotics (azithromycin or metronidazole), can reduce the gingival enlargements in patients receiving these drugs.1 Finally surgical treatment of gingival enlargement is also indicated for some patients, especially in patients with severe fibrotic growths that are compromising esthetics and function.
REFERENCES 1. 2. 3.
4. 5.
6. 7. 8.
9.
10.
Dongari-Bagtzoglou A. Academy report. Informational paper. Drug-induced gingival enlargement. J Periodontol 2004;75:1424-31. Seymour RA. Effects of medications on the periodontal tissues in health and disease. Periodontol 2000 2006;40:120-9. Hallmon WW, Rossman JA. The role of drugs in the pathogenis of gingival overgrowth. A collective review of current concepts. Periodontol 2000 1999;21: 176-96. Barclay S, Thompson JM, Idle JR, et al. The incidence and severity of nifidipineinduced gingival overgrowth. J Clin Periodontol 1992;19:311-4. Ellis JS, Seymore RA, Steele JG et al. Prevalence of gingival overgrowth induced by calcium channel blockers: A community based study. J Periodontol 1999;70: 63-7. Kaur G, Verhamme KMC, Dieleman JP, et al. Association between calcium channel blockers and gingival hyperplasia. J Clin Periodontal 2010;37:625-30. Seymore R, Heasman P. Drugs and the periodontium. J Clin Periodontal 1988; 15:1-16. King GN, Fullinfaw R, Higgins TJ, et al. Gingival hyperplasia in renal allograft recipients receiving cyclosporin-A and calcium antagonists. J Clin Periodontol 1993;20:286-93. Nuki K, Cooper SH. The role of inflammation in the pathogenesis of gingival enlargement during the administration of diphenylhydantion sodium in cats. J Periodontal Res 1972;7:91. Carranza FA, Hogan E. Gingival enlargement chapter 23; Philaelphia PA: WB Saunders company, 2002. p. 281-85.
DM, April 2011
229
11.
12. 13.
230
Ellis JS, Seymore RA, Monkman SC, et al. Disposition of nifedipine in plasma and gingival crevicular fluid in relation to drug-induced gingival overgrowth. J Periodontal Res 1993;28:373-8. Seymore RA, Jacobs DJ. Cyclosporine and gingival tissues. J Clin Periodontol 1992;19:1-11. Khocht A, Schneider LC. Periodontal management of gingival overgrowth in the heart transplant patient: A case report. J Periodontol 1997;68:1140-6.
DM, April 2011