Incidence of Verapamil-Induced Gingival Hyperplasia in a Dental
Population Craig S.
Miller* and
Douglas D. Damm"1
The records of 5,000 dental patients were reviewed for history of Verapamil use between 1987 and 1990. Twenty-four dentate patients who received Verapamil for more than 1 year were identified. Of these, gingival hyperplasia occurred in 1 patient (4.1%) that was limited to the mandibular attached gingiva. Onset of gingival overgrowth was associated with drug dosage, bacterial accumulation, and gingival inflammation. His tologically, the findings resembled that seen in hyperplasia induced by phenytoin, cyclosporin, and other calcium channel blockers. Our data suggest that gingival hyperplasia caused by Verapamil occurs less frequently than nifedipine-induced gingival hyperplasia. /. Periodontol 1992; 63:453-456.
KeyWords: Gingival hyperplasia/etiology; verapamil/adverse effects; phenytoin/adverse effects; cyclosporin/adverse effects; nifedipine/adverse effects.
Verapamil is a slow, calcium channel blocking agent known to cause gingival hyperplasia. The clinical and histologie findings associated with this phenomenon are well established. Gingival hyperplasia occurs most frequently in the labial anterior gingiva in the presence of bacterial accumulation and gingival inflammation.1'2 Swelling begins interdentally, with eventual encroachment on the adjacent tooth crown. Nodular enlargement occurs when interventive therapy is withheld. Microscopically, one sees collagenous hyperplasia, acanthotic epithelium with elongated test-tubelike rete ridges, and varying amounts of subepithelial inflammatory infiltrate. The clinical and microscopic features are remarkably similar to those induced by phenytoin, cyclosporin, and other calcium channel blocking agents.14 Nifedipine is the most recognized calcium channel blocking drug associated with gingival hyperplasia. Over 70 cases of nifedipine-induced gingival hyperplasia have been reported (Table 1). The incidence of nifedipine-induced gingival enlargement varies from 0.5 to 83%. The Barak et al. study of 34 cardiac patients taking nifedipine showed that gingival hyperplasia occurred in 14.7% of these patients.9 Fattore et al. studied 89 veterans and found hyperplastic gingiva in 83% of those on nifedipine and 74% on diltiazem.10 Drug reference texts report the incidence of gingival hyperplasia caused by calcium channel blockers to range from 0.5 to 3%.35·36 In contrast, there is a paucity of reports of
verapamil-
Diagnosis/Oral Medicine Section, Department of Oral Health University of Kentucky College of Dentistry, Lexington, KY. Oral Pathology Section. *Oral
ence,
Sci-
Table 1. Calcium Channel
Hyperplasia
Blocking Drugs Associated with Gingival Cases
Generic Name
Diltiazem5-7-10
Felodipine8 31 Nifedipine9 Nitrendipine32 Verapamil33-34
Trade Name Cardizem
Splendil
Adalat, Procardia Baypress Calan, Isoptin
Reported 30 1
80 1 3
Verelan
induced gingival hyperplasia and the incidence remains poorly defined. Therefore, this study determined the incidence of gingival hyperplasia caused by Verapamil in a dental
population.
MATERIALS AND METHODS Records of 5,000 dental patients were reviewed for history of Verapamil use between 1987 and 1990. Twenty-four dentate patients who received Verapamil for more than 1 year were identified. The amount and type of each prescription medication taken by patients were recorded. Patients taking other drugs known to induce gingival hyperplasia were excluded from study. A minimum of 10 anterior teeth were required for inclusion of patients in the study. Patient's ages ranged from 24 to 76 years, with the mean age of 55.8 years. Thirteen patients were male and 11 female; 18 were white and 6 black. All patients were examined clinically by 1 examiner. The attached and marginal gingiva were inspected for signs of hyperplasia and the periodontal crevicular depths were re-
454
J Periodontol May 1992
VERAPAMIL-INDUCED GINGIVAL HYPERPLASIA Table 2.
Gingival Hyperplasia
in
a
Dental
Population Anterior Teeth
Grade of
Age/Race/Sex 53 24 61 51 43 41 59 50 52 71 58 65 36 56 63 56 50 54 65 68 62 62 76 63
Gingival Hyperplasia
WM WM WM WM BM WF WM WM BF BF WF WM WM BF WF BF WM WF WM BF WM WF WM WF
Mean 55.8 *
Gingival
Verapamil dosage mg/day
Duration of Treatment
Mean Sulcular
(months)
Depth (mm)
480 240 240 240 240 360 120 240 180 240 240 240 120 240 360 240 240 120 120 240 120 120 360 240
15 52 51 28 20 60 26 14 21 12 16 17 27 12 85 12 24 54 27 12 17 24 20 25
232.5
29.2
Plaque (%)
Index
Bleeding (%)
Index
2.94 1.80 3.42 3.61 3.84 2.51 4.51 *2.69 3.12 *2.31 2.72 *2.88 *3.29 2.65 2.57 •1.92 2.82 *2.74 2.51 *2.12 3.04 2.38 2.99 2.47
94.1 10.1 62.1 66.2 83.3 8.3 100.0 20.8 91.7 16.7 33.0 66.7 58.3 79.2 50.0 37.5 41.7 54.2 41.7 12.5 58.3 29.2 4.2 25.0
45.8 8.3 50.0 54.2 45.8 29.2 83.3 25.0 100.0 25.0 45.8 16.7 58.3 29.2 45.8 29.2 45.8 37.5 58.3 8.3 62.5 37.5 37.5 45.8
2.83
47.7
42.7
recession noted.
and Goaz.38 The height of gingival tissue was measured from the cemento-enamel junction to the free gingival margin. The gingival width was measured from the enamel tooth surface to the labial margin of the gingival tissue. The following grades were assigned. Grade 0, no hyperplasia normal gingiva. Grade 1, minimal hyperplasia less than 2 mm increased in size and gingiva covered the cervical third or less of the anatomic crown. Grade 2, moderate hyperplasia 2 to 4 mm increased in size, and/or gingiva extended into middle third of anatomic nodular growth greater crown. Grade 3, severe hyperplasia than 4 mm increased in size, and/or gingiva covered more than two-thirds of the tooth crown. Patients who had hyperplastic gingiva were provided monthly non-surgical periodontal therapy that included root curettage, scaling and polishing, and oral hygiene instructions. If nonresponsive to therapy after 3 months, the hyperplastic tissue was excised, fixed in 10% neutral formalin, and processed for histologie examination.
gelopoulos
=
=
=
=
1. Firm, bulbous, interdental papillae initial presentation.
Figure
of mandibular incisors
at
corded. The Gingival Bleeding Index and Visible Plaque Index by Ainamo and Bay were used to assess gingival health and plaque accumulation.37 Positive findings were expressed as a percentage derived from the number of surfaces affected divided by the total number of surfaces examined. Gingival hyperplasia was identified by location and graded according to a modified index originally described by An-
RESULTS
Twenty-four dental patients, with a minimum of 10 anterior teeth, who took Verapamil for 1 or more years were studied. Table 2 shows the relationship of age, race, sex, gingival hyperplasia, degree of hyperplasia, plaque index, bleeding index, mean sulcular depth of the anterior teeth, and dosage of Verapamil taken by study participants. Gingival hyperplasia occurred clinically in 1 patient. On-
Volume 63 Number 5
MILLER,
Figure 2. Parakeratotic, acanthotic, stratified, squamous epithelium overlying fibrous connnective tissue (hematoxylin and eosin; original magnification, 20; bar 50 µ ).
DAMM
Figure 3. Abundant fibroblasts and anastomosing elongated (hematoxylin and eosin; original magnification, 40; bar
=
rete
50
455
ridges µ ).
=
cardiac and vascular smooth muscle mema result, Verapamil relaxes muscular blood reduces vessels, myocardial oxygen consumption, and decreases arterial blood pressure. Currently, Verapamil ranks 13th on the list of most-frequently-prescribed, refillable medications.41 Popularity of the drug is explained by its specificity of action, low cost, 24-hour controlled-release formulation, and low side effect profile. Gingival hyperplasia is an infrequent adverse effect of Verapamil use. It is estimated to occur in less than 5% of those who take the drug. In this dental population the incidence of verapamil-induced gingival hyperplasia was 4.1%. This is lower than the 14% to 83% incidence of gingival hyperplasia in patients taking nifedipine reported by dental researchers.9'27,28 It suggests that Verapamil is a less potent inducer of gingival overgrowth than nifedipine. This premise is supported by the paucity of cases of verapamil-induced gingival hyperplasia in the literature compared to that of nifedipine. Both drugs entered the market in 1982. The premise is also supported by data from a retrospective analysis of 10,000 biopsy specimens at our pathology service that revealed that cases of verapamil-induced gingival hyperplasia were submitted for analysis 50% less often than that of nifedipine. Verapamil-induced gingival hyperplasia begins several ions
set of hyperplasia began in the third month of drug treatment. The dosage of Verapamil taken by this patient exceeded
twice the
mean
dose of other
Index, Gingival Bleeding
patients.
The Visible Plaque sulcular depth exceeded the mean hyperplasia
Index, and
mean
of the patient with gingival values of patients without gingival hyperplasia. Clinically, the hyperplastic tissue was localized to the anterior mandibular labial gingiva (Fig. 1). The gingiva was firm, bulbous, asymptomatic, pale pink, and stippled. The marginal gingiva was erythematous and covered minimally the interdental region of adjacent tooth crowns. Microscopically, the gingival specimen showed parakeratotic, acanthotic, stratified squamous epithelium (Fig. 2). Thin,
elongated, anastomosing rete ridges were variably present (Fig. 3). The underlying lamina propria consisted of wellcollagenized, fibrous connective tissue; scattered small vascular channels; and aggregates of lymphocytes and plasma cells.
DISCUSSION Verapamil is a calcium channel blocking agent important to dentistry. It is used in the treatment of angina pectoris, essential hypertension, and supraventricular arrhythmias. Verapamil inhibits the movement of extracellular calcium
across
branes.39'40 As
456
J Periodontol May 1992
VERAPAMIL-INDUCED GINGIVAL HYPERPLASIA
weeks to several months after initiation of therapy. The clinical histologie picture is strikingly similar to that caused by phenytoin, cyclosporin, and other calcium channel blocking agents. Significant levels of drug, bacterial accumulation, and gingival inflammation are essential to induce gingival hyperplasia.42 45 However, the presence of minimum or threshold values of drug, bacteria, and inflammation have yet to be determined. Strict plaque control 45 Discontinuation of measures limit disease progression.42 the drug results in regression of the overgrowth.
21.
-
22.
23. 24. 25. 26. 27.
REFERENCES 1.
Wynn Dent
RL. Calcium channel blockers and
1991;39:240-243.
gingival hyperplasia.
Lundergan WP. Drug-induced gingival enlargements. Calif Dent Assn J 1989;17:48-52. 3. Carranza FA. Glickman's Clinical Periodontology. 7th ed. Philadelphia: WB Saunders Co.; 1990:125-134. 4. Butler RT, Kalkwarf KL, Kaidahl WB. Drug induced gingival hyperplasia: Phenytoin, cyclosporin, and nifedipine. J Am Dent Assoc 1987;114:56-60. JM, Levy BA, Grubb
5. Bowman
RV. Gingival overgrowth induced by diltiazem.Ora/ Surg Oral Med Oral Pathol 1988;65:183-185. 6. Giustiniani S, Cuna FR, Marieni M. Hyperplastic gingivitis during diltiazem therapy. Jnt J Cardiol 1987;15:247-249. 7. Colvard MD, Bishop J, Weissman D, Gargiulo AV. Cardizem induced gingival hyperplasia: A report of two cases. Periodont Case
Rep 1986;8:67-68.
8. Lombardi , Fiore-Donno G, Belser U, Di Felice R. Felodipineinduced gingival hyperplasia: A clinical and histologie study. J Oral Pathol Med 1991;20:89-92. 9. Barak S, Engelberg IS, Hiss J. Gingival hyperplasia caused by nifedipine histopathologic findings. J Periodontol 1987;58:639-642. 10. Fattore L, Stablein M, Bredfeldt G, et al. Gingival hyperplasia: A side effect of nifedipine and diltiazem. Spec Care Dent 1991;11:107109. 12. Nishikawa S, Tada H, Hamasaki A, et al. Nifedipine-induced gingival hyperplasia: A clinical and in vitro study. J Periodontol 1991;62:3035. 13. Lederman D, Lumerman H, Reuben S, Freedman PD. Gingival hyperplasia associated with nifedipine therapy. Oral Surg Oral Med Oral Pathol 1984;57:620-622. 14. Bencini PL, Crosti C, Sala F, et al. Gingival hyperplasia by nifedipine: Report of case. Acta Derm Venereol (Stockholm) 1985;65:362365. 15. Lucas RM, Howell LP, Wall BA. Nifedipine-induced gingival hyperplasia. A histochemical and ultrastructural study. J Periodontol -
1985;56:211-215.
16. Ramon Y, Behar S, Kishon Y, Engelberg IS. Gingival hyperplasia caused by nifedipine a preliminary report. IntJ Cardiol 1984;5:195204. 17. Satoth T, Uchikawa H, Tokiyasu Y, et al. Gingival hyperplasia induced by nifedipine. Jpn J Maxillofac Surg 1988;34:2025-2030. 18. Shaftic AA, Widdup LL, Abate MA, Jacknowitz AI. Nifedipineinduced gingival hyperplasia. Drug Intell Clin Pharm 1986;20:602605. 19. Van der Wall EE, Tuinzing DB, Hes J. Gingival hyperplasia induced by nifedipine, an arterial vasodilating drug. Oral Surg Oral Med Oral Pathol 1985;60:38^10. 20. Bezan KT. Gingival enlargement secondary to nifedipine therapy. Gen Dent 1987;35:353-354. -
Issue):699(Abstr. 248).
Gen
2.
Myrhed M, Wiholm BE. Nifedipine a survey of adverse effects. Acta Pharmacol Toxicol 1986;58(Suppl 2):133-136. Barak S, Kaplan I. The C02 laser in the excision of gingival hyperplasia caused by nifedipine. / Clin Periodontol 1988;15:633-635. Tagawa T, Nakamura H, Murata M. Marked gingival hyperplasia induced by nifedipine. Int J Oral Maxillofac Surg 1989;19:72-73. Jones CM. Gingival hyperplasia associated with nifedipine. Br Dent J 1986;160:416-417. Puolijoki H, Siitonen L, Saha H, Suojanen I. Gingival hyperplasia caused by nifedipine. Proc Finn Dent Soc 1988;84:311-314. Scardi S, Pivootti F, Flaminio R. Gingival hyperplasia caused by nifedipine. G Ital Cardiol 1986;16:368-369. Barclay S, Thomason JM, Seymour RA. The incidence and severity of nifedipine-induced gingival overgrowth. JDentRes 1991; 70(Spec.
28. Slavin J, Taylor J. Cyclosporin, nifedipine and gingival hyperplasia. Lancet 1987;2(8561):739. 29. Sooriyamoorthy M, Gower DB, Eley BM. Androgen metabolism in gingival hyperplasia induced by nifedipine and cyclosporin. / Periodont Res 1990;25:25-30. 30. Yusof WZW. Nifedipine-induced gingival hyperplasia. / Can Dent Assn 1989;55:389-391. 31. Zlotogorski A, Nyska M, Sela M, et al. Nifedipine-induced gingival hyperplasia: case reports and literature review. Israel J Med Soc
1989;25:453-455. RS, Sein , Corio R, Bottomley
32. Brown
WK. Nitrendipine-induced gingival hyperplasia. Oral Surg Oral Med Oral Pathol 1990;70:593-
596. 33. Cucchi 34.
G, Giustiniani S, Robustelli F. Gingival hyperplasia caused by Verapamil. G Ital Cardiol 1985;15:556-557. Pernu HE, Oikarinen K, Hietanen J, Knuuttila M. Verapamil-induced gingival overgrowth: A clinical, histologie, and biochemic approach.
J Oral Pathol Med 1989;18:422-425. 35. Facts and Comparisons. St. Louis: Facts and Comparisons, Inc.; 1991:149-150b. 36. Physician's Desk Reference, 45th ed. Oradell, NJ: Medical Economics Co. Inc.; 1991:2055-2058. 37. Ainamo J, Bay I. Problems and proposals for recording gingivitis and plaque. Int Dent J 1975;25:229-230. 38. Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin hyperplasia. Oral Surg Oral Med Oral Pathol 1972;34:898-906. 39. Braunwald E. Mechanism of action of calcium channel-blocking agents. Engl J Med 1982;307:1618-1627. 40. Gilman AG, Rail TW, Niew AS, Taylor P. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. New York: Pergamon Press; 1990:774-780, 805-806, 869-870. 41. Top 200 Rx Drugs of 1990. Amer Druggist 1991; 203(2):56-60. 42. Nuki I, Cooper SH. The role of inflammation in the pathogenesis of gingival enlargement during the administration of diphenylhydantoin in cats. / Periodont Res 1972;7:102-110. 43. O'Neil T, Figures K. The effects of Chlorhexidine and mechanical methods of plaque control on recurrence of gingival hyperplasia in young patients taking phenytoin. Br Dent J 1982;152:130-133. 44. Heijl L, Sundín Y. Nitrendipine-induced gingival overgrowth in dogs. J Periodontol 1989;60:104-112. 45. Daley TD, Wysocki GP, Day C. Clinical and pharmacological correlations in cyclosporin-induced gingival hyperplasia. Oral Surg Oral Med Oral Pathol 1986;62:417-421. Send reprint requests to: Dr. Craig S. Miller, Assistant Professor, Oral Medicine Section, Department of Oral Health Science, University of Kentucky College of Dentistry, Lexington, KY 40536-0084. Accepted for publication December 17, 1991.
Population Craig S.
Miller* and
Douglas D. Damm"1
The records of 5,000 dental patients were reviewed for history of Verapamil use between 1987 and 1990. Twenty-four dentate patients who received Verapamil for more than 1 year were identified. Of these, gingival hyperplasia occurred in 1 patient (4.1%) that was limited to the mandibular attached gingiva. Onset of gingival overgrowth was associated with drug dosage, bacterial accumulation, and gingival inflammation. His tologically, the findings resembled that seen in hyperplasia induced by phenytoin, cyclosporin, and other calcium channel blockers. Our data suggest that gingival hyperplasia caused by Verapamil occurs less frequently than nifedipine-induced gingival hyperplasia. /. Periodontol 1992; 63:453-456.
KeyWords: Gingival hyperplasia/etiology; verapamil/adverse effects; phenytoin/adverse effects; cyclosporin/adverse effects; nifedipine/adverse effects.
Verapamil is a slow, calcium channel blocking agent known to cause gingival hyperplasia. The clinical and histologie findings associated with this phenomenon are well established. Gingival hyperplasia occurs most frequently in the labial anterior gingiva in the presence of bacterial accumulation and gingival inflammation.1'2 Swelling begins interdentally, with eventual encroachment on the adjacent tooth crown. Nodular enlargement occurs when interventive therapy is withheld. Microscopically, one sees collagenous hyperplasia, acanthotic epithelium with elongated test-tubelike rete ridges, and varying amounts of subepithelial inflammatory infiltrate. The clinical and microscopic features are remarkably similar to those induced by phenytoin, cyclosporin, and other calcium channel blocking agents.14 Nifedipine is the most recognized calcium channel blocking drug associated with gingival hyperplasia. Over 70 cases of nifedipine-induced gingival hyperplasia have been reported (Table 1). The incidence of nifedipine-induced gingival enlargement varies from 0.5 to 83%. The Barak et al. study of 34 cardiac patients taking nifedipine showed that gingival hyperplasia occurred in 14.7% of these patients.9 Fattore et al. studied 89 veterans and found hyperplastic gingiva in 83% of those on nifedipine and 74% on diltiazem.10 Drug reference texts report the incidence of gingival hyperplasia caused by calcium channel blockers to range from 0.5 to 3%.35·36 In contrast, there is a paucity of reports of
verapamil-
Diagnosis/Oral Medicine Section, Department of Oral Health University of Kentucky College of Dentistry, Lexington, KY. Oral Pathology Section. *Oral
ence,
Sci-
Table 1. Calcium Channel
Hyperplasia
Blocking Drugs Associated with Gingival Cases
Generic Name
Diltiazem5-7-10
Felodipine8 31 Nifedipine9 Nitrendipine32 Verapamil33-34
Trade Name Cardizem
Splendil
Adalat, Procardia Baypress Calan, Isoptin
Reported 30 1
80 1 3
Verelan
induced gingival hyperplasia and the incidence remains poorly defined. Therefore, this study determined the incidence of gingival hyperplasia caused by Verapamil in a dental
population.
MATERIALS AND METHODS Records of 5,000 dental patients were reviewed for history of Verapamil use between 1987 and 1990. Twenty-four dentate patients who received Verapamil for more than 1 year were identified. The amount and type of each prescription medication taken by patients were recorded. Patients taking other drugs known to induce gingival hyperplasia were excluded from study. A minimum of 10 anterior teeth were required for inclusion of patients in the study. Patient's ages ranged from 24 to 76 years, with the mean age of 55.8 years. Thirteen patients were male and 11 female; 18 were white and 6 black. All patients were examined clinically by 1 examiner. The attached and marginal gingiva were inspected for signs of hyperplasia and the periodontal crevicular depths were re-
454
J Periodontol May 1992
VERAPAMIL-INDUCED GINGIVAL HYPERPLASIA Table 2.
Gingival Hyperplasia
in
a
Dental
Population Anterior Teeth
Grade of
Age/Race/Sex 53 24 61 51 43 41 59 50 52 71 58 65 36 56 63 56 50 54 65 68 62 62 76 63
Gingival Hyperplasia
WM WM WM WM BM WF WM WM BF BF WF WM WM BF WF BF WM WF WM BF WM WF WM WF
Mean 55.8 *
Gingival
Verapamil dosage mg/day
Duration of Treatment
Mean Sulcular
(months)
Depth (mm)
480 240 240 240 240 360 120 240 180 240 240 240 120 240 360 240 240 120 120 240 120 120 360 240
15 52 51 28 20 60 26 14 21 12 16 17 27 12 85 12 24 54 27 12 17 24 20 25
232.5
29.2
Plaque (%)
Index
Bleeding (%)
Index
2.94 1.80 3.42 3.61 3.84 2.51 4.51 *2.69 3.12 *2.31 2.72 *2.88 *3.29 2.65 2.57 •1.92 2.82 *2.74 2.51 *2.12 3.04 2.38 2.99 2.47
94.1 10.1 62.1 66.2 83.3 8.3 100.0 20.8 91.7 16.7 33.0 66.7 58.3 79.2 50.0 37.5 41.7 54.2 41.7 12.5 58.3 29.2 4.2 25.0
45.8 8.3 50.0 54.2 45.8 29.2 83.3 25.0 100.0 25.0 45.8 16.7 58.3 29.2 45.8 29.2 45.8 37.5 58.3 8.3 62.5 37.5 37.5 45.8
2.83
47.7
42.7
recession noted.
and Goaz.38 The height of gingival tissue was measured from the cemento-enamel junction to the free gingival margin. The gingival width was measured from the enamel tooth surface to the labial margin of the gingival tissue. The following grades were assigned. Grade 0, no hyperplasia normal gingiva. Grade 1, minimal hyperplasia less than 2 mm increased in size and gingiva covered the cervical third or less of the anatomic crown. Grade 2, moderate hyperplasia 2 to 4 mm increased in size, and/or gingiva extended into middle third of anatomic nodular growth greater crown. Grade 3, severe hyperplasia than 4 mm increased in size, and/or gingiva covered more than two-thirds of the tooth crown. Patients who had hyperplastic gingiva were provided monthly non-surgical periodontal therapy that included root curettage, scaling and polishing, and oral hygiene instructions. If nonresponsive to therapy after 3 months, the hyperplastic tissue was excised, fixed in 10% neutral formalin, and processed for histologie examination.
gelopoulos
=
=
=
=
1. Firm, bulbous, interdental papillae initial presentation.
Figure
of mandibular incisors
at
corded. The Gingival Bleeding Index and Visible Plaque Index by Ainamo and Bay were used to assess gingival health and plaque accumulation.37 Positive findings were expressed as a percentage derived from the number of surfaces affected divided by the total number of surfaces examined. Gingival hyperplasia was identified by location and graded according to a modified index originally described by An-
RESULTS
Twenty-four dental patients, with a minimum of 10 anterior teeth, who took Verapamil for 1 or more years were studied. Table 2 shows the relationship of age, race, sex, gingival hyperplasia, degree of hyperplasia, plaque index, bleeding index, mean sulcular depth of the anterior teeth, and dosage of Verapamil taken by study participants. Gingival hyperplasia occurred clinically in 1 patient. On-
Volume 63 Number 5
MILLER,
Figure 2. Parakeratotic, acanthotic, stratified, squamous epithelium overlying fibrous connnective tissue (hematoxylin and eosin; original magnification, 20; bar 50 µ ).
DAMM
Figure 3. Abundant fibroblasts and anastomosing elongated (hematoxylin and eosin; original magnification, 40; bar
=
rete
50
455
ridges µ ).
=
cardiac and vascular smooth muscle mema result, Verapamil relaxes muscular blood reduces vessels, myocardial oxygen consumption, and decreases arterial blood pressure. Currently, Verapamil ranks 13th on the list of most-frequently-prescribed, refillable medications.41 Popularity of the drug is explained by its specificity of action, low cost, 24-hour controlled-release formulation, and low side effect profile. Gingival hyperplasia is an infrequent adverse effect of Verapamil use. It is estimated to occur in less than 5% of those who take the drug. In this dental population the incidence of verapamil-induced gingival hyperplasia was 4.1%. This is lower than the 14% to 83% incidence of gingival hyperplasia in patients taking nifedipine reported by dental researchers.9'27,28 It suggests that Verapamil is a less potent inducer of gingival overgrowth than nifedipine. This premise is supported by the paucity of cases of verapamil-induced gingival hyperplasia in the literature compared to that of nifedipine. Both drugs entered the market in 1982. The premise is also supported by data from a retrospective analysis of 10,000 biopsy specimens at our pathology service that revealed that cases of verapamil-induced gingival hyperplasia were submitted for analysis 50% less often than that of nifedipine. Verapamil-induced gingival hyperplasia begins several ions
set of hyperplasia began in the third month of drug treatment. The dosage of Verapamil taken by this patient exceeded
twice the
mean
dose of other
Index, Gingival Bleeding
patients.
The Visible Plaque sulcular depth exceeded the mean hyperplasia
Index, and
mean
of the patient with gingival values of patients without gingival hyperplasia. Clinically, the hyperplastic tissue was localized to the anterior mandibular labial gingiva (Fig. 1). The gingiva was firm, bulbous, asymptomatic, pale pink, and stippled. The marginal gingiva was erythematous and covered minimally the interdental region of adjacent tooth crowns. Microscopically, the gingival specimen showed parakeratotic, acanthotic, stratified squamous epithelium (Fig. 2). Thin,
elongated, anastomosing rete ridges were variably present (Fig. 3). The underlying lamina propria consisted of wellcollagenized, fibrous connective tissue; scattered small vascular channels; and aggregates of lymphocytes and plasma cells.
DISCUSSION Verapamil is a calcium channel blocking agent important to dentistry. It is used in the treatment of angina pectoris, essential hypertension, and supraventricular arrhythmias. Verapamil inhibits the movement of extracellular calcium
across
branes.39'40 As
456
J Periodontol May 1992
VERAPAMIL-INDUCED GINGIVAL HYPERPLASIA
weeks to several months after initiation of therapy. The clinical histologie picture is strikingly similar to that caused by phenytoin, cyclosporin, and other calcium channel blocking agents. Significant levels of drug, bacterial accumulation, and gingival inflammation are essential to induce gingival hyperplasia.42 45 However, the presence of minimum or threshold values of drug, bacteria, and inflammation have yet to be determined. Strict plaque control 45 Discontinuation of measures limit disease progression.42 the drug results in regression of the overgrowth.
21.
-
22.
23. 24. 25. 26. 27.
REFERENCES 1.
Wynn Dent
RL. Calcium channel blockers and
1991;39:240-243.
gingival hyperplasia.
Lundergan WP. Drug-induced gingival enlargements. Calif Dent Assn J 1989;17:48-52. 3. Carranza FA. Glickman's Clinical Periodontology. 7th ed. Philadelphia: WB Saunders Co.; 1990:125-134. 4. Butler RT, Kalkwarf KL, Kaidahl WB. Drug induced gingival hyperplasia: Phenytoin, cyclosporin, and nifedipine. J Am Dent Assoc 1987;114:56-60. JM, Levy BA, Grubb
5. Bowman
RV. Gingival overgrowth induced by diltiazem.Ora/ Surg Oral Med Oral Pathol 1988;65:183-185. 6. Giustiniani S, Cuna FR, Marieni M. Hyperplastic gingivitis during diltiazem therapy. Jnt J Cardiol 1987;15:247-249. 7. Colvard MD, Bishop J, Weissman D, Gargiulo AV. Cardizem induced gingival hyperplasia: A report of two cases. Periodont Case
Rep 1986;8:67-68.
8. Lombardi , Fiore-Donno G, Belser U, Di Felice R. Felodipineinduced gingival hyperplasia: A clinical and histologie study. J Oral Pathol Med 1991;20:89-92. 9. Barak S, Engelberg IS, Hiss J. Gingival hyperplasia caused by nifedipine histopathologic findings. J Periodontol 1987;58:639-642. 10. Fattore L, Stablein M, Bredfeldt G, et al. Gingival hyperplasia: A side effect of nifedipine and diltiazem. Spec Care Dent 1991;11:107109. 12. Nishikawa S, Tada H, Hamasaki A, et al. Nifedipine-induced gingival hyperplasia: A clinical and in vitro study. J Periodontol 1991;62:3035. 13. Lederman D, Lumerman H, Reuben S, Freedman PD. Gingival hyperplasia associated with nifedipine therapy. Oral Surg Oral Med Oral Pathol 1984;57:620-622. 14. Bencini PL, Crosti C, Sala F, et al. Gingival hyperplasia by nifedipine: Report of case. Acta Derm Venereol (Stockholm) 1985;65:362365. 15. Lucas RM, Howell LP, Wall BA. Nifedipine-induced gingival hyperplasia. A histochemical and ultrastructural study. J Periodontol -
1985;56:211-215.
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