Calcium Antagonist-Induced Gingival Hyperplasia

Methods

Our evaluator-blinded, case–control, cross-sectional study was done in the hypertension, general medicine, and geriatric outpatient clinics at the Veterans Affairs Hospital in Madison, Wisconsin, from November 1991 to June 1992. All patients taking a calcium antagonist for a minimum of 3 months were eligible for enrollment and were identified from a computer-generated list. These patients were classified into three groups according to drug regimen (nifedipine, verapamil, or diltiazem) and compared with a control group selected from the same clinics that did not receive a calcium antagonist. Exclusion criteria included edentia, calcium antagonist therapy lasting less than 3 months, a history of gingival overgrowth before calcium antagonist treatment, the use of other agents associated with gingival overgrowth (for example, phenytoin or cyclosporine), or a requirement for antibiotic prophylaxis before dental procedures.

After informed consent was obtained, gingival tissue was measured from the cementoenamel junction to the free gingival margin using a periodontal probe [3] and was categorized as one of four grades according to a modified scale described by Angelopoulos and Goaz [6]. When possible, four measurements were made, one in each quadrant of the oral cavity. The quadrant with the highest grade determined the overall grading for that patient. Bleeding with probing, tenderness, and presence of nodules were noted; patients were questioned about oral hygiene. During measurement, the evaluator was blinded to the patient's treatment group. Random patients were referred to the dental department, where a dentist independently validated the measurements.

The prevalence of gingival hyperplasia in the drug and control groups was compared using the chi-square method. For statistical comparisons, all gingival grades greater than 0 were combined. This method was also used to compare other prevalence data relative to grade. The means for age, duration of therapy, and frequency of brushing and flossing were compared using a two-tailed t-test.

Results

Of 324 patients screened, 63% were excluded because of edentia. Therefore, of 120 eligible male patients, 115 completed the study. The mean age of patients receiving nifedipine was 63 years (median age, 66 years; range, 40 to 78 years); of patients receiving diltiazem, 68 years (median age, 69 years; range, 55 to 79 years); of patients receiving verapamil, 63 years (median age, 65 years; range, 34 to 83 years); and of patients in the control group, 56 years (median age, 57 years; range, 28 to 78 years). The prevalence of gingival hyperplasia in the four groups is shown in Table 1. No patients were classified as grade 3 (severe overgrowth). The overall prevalence of gingival hyperplasia in patients receiving nifedipine was 38%, compared with 4% for controls (P = 0.006). The overall prevalence for gingival overgrowth was 21% (P = 0.12 compared with controls) in patients receiving diltiazem and 19% (P = 0.21 compared with controls) in patients receiving verapamil. The nifedipine group had the most patients with positive measurements (grades 1 and 2 combined) and the highest percentage of patients with moderate overgrowth (grade 2). Patients with gingival overgrowth were more likely than patients without hyperplasia to have nodules (23 of 24 [95.8%] compared with 6 of 91 [6.6%]; P < 0.001), to have bleeding with probing (4 of 24 [16.7%] compared with 3 of 91 [3.3%]; P = 0.05), and to have brushed their teeth less often (7.5 ±4.5 times a week) than patients without overgrowth (10.3 ±5.8 times a week) (P = 0.03). No statistical difference was found in tenderness, frequency of flossing, age, mean duration of calcium antagonist therapy, and occurrence of gingival overgrowth.

Discussion

Our findings confirm that gingival hyperplasia is an important side effect of calcium antagonists [1, 2]. Clinical features include a markedly lobulated enlargement of the buccal and lingual gingiva, primarily in the anterior portions of the oral cavity, occurring within 1 to several months after initiation of treatment with varying doses [1, 2]. We observed that bleeding with probing was more common among such patients, a finding consistent with earlier case reports [1, 2]. Secondary inflammation caused by local irritants can lead to pain, redness, bleeding, and a further increase in gingival size. If hyperplastic tissue continues to progress, it can interfere with dental occlusion and mastication [7]. Gingival tissue may completely cover the tooth and require surgical removal. Difficulty in maintaining proper oral hygiene may lead to the further development of pseudopockets, bacterial growth, and periodontitis. Although no complications were observed during our study, one patient had previously required surgical removal of enlarged gingival tissue during treatment with nifedipine.

The importance of good oral hygiene in preventing hyperplasia was supported by our finding that patients without gingival overgrowth brushed their teeth more frequently. In a previously reported case, nifedipine-induced gingival overgrowth was treated by controlling plaque [8]. In dogs treated with nitrendipine, enlargement occurred in areas of inflamed rather than healthy tissue [9]. Inflammation or local irritation combined with a minimum dose of a calcium antagonist may be a prerequisite for its development. It is important to note that our study was not a randomized, controlled trial and that patients were not examined before they received calcium antagonist therapy. We therefore could not control for preexisting gingival hyperplasia. However, the low prevalence found in our control group suggests that this is uncommon in our patient population.

The mechanism of calcium antagonist-induced overgrowth is unknown. However, both phenytoin and calcium antagonists alter calcium flux in gingival fibroblasts, which may produce a disturbance in the balance between production and removal of collagen [2, 7, 10]. The combination of cyclosporine and nifedipine has been shown to have a higher prevalence of gingival overgrowth than either drug used alone [10].

We recommend that practitioners examine patients who are to be treated with a calcium antagonist for gingival overgrowth. They should also inform patients of the possibility of this side effect and provide instruction in proper oral hygiene to decrease the occurrence. Alternative treatment choices may be considered in patients unable to maintain adequate oral hygiene and in those who require therapy with concomitant phenytoin or cyclosporine.