Vol.27 No.2 2008 歯 薬 療 法79 Present research status on drug-induced gingival overgrowth Incidence of gingival overgrowth caused by calcium channel blockers MAKIKO ONO1, NAOKO OHNO1, KAZUHIRO HASEGAWA1, SHIGEO TANAKA1, MASAMICHI KOMIYA1, HIROKO MATSUMOTO2, AKIRA FUJII2 and YOSHIAKI AKIMOTO1 Abstract : The incidence of gingival overgrowth caused by calcium channel blockers was determined. The overgrowth was found in patients receiving amlodipine, diltiazem, manidipine, nicardipine, nifedipine and nisoldipine. The highest rate of gingival overgrowth was obtained by nifedipine (7.6%), followed by diltiazem (4.1%), manidipine (1.8%), amlodipine (1.l%), nisoldipine (1.1%) and nicardipine (0.5%). The rate of nifedipine-induced gingival overgrowth was significant- ly higher than those of amlodipine, manidipine, nicardipine and nisoldipine, but not diltiazem. Key words : calcium channel blocker, gingival overgrowth, incidence treatment of their various oral diseases. The patients Introduction were surveyed to determine the calcium channel Gingival overgrowth induced by calcium channel blocker-induced gingival overgrowth. The 15 kinds of blockers is a well-known adverse effect. Amlodipine1-3), calcium channel blocker and numbers of cases were as diltiazem4,5), felodipine6), manidipine7,8) nicardipine9), follows: amlodipine (n=267), azelnipine (n=11), barni- nifedipine3-5.8.10-12)nisoldipine13), nitrendipine14) and dipine (n=25), benidipine (n=28), diltiazem (n= verapamil3-5,15.16) were reported as causative drugs 196), efonidipine (n=14), felodipine (n=4), flunarizine for gingival overgrowth. However, this evidence has (n=32), manidipine (n=111), nicardipine (n=219), come from several case reports, and there have been nifedipine (n=347), nilvadipine (n=58), nisoldipine few prevalence studyies to evaluate the magnitude of (n=89), nitrendipine (n=25) or verapamil (n=41). this effect. Since the incidence of gingival overgrowth Patients taking other drugs known to induce gingival induced by calcium channel blockers remains poorly overgrowth such as phenytoin and cyclosporin A were defined, the rates of 15 calcium channel blockers were excluded from this study. Clinical diagnosis of calcium determined. channel blocker-induced gingival overgrowth was veri- fied by disappearance or decreased severity of gingival Patients and Methods overgrowth after withdrawal of the causative drug. During a 17-year period (1991-2007),1,467 dental pa- Results tients taking a calcium channel blocker for a minimum of 3 months attended the Department of Oral Surgery, Gngival overgrowth was found in patients receiving Nihon University School of Dentistry at Matsudo for amlodipine (n=3), diltiazem (n=8), manidipine (n 1 Departments of Oral Surgery, Nihon University School of Dentistry at Matsudo (Chief: Prof. YOSHIAKIAKIMOTO) 2 Department of Oral Molecular Pharmacology , Nihon University School of Dentistry at Matsudo (Chief: Prof. AKIRA FUJII) 1日 本 大 学 松 戸 歯 学 部 口腔 外 科 学 講 座(主 任:秋 元 芳 明教 授) 2日 本 大 学 松 戸 歯 学 部 口腔 分 子 薬 理 学 講 座(主 任:藤 井 彰 教 授) 〔2007年11月26日 受 付 〕 80 歯 薬 療 法 Vol.27 No.2 2008 =2) , nicardipine (n=1), nifedipine (n=27) and ni- other calcium channel blockers such as nifedipine and soldipine (n=1), but not azelnipine, barnidipine, beni- diltiazem, a tentative diagnosis of gingival overgrowth dipine, efonidipine, felodipine, fiunarizine, nilvadipine, induced by amlodipine was made. A gingival speci- nitrendipine and verapamil (Table 1). The highest men was obtained for histological examination, which rate was obtained by nifedipine (7.6%), followed by revealed gingival overgrowth (Fig. 2). Amlodipine diltiazem (4.1%), manidipine (1.8%), amlodipine (1.1%), was discontinued after consultation with the patient's nisoldipine (1.1%) and nicardipine (0.5%). The inci- physician and was replaced with an ACE (angiotensin dence of nifedipine-induced gingival overgrowth was converting enzyme) inhibitor. No specific periodontal significantly higher than those of amlodipine, mani- treatment was provided to the patient for the gingival dipine, nicardipine and nisoldipine, but not diltiazem overgrowth. Marked reduction of gingival overgrowth (Table 1). Concerning amlodipine, diltiazem and nife- was evident 2 months after withdrawal of amlodipine dipine, males were 2.0-3.5 times more likely to develop (Fig. 3). We concluded that this gingival overgrowth overgrowth. was induced by amlodipine. A typical case of gingival overgrowth is as follows: Discussion A 48-years-old man was on amlodipine (5 mg/day) for hypertension. A marked painless gingival swelling at There are two main classes of calcium channel interdental papillae on the labial side of the lower and blockers: dihydropyridines (amlodipine, felodipine, upper anterior teeth was found at nine months follow- manidipine, nifedipine, nicardipine and nisoldipine) ing administration of amlodipine. The gingival tissues and nondihydropyridines which include a benzothi- were firm and fairly hard, but bled rather easily upon azepine (diltiazem) and a phenylalkylamine (vera- probing and brushing (Fig. 1). Since the clinical find- pamil)1.5,17) Calcium channel blockerinduced gingival ings of gingival overgrowth were similar to those of overgrowth was reported in both classes, in which Table 1 Gingival overgrowth induced by calcium channel blockers Statistical difference vs nifedipine : a, Fisher's test (two tail); b, ƒÔ 2-test (Yate's correlation). **p<0 .01; *p<0.05 Vol.27 No.2 2008 Incidence of calcium channel blocker-induced gingival overgrowth 81 Fig. 1 Amlodipine-induced gingival overgrowth Fig. 3 Amlodipine-induced gingival overgrowth at interdental papillae. at interdental papillae. Marked reduction was evident 2 months after withdrawal of manidipine. nifedipine3-5,8.11-12) nisoldipine13), nitrendipine14) and verapamil3-5.15,16) were reported as the causative drug for gingival overgrowth. However, felodipine, nitren- dipine and verapamil were not found in the present study. The number of felodipine samples was small in the study. The low incidence with nitrendipine and verapamil, might be also found in future studies. Previous reports concerning the incidence of cal- cium channel blocker-related gingival overgrowth with sample size of more than 100 are summarized in Table 2. The highest rate was found with nifedipine Fig. 2 Histological view of gingival overgrowth and varied from 6.3 to 43.6%3,4,11). Those of amlodipine (Hematoxylin and eosin, •~ 40). and diltiazem were 1.7, 3.3 and 2.2%, respectively2,3). The surface was covered by parakeratotic Compared with the present results, amlodipine showed and acanthotic stratified squamous epithe- lium with irregular elongation and fusion a lower rate, but diltiazem and nifedipine higher rates. of rete ridges. In the subepithelial con- Since the patients of the present study were not well nective tissue, bundles of collagen fibers controlled and community-based, these differences with normal density of fibroblasts were might be observed. Ellis et al. reported that males proliferated, and increased vascularity and mild lymphocyte infiltration were also rec- were 3 times as likely to develop overgrowth. The ognized. present results identified the same tendency. As mentioned, there are many kinds of calcium channel blockers, and usage of the drug has changed the first report of gingival overgrowth among calcium with the times. In the 1980s and 1990s, nifedipine channel blockers was nifedipine10-. Since then, many (AdalatðF) was common, but the recently used drug is cases concerning nifedipine as well as other calcium amlodipine (NorvascðF). channel blockers have been reported. Amlodipine1-3), Gingival overgrowth induced by phenytoin and cy- diltiazem4,5), felodipine6), manidipine7,8), nicardipines9), closporine A is also a well-known adverse effect. The 82 Vol.27 No.2 2008 Table 2 Previous reports on incidence of calcium channel blocker-related gingival overgrowth with sample size of more than 100 incidence was reported to be about 5018-19) and 30- impairs nutrition and access for oral hygiene, resulting 70%20-22),respectively, which were higher than those of in an increased susceptibility to oral infection, caries, calcium channel blockers. and periodontal diseases. Most drug-associated gingi- Plaque is a well-known risk factor for drug induced val overgrowth is similar in characteristics among the gingival overgrowth. The severity of gingival over- causative drugs29). growth in patients taking calcium channel blockers The most effective treatment for drug-related gingi- correlates well with poor plaque control and is com- val overgrowth is withdrawal or substitution of medi- mensurate with the degree of plaque induced inflam- cation. When this treatment approach is taken, as sug- mation3,12) The importance of plaque as a cofactor in gested by a case report, it may take from 1 to 8 weeks the etiology of drug associated gingival overgrowth for resolution of gingival lesions2). Unfortunately, not has been recognized in the most recent classification all patients respond to this mode of treatment, espe- system for periodontal diseases23). Another factor af- cially those with longstanding gingival lesions. Substi- fecting the occurrence of gingival overgrowth may in- tution of phenytoin with a different anticonvulsant has clude gender, with males being three times as likely to long been suggested as the treatment of choice for the develop overgrowth24). Although there are conflicting severely affected gingiva. Recently, the feasibility of data with respect to the relationship