Vol.27 No.2 2008 歯 薬 療 法79

Present research status on drug-induced gingival overgrowth

Incidence of gingival overgrowth caused by 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 , , , , and . 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 , gingival overgrowth, incidence

treatment of their various oral diseases. The patients Introduction were surveyed to determine the calcium channel Gingival overgrowth induced by -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), (n=14), (n=4), 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), (n=58), nisoldipine few prevalence studyies to evaluate the magnitude of (n=89), (n=25) or (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 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, , 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 between severity phenytoin substitution has increased with the addition of overgrowth and daily medication dose, most studies of a new generation of anticonvulsants such as loma- have not reported a significant association with dos- trigine, , sulthiame, and . Chang- age11,25,26). es from nifedipine to diltiazem or verapamil by the pa- Clinical manifestation of gingival overgrowth fre- tient's physician are an option. Changing hypertensive quently appears within 1 to 3 months after initiation of therapy from nifedipine to an antihypertensive of the treatment with the associated medications26). Gingival same class, such as , may result in regression overgrowth normally begins at the interdental papillae of gingival overgrowth30). Professional debridement and is more frequently found in the anterior segment with scaling and root planing as needed has been of the labial surfaces27,28), as was found in the pres- shown to offer some relief in gingival overgrowth pa- ent case. Gradually, gingival lobulations are formed tients31). Another non-surgical treatment, tenidap (an that may appear inflamed or more fibrotic in nature, anti-inflammatory drug), was suggested as a possible depending on the degree of local factor-induced inflam- way to prevent drug-related gingival overgrowth32). mation. The fibrotic enlargement is normally confined Because the anterior labial gingiva is frequently to the attached gingiva but may extend coronally and involved, surgery is commonly performed for esthetic interfere with esthetics, mastication, or speech27,28) reasons before any functional consequences are pres- Disfiguring gingival overgrowth triggered by the med- ent. The classical surgical approach has been the ex- ications is not only esthetically displeasing but often ternal bevel gingivectomy. However, a total or partial Vol.27 No.2 2008 Incidence of calcium channel blocker-induced gingival overgrowth 83 internal gingivectomy approach has been suggested 7) Akimoto, Y., et al: Gingival overgrowth induced as an alternative33). This more technically demanding by manidipine. Jpn J Clin Pharmacol Therapeut 1999 30:329•`330. approach has the benefit of limiting the large denuded 8) Muramoto, G., et al: Three cases of calcium antag- connective tissue wound that results from the external onist-induced gingival overgrowth -Two cases gingivectomy, thereby minimizing postoperative pain of nifedipin-induced and one case of manidipine and bleeding. induced gingival overgrowth. Jpn Clin Dermatol 2000 54 : 913•`916. The recurrence rate of severe gingival enlargement 9) Akimoto, Y., et al: Gingival overgrowth induced in cyclosporin A- or nifedipine-treated patients after by nicardipine. In Proceeding of the 23th Inter- surgical periodontal therapy was found to be about national Congress of Internal Medicine 11•`14 Monduzzi Editore Bologna Italy 1996. 40% within 18 months after active treatment. Sig- 10) Lederman, D., et al: Gingival hyperplasia associat- nificant determinants of recurrence were found to be ed with nifedipine therapy. Report of a case. Oral younger age, gingival inflammation, and poor compli- Surg Oral Med Oral Pathol 1984 57: 620•`622. 11) Nery, E. B.: Prevalence of nifedipine-induced gin- ance with maintenance visits34) gival hyperplasia. J Periodontol 1995 66: 572•` 578. Conclusions 12) Nakou, M., et al: Subgingival microflora associated with nifedipine-induced gingival overgrowth. J Gingival overgrowth induced by amlodipine, diltiaz- Periodontol 1998 69: 664•`669. em, manidipine, nicardipine, nifedipine and nisoldipine 13) Akimoto, Y., et al: Gingival overgrowth induced was found in surveyed patients, and the incidence of by nisoldipine. Jpn J Clin Pharmacol Therapeu overgrowth varied among the drugs. Calcium chan- 2002 33:151•`152. 14) Brown, R. S., et al: Nitrendipineinduced gingival nel blocker-induced gingival overgrowth, especially by hyperplasia. First case report. Oral Surg Oral Med nifedipine, appears more frequently and is now not a Oral Pathol 1990 70 : 593•`596. rare adverse effect. 15) Miller, S. C., et al: Incidence of verapamil-induced gingival hyperplasia in a dental population. J. Peri- Acknowlegement odontol 1992 63:453•`456. 16) Matharu, M. S., et al: Verapamil induced gingival This study was supported in part by Grant-in Aid enlargement in cluster headache. J Neurol Neuro- surg Psychiatry 2005 76 :124•`127. for Scientific Research (C) 16592023, Japan Society for 17) Hardman, J. G., et al: Goodman & Gilman's the the Promotion of Science, and Academic Frontier Proj- pharmacological basis of therapeutics. 9th ed ect for Private Universities, with a matching fund sub- 767•`774 McGrawHill New York USA 1996. sidy from the Ministry of Education, Culture, Sports, 18) Ciancio, S., et al: Cyclosporine-induced gingival hy- perplasia and chlorhexidine: A case report. Int J Science and Technology, 2003-2007. Periodontics Restorative Dent 1991 11 : 241•` References 245. 19) Casetta, I., et al: A community-based cross-section- 1) Ciancio, S. G.: Medications' impact on oral health. J al study in Ferrara Italy Neuroepidemiol 1997 Am Dent Assoc 2004 135:1440•`1448. 16 : 296•`303. 2) Jorgensen, M. G.: Prevalence of amlodipine-related 20) Myers, B. D., et al: Cyclosporine-induced chronic gingival hyperplasia. J Periodontol 1997 68 nephropathy: An obliterative microvascular renal : 676•`678. injury. J Am Soc Nephrol 1991 2 (2 Suppl. 1) : Ellis, J. S., et al: Prevalence of gingival overgrowth 3) S45•`S52. induced by calcium channel blockers: a communi- 21) Kilpatrick N. M., et al: Gingival overgrowth in pe- tybased study. J Periodontol 1999 70 : 63•`67. diatric heart and heart-lung transplant recipients. 4) Katsumi, Y., et al: Statistical study of incidence of J Heart LungTransplant 1997 16 :1231•`1237. gingival hyperplasia induced by calcium channel 22) Boltchi, F. E., et al: Cyclosporine A induced gingi- blockers. Jpn J Stomatol 1991 40:169•`178. val overgrowth: A comprehensive review. Quin- 5) Kataoka, M., et al: Druginduced gingival overgrowth tessence Int 1999 30 : 775•`783. -a review . Biol Pharm Bull 2005 28: 1817•` 23) Armitage G. C.: Development of a classification 1821. system for periodontal diseases and conditions. 6) Fay, A. A., et al: Felodipineinfluenced gingival Ann Periodontol 1999 4 : 1•`6. enlargement in an uncontrolled type 2 diabetic pa- 24) Tavassoli S., et al: The clinical effects of nifedipine tient. J Periodontol 2005 76 :1217. on periodontal status. J Periodontol 1998 69 : 84 歯 薬 療 法 Vol.27 No.2 2008

108•`112. Periodontol 1997 68:645•`650. 25) Penarrocha-Diago, M., et al: Diphenylhydantoin- 31) Khocht, A., et al: Periodontal management of gin-

induced gingival overgrowth in man: A clinico- gival overgrowth in the heart transplant patient: pathological study. J Periodontol 1990 61: A case report. J Periodontol 1997 68: 1140•` 571•`574. 1146. 26) Meraw, S. J., et al: Medically induced gingival 32) Matsumoto, H., et al: Tenidap, an antiInflamma- hyperplasia. Mayo Clin Proc 1998 73 :1196•` tory agent, inhibits DNA and collagen syntheses, 1199. depresses cell proliferation, and lowers intracel- 27) Hallmon, W. W., et al: The role of drugs in the lular pH in cultured human gingival fibroblasts. J

pathogenesis of gingival overgrowth. A collective Pharmacol Exp Ther 2002 300 : 668•`672. review of current concepts. Periodontol 2000 33) Marshall, R. I., et al: A clinical review of drug- 21 : 176•`196. induced gingival overgrowth. Aust Dent J 1999 28) Hassell, T. M., et al: Drug-induced gingival over- 44 : 219•`232.

growth: Old problem, new problem. Crit Rev Oral 34) Ilgenli, T., et al: Effectiveness of periodontal ther- Biol Med 1991 2 :103•`137. apy in patients with drug-induced gingival over-

29) Gregoriou, A. P., et al: Phenobarbital-induced gin- growth. Long-term results. J Periodontol 1999 gival overgrowth? Report of two cases andcompli- 70 : 967•`972. cations in management. ASDC J Dent Child 1996 63 : 408•`413. 30) Westbrook, P., et al: Regression of nifedipine- induced gingival hyperplasia following switch to a same class calcium channel blocker. Isradipine. J Vol.27 No.2 2008 Incidence of calcium channel blocker-induced gingival overgrowth 85

薬 物 性 歯 肉 増 殖 症 に 関 す る 研 究 の 現 状

カ ル シ ウ ム 拮 抗 薬 の 歯 肉 増 殖 症 発 生 頻 度

小 野 眞 紀 子1,大 野 奈 穂 子1,長 谷 川 一 弘1 田 中 茂 男1,小 宮 正 道1,松 本 裕 子2

藤 井 彰2,秋 元 芳 明1

15種 類 の カ ル シ ウ ム 拮 抗 薬 に よ る 歯 肉 増 殖 症 発 生 頻 度 を 検 討 し た.歯 肉 増 殖 症 はamlodipine, diltiazem,

manidipine, nicardipine, nifedipineお よ びnisoldipine服 用 者 に 認 め ら れ た が,azelnipine, barnidipine,

benidipine, efonidipine, felodipine,flunarizine, nilvadipine, nitrendipineお よ びverapamil服 用 者 に は み ら れ

な っ た.最 も 高 い 発 生 頻 度 はnifedipine(7.6%)で あ り,diltiazem(4.1%),manidipine(1.8%),amlodipine

(1.1%),nisoldipine(1.1%),nicardipine(0。5%)のlq頁 で あ っ た.Nifedipineに よ る 歯 肉 増 殖 症 発 生 頻 度 は,

amlodipine, manidipine, nicardipine, nisoldipineの 発 生 頻 度 と比 較 し て 有 意 に 高 か っ た.

キ ー ワ ー ド:カ ル シ ウ ム 拮 抗 薬,歯 肉 増 殖 症,発 生 頻 度