And Amlodipine-Induced Gingival Overgrowth

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provided by Elsevier - Publisher Connector Journal of Dental Sciences (2012) 7,85e88

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CASE REPORT Phenytoin- and amlodipine-induced gingival overgrowth

Ching-Wen Chang a,b, Chih-Jen Yang a, Yu-Lin Lai b,c*

a Department of Dentistry, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan b School of Dentistry, National Yang-Ming University, Taipei, Taiwan c Department of Stomatology, Division of Endodontics and Periodontology, Taipei Veterans General Hospital, Taipei, Taiwan

Final revision received 1 October 2011; accepted 31 December 2011 Available online 17 March 2012

KEYWORDS Abstract Drug-induced gingival overgrowth is an adverse event associated with three types amlodipine; of drugs, i.e., anticonvulsants, immunosuppressants, and calcium-channel blockers. It was drug-induced gingival shown that the combined use of an immunosuppressant (cyclosporine) and a calcium- overgrowth; channel blocker increases the prevalence and severity of gingival overgrowth. However, few gingivectomy; reports discussed the effects of the combinationofananticonvulsant(phenytoin)and phenytoin a calcium-channel blocker (amlodipine). In this case report, we present an epilepsy patient who was using both phenytoin and amlodipine, which caused extensive gingival overgrowth. After periodontal treatment and a gingivectomy, the gingival overgrowth was signiﬁcantly reduced. A postoperative drug-substitution regimen and intensive professional care ensured a stable result 1 year after surgery. Copyright ª 2012, Association for Dental Sciences of the Republic of China. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction and neoplastic enlargement. Drug-induced gingival overgrowth is a common consequence of the administration of some anticonvulsants, immunosuppressants, and calcium- Gingival overgrowth is associated with multiple factors 1 including inﬂammation, adverse events, systemic disease, channel blockers. Although the pathology of drug-induced gingival overgrowth is not deﬁnitively known, these disorders seem to be induced through disruption of homeostasis of collagen synthesis and degradation of gingival connective * Corresponding author. Department of Stomatology, Division of Endodontics and Periodontology, Taipei Veterans General Hospital, tissues. 201 Shih-Pai Road, Section 2, Beitou District, Taipei 112, Taiwan. It was shown that the combined use of cyclosporine and E-mail address: [email protected] (Y.-L. Lai). a calcium-channel blocker (CCB) increased the prevalence

the posterior teeth revealed 20%w50% bone loss. There were subgingival caries around Tooth Numbers 27 and 36 (Fig. 2). The diagnosis of this case was drug-induced gingival overgrowth with plaque-induced chronic periodontitis. Following scaling and oral hygiene instructions given to the patient, surgical excision of the overgrowing gingiva under general anesthesia was scheduled because of the patient’s disability and uncooperative behavior. During the surgery, a gingivectomy and gingivoplasty were carried out using surgical knives as well as electrosurgery, which was used to delicately shape the gingival contour without causing active tissue bleeding. In addition, full-mouth scaling and root planing were performed after gingival contouring. After the surgery, the caries lesions of Tooth Numbers 27 and 36 were treated. The gingival contour was Figure 1 Preoperative view showing the severe generalized much improved. To prevent gingival regrowth, a plaque- gingival overgrowth. control program was begun for the patient. The patient’s physician substituted vaproic acid for phenytoin, and captopril [angiotensin-converting enzyme (ACE) inhibitor] and severity of gingival overgrowth compared with mono- for amlodipine. The 1-year postoperative follow-up therapy using cyclosporine or the CCB alone.2e5 However, revealed no recurrence of gingival overgrowth (Fig. 3). few reports mentioned the gingival status in those receiving The overall gingival inflammation had improved, and the a combination of phenytoin and a CCB. This article presents probing depths of the teeth were reduced to 3w4 mm. a case of probable synergism with the combined use of The excised tissues were sent for biopsy. Histologic phenytoin and a CCB that caused extensive gingival over- sections showed thickened epithelium and pseudoepithe- growth in a patient with epilepsy. liomatous hyperplasia (Fig. 4), a large amount of dense bundles of collagen fibers, and mononuclear inflammatory Case report cell infiltration (Fig. 5).

A woman 67 years of age presented at the Department Discussion of Dentistry in the Hsin-Chu Hospital in Taiwan, with a complaint of gum swelling around the entire dentition. Drug-induced gingival overgrowth is known to be an adverse The patient’s medical history disclosed epilepsy for more effect of three main types of drugs, i.e., phenytoin, an than 10 years due to left-brain trauma in a trafﬁc accident. anticonvulsant; cyclosporine, an immunosuppressant; and She had taken phenytoin since that time. The patient had nifedipine, a CCB, which is widely used to manage cardio- a stroke attack 1 year before and subsequently took vascular disorders. The prevalence rate of drug-induced amlodipine in addition to phenytoin. gingival enlargement was reported to vary: 10%w15% for A clinical examination showed generalized gingival phenytoin, 8%w70% for cyclosporine, and 0.5%w83% for enlargement. The enlarged tissue covered from one-half to nifedipine.1 Gingival tissue reacts differently to various two-thirds of the crowns (Fig. 1). Excessive spacing of the types of medication. As an anticonvulsant, phenytoin has anterior teeth was also noted. Probing depths of gingival long been used to treat epilepsy, whereas valproic acid is pockets were at least 5 mm. The patient had compromised a new antiepileptic and appears to be as effective as oral hygiene. Generalized plaque accumulation and gingival phenytoin at controlling seizures. In addition, valproic acid inﬂammation were evident. A radiographic examination of also exhibited a lower occurrence of gingival enlargement.6

Figure 2 Initial periapical radiography. Drug-induced gingival overgrowth 87

Figure 3 One-year postoperative view revealing normal and Figure 5 Dense bundle of collagen ﬁber in subepithelium stable gingival contour. (hematoxylin & eosin, 10).

that the prevalence of gingival overgrowth was 58.3% for As an immunosuppressant, cyclosporine was the main cyclosporine use alone and was 84.3% for the combined use choice for organ transplantation in the last two decades. of cyclosporine and a CCB. Similarly, Greenberg and Tacrolimus is a new-generation immunosuppressant and is colleagues5 reported that the concomitant use of cyclo- an excellent alterative to cyclosporine due to its lower sporine and a CCB exhibited a higher occurrence of gingival incidence of gingival overgrowth and a comparable success overgrowth (76%) than in those treated with cyclosporine rate in organ-graft survival.7 As a CCB, nifedipine is alone (36%). The synergistic effect when using phenytoin extensively used to manage hypertension. Amlodipine is and cyclosporine caused severe gingival overgrowth in a third-generation dihydropyridine calcium antagonist that a kidney-transplant patient.9 However, few reports has similar pharmacodynamic effects as nifedipine. mentioned the gingival status related to the combined use However, amlodipine is characterized by nearly complete of phenytoin and a CCB, which was demonstrated in this absorption and slow hepatic biodegradation. Patients article. The pathogenesis of extensive gingival overgrowth undergoing monotherapy with amlodipine had less gingival following concomitant use of amlodipine and phenytoin in overgrowth than those taking nifedipine.8 A cohort study of this patient is not clear. Both phenytoin and the CCB inhibit 135 renal-transplantation patients demonstrated that the the intracellular uptake of calcium. This synergistic inhib- combined use of cyclosporine and nifedipine caused less itory action may have affected the secretory properties of gingival overgrowth (53%) than that in patients treated with gingival fibroblasts or the production of collagenase, cyclosporine and amlodipine (72%).8 subsequently exacerbating the development of gingival Many studies showed that the combined use of CCBs and enlargement10 (Table 1).2e5,7e9 immunosuppressants enhanced the risk and severity of e The most effective approach to ameliorate gingival gingival overgrowth.2 5 Spolidorio and colleagues4 found overgrowth is withdrawing or substituting medication. In this case, valproic acid and captopril (an ACE inhibitor) were substituted for phenytoin and amlodipine. Gingival hyperplasia associated with valproic acid seems to be extremely rare,6 and this drug was proposed as an alter- native medication in patients with phenytoin-induced gingival hyperplasia. ACE inhibitors are a group of phar- maceuticals that are primarily used to treat hypertension and congestive heart failure. It was suggested that long- term use of an ACE inhibitor may also limit the degree of fibrosis within grafts during chronic cyclosporine usage. To prevent the development of gingival overgrowth, ACE inhibitors may therefore provide greater benefit than CCBs.11 Treating the gingival overgrowth lesion itself can be complicated due to the inflammation superimposed on fibrotic tissue enlargement. Several investigations indi- cated that the severity of gingival overgrowth is directly related to the level of oral hygiene and gingival inflammation. Seymour and colleagues6 showed that bacterial Figure 4 Gingival hyperplasia, showing pseudoepithelioma- plaque was a key determinant of the severity of phenytoin- tous hyperplasia of the epithelium (hematoxylin & eosin, 10). induced gingival overgrowth. It was also demonstrated 88 C.-W. Chang et al

Table 1 Effect of combined drug-induced gingival overgrowth. Combined Type of drug Study Type of study Result drug CCB þ CsA CsA vs. CCB þ CsA (nifedipine) Thomason2 Cohort study GO: CCB þ CsA > CsA CsA vs. CCB vs. CCB þ CsA Bokenkamp3 Cohort study GO: CCB þ CsA > CsA (nifedipine) CCB þ CsA (nifedipine vs. James8 Cohort study Amlodipine þ CsA (72%) > nifedipine þ CsA (53%) amlodipine) CCB þ CsA vs. CCB þ Tac Spolidorio4 Cohort study Severity of GO: CsA: Tac: CCB þ CsA: CCB þ Tac Z 58.3%:0%:84.3%:100% CCB þ CsA vs. CCB þ Tac Greenberg5 Cohort study Prevalence of GO: CsA: Tac: CCB þ CsA: CCB þ Tac Z 36%:15%:76%:27% CCB þ Tac Tac vs. CCB þ Tac Ellis7 Cohort study Severity of GO: Tac: CCB þ Tac Z 8.18%:21.3% CCB þ CsA vs. CCB þ Tac Spolidorio4 Cohort study Prevalence of GO: CsA: Tac: CCB þ CsA: CCB þ Tac Z 58.3%:0%:84.3%:100% CCB þ CsA vs. CCB þ Tac Greenberg5 Cohort study Prevalence of GO: CsA: Tac: CCB þ CsA: CCBþ Tac Z 36%:15%:76%:27% PH þ CsA PH þ CsA change to PH þ Tac Hernanadez9 Case report After PH þ Tac: 6 months: GO reduction, 12 months: gingiva no transformation

CCB Z calcium channel blocker; CsA Z cyclosporine-A; GO Z gingival overgrowth; PH Z phenytoin; Tac Z tacrolimus.

that gingival inﬂammation is a signiﬁcant risk factor 3. Bo¨kenkamp A, Bohnhorst B, Beier C, Albers N, Offner G, for phenytoin-,6 nifedipine-,2 and cyclosporine-associated2 Brodehl J. Nifedipine aggravates cyclosporine A-induced gingival overgrowth. Therefore, a preventive plaque-control gingival hyperplasia. Pediatric nephrology 1994;8:181e5. program is particularly important for managing drug- 4. Spolidorio LC, Spolidorio DMP, Massucato EMS, induced gingival overgrowth. To achieve excellent plaque Neppelenbroek KH, Campanha NH, Sanches MH. Oral health in renal transplant recipients administered cyclosporin A or control, comprehensive oral hygiene instruction was tacrolimus. Oral dis 2006;1:309e14. provided to the patient’s family, and meticulous profes- 5. Greenberg KV, Armitage GC, Shiboski CH. Gingival enlargement sional care was delivered to the patient. The 1-year post- among renal transplant recipients in the era of new-generation surgical follow-up revealed healthy gingiva, and there was immunosuppressants. J Periodontol 2008;79:453e60. no recurrence of gingival overgrowth in the patient. 6. Seymour RA, Smith DG, Turnbull DN. The effects of phenytoin A case of phenytoin- and amlodipine-induced gingival and sodium valproate on the periodontal health of adult overgrowth is presented herein. The patient’s normal epileptic patients. J Clin Periodontol 1985;12:413e9. gingival contour was achieved using a gingivectomy. A post- 7. Ellis JS, Seymour RA, Taylor JJ, Thomason JM. Prevalence of operative drug-substitution regimen and intensive profes- gingival overgrowth in transplant patients immunosuppressed e sional care ensured a stable result. with tacrolimus. J Clin Periodontol 2004;31:126 31. 8. James JA, Marley JJ, Jamal S, et al. The calcium channel blocker used with cyclosporin has an effect on gingival overgrowth. J Clin Periodontol 2000;27:109e15. References 9. Hernandez G, Arriba L, Lucas M, de Andres A. Reduction of severe gingival overgrowth in a kidney transplant patient by 1. Kataoka M, Kido J, Shinohara Y, Nagata T. Drug-induced replacing cyclosporin A with tacrolimus. J Periodontol 2000;71: gingival overgrowth-a review. Biol Pham Bull 2005;28: 1630e6. 1817e21. 10. Seymour RA. Calcium channel blockers and gingival over- 2. Thomason JM, Seymour RA, Rice N. The prevalence and growth. Br Dent J 1991;170:376e9. severity of cyclosporin and nifedipine-induced gingival over- 11. Pradhan S, Mishra P. Gingival enlargement in antihypertensive growth. J Clin Periodontol 1993;20:37e40. medication. J Nepal Med Assoc 2009;48(174):149e52.