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Year : 2016  |  Volume : 8  |  Issue : 3  |  Page : 154-158

A rare case of amlodipine-induced gingival overgrowth circumferential to dental implant healing abutments and its management: A 2-year follow-up study

1 Department of Periodontics and Oral Implantology, Faculty of Dental Sciences, SGT University, Gurgaon, Haryana, India
2 Department of Periodontics and Oral Implantology, Inderprastha Dental College, Ghaziabad, Uttar Pradesh, India

Date of Web Publication7-Oct-2016

Correspondence Address:
Vikram Blaggana
House Number 7185, Sector-B, Pocket-10, Vasant Kunj, New Delhi - 110 070
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0976-4003.191729

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Calcium channel blockers have been implicated throughout literature for gingival hyperplasia around natural teeth as an untoward side effect, with amlodipine exhibiting the least prevalence rate. This clinical report describes a rare case of hyperplasia of tissues around titanium dental implants in a 62-year-old hypertensive Caucasian male patient receiving Amlodipine® 5 mg/day for 10 years. Clinically, the enlargement appeared circumferentially enveloping the healing abutments placed 4 months, following the placement of the implants. Elimination of local factors followed by surgical resection to facilitate the insertion of prosthesis with supportive periodontal therapy was planned. The area healed satisfactorily with no recurrence observed for the next 2 years, thus confirming that periodontal treatment alone without any drug substitution or withdrawal can efficiently generate agreeable gingival response.

Keywords: Calcium channel blockers, drug-induced gingival overgrowth, laser-assisted gingivectomy, peri-implant tissues

How to cite this article:
Blaggana A, Blaggana V. A rare case of amlodipine-induced gingival overgrowth circumferential to dental implant healing abutments and its management: A 2-year follow-up study. Indian J Dent Sci 2016;8:154-8

How to cite this URL:
Blaggana A, Blaggana V. A rare case of amlodipine-induced gingival overgrowth circumferential to dental implant healing abutments and its management: A 2-year follow-up study. Indian J Dent Sci [serial online] 2016 [cited 2022 Jul 4];8:154-8. Available from: http://www.ijds.in/text.asp?2016/8/3/154/191729

  Introduction Top

Recent expansion in our knowledge pertaining to the medical health-care sector and the concomitant upsurge in medicine and surgical treatment seems to have augmented the life expectancy of the adult population. With growing emphasis on esthetics and function, edentulous and partially edentulous patients are resorting to various tooth replacement options, particularly dental implants.[1]

Literature amply documents the fact that the epithelial and connective tissue constituents of the periodontium around natural teeth and implants are similar and react correspondingly to various local and systemic stimuli.[2] It has been noted that the administration of specific medications can amplify and/or potentiate the effects of local factors on the gingival connective tissue with one of the consequences of gingival enlargement.

Drug-induced gingival overgrowth remains the most widespread unwanted effect of systemic medication on the periodontal tissues. A multitude of medications has been implicated with each exhibiting a diverse pharmacologic effect directed toward dissimilar primary target tissues yet acting comparably on the secondary target tissue, i.e., the gingival connective tissue, causing common clinical histopathological findings.[3]

Medical practice had witnessed a significant boost in the use of calcium channel blockers (CCBs) among heart patients. Amid these, the dihydropyridines have been most frequently implicated in the incidence of gingival hyperplasia. While the estimates of the prevalence of gingival enlargement related to nifedipine reflect a range from 20% to 83% of patients exhibiting this untoward side effect,[4] only 1.7% of cases have been reported for amlodipine by Ellis et al.[5] This prevalence study also provided the benchmark by accounting amlodipine-induced gingival enlargement for the first time in literature.

A male preponderance has been identified though no correlation of age with overgrowth could be elicited since the drug is chiefly confined to the middle-aged and elderly people.[6],[7] Focusing on the pharmacokinetic profile of the drug, Seymour [6] agreed to various factors namely bioavailability, degree of protein binding, volume of distribution, and an overall assessment of the drug concentration in relation to time or the “area under the plasma/serum concentration curve” may boast an amplified potential in relation to the expression of gingival overgrowth. However, till date, the lack of any such clear relationship only reflects on the pitfalls of either sampling techniques or deficiency of our knowledge and exploration of relevant variables.

Concomitant occurrence of hyperplasia with underlying periodontal disease allows for uninhibited plaque accumulation which is cleanable neither by the natural pathways nor by the patients, thus not only aggravating the disease further but also posing as a therapeutic challenge requiring respective surgeries.[8]

Unaesthetic appearance, foul odor, bleeding from the gums, following mechanical stimulation, impaired nutrition, and interference with normal speech, mastication, and oral hygiene measures, thereby increasing the susceptibility to oral infection, caries, and periodontal disease are to mention a few predicaments faced by the patients.

Executing a comprehensive and effectual treatment plan for drug-induced enlargements however is a quandary owing to its high recurrence rate. Long-term nonsurgical/surgical therapy with routine follow-ups and the option of replacement of the offending drug whenever necessary are hence mandatory in such case.

The aim of this report is to put forth a rare case of amlodipine-induced gingival overgrowth in a dental implant patient while emphasizing on an objective treatment plan.

  Case Report Top

A 62-year-old patient reported to our dental office with the chief complaint of a fractured abutment tooth for porcelain fused to metal bridge. Intraoral examination revealed a long-standing bridge prosthesis [Figure 1]a, spanning from right upper first premolar 14 to left upper first premolar 24 with 14, 13, 12 (right upper lateral incisor), and 24 providing the abutment support for the missing right upper central incisor,[9] left upper central and lateral incisor,[10],[11] and canine.[12] Abutment tooth 24 was fractured [Figure 1]b rendering the fixed bridge prosthesis redundant for further use. Radiographic investigations disclosed periapical cyst in relation to 12. Patient's oral hygiene status was good with only a few localized areas of plaque accumulation. Periodontal inspection divulged normal clinical probing depth and periodontal status without any overt signs of inflammation.
Figure 1: (a) Long span porcelain-fused-to-metal bridge with a fractured abutment tooth no. 24. (b) Fractured abutment tooth no. 24. (c) Extraction socket after atraumatic extraction. (d) Extracted root stump of tooth no. 24.

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The patient had a relevant medical history of hypertension and had been taking the CCB amlodipine for the preceding 10 years. A close routine monitoring of his cardiovascular status and medication compliance was being performed by his cardiologist.

Keeping in view the patient's aspirations, dental implants (BioHorizons ®, Birmingham, Alabama, USA) as a fixed replacement option resorted to utilizing four implants at 11, 22, 23, and 24. Extraction followed by immediate implant placement was planned for the fractured tooth 24. Porcelain fused to metal crowns was planned for the already prepared 12, 13, and 14. Echocardiography and routine blood and urine examination were found to be noncontributory. Before the planned surgical procedure, root canal therapy of 12 and enucleation of the associated periapical cyst were performed with subsequent placement of regenerative bone grafting material (Bio-Oss ®, Osteohealth Company, Shirley, New York, USA) and guided tissue regeneration membrane (ProGide ®, Equinox Medical Technologies, Ljubljana, Republic of Slovenia, Central Europe).

Extraction of root stump of 24 followed by immediate placement of implant in the palatal root socket was done [Figure 1]c and [Figure 1]d. The buccal root socket was filled with the bone graft material so as to maintain the buccal bone plate. The other implants were placed in the regions of 11, 22, and 23 as planned [Figure 2]. A 7-month healing period was observed after which healing collars were placed.
Figure 2: Orthopantomogram radiograph of implants in position.

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After 3 weeks of placement of healing collars, when the patient returned for impression making, an inflammatory gingival enlargement was observed covering the healing abutments completely with respect to 22, 23 and partially with respect to 24 [Figure 3]a. The patient was instructed to maintain oral hygiene using chlorhexidine-based mouth rinse. Removal of the hypertrophied gingiva was done with the help of a soft tissue laser surgery unit [Figure 3]b, thereby facilitating impression making. The impressions were then sent for the fabrication of the implant-retained fixed bridge prosthesis spanning from 11 to 24. To maintain good esthetics, the crowns for teeth 12, 13, and 14 were also fabricated along with the implant prosthesis.
Figure 3: (a) Inflammatory gingival enlargement covering the healing abutments. (b) Following the removal of hypertrophied gingiva. (c) Implant abutments in position. (d) Implant-retained porcelain-fused-to-metal bridge post fit in.

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At the time of fixation of the prosthesis, mild inflammatory gingival enlargement was observed in the 22 area [Figure 3]c and [Figure 3]d. After the placement of the prosthesis [Figure 4]a, it was easier for the patient to maintain oral hygiene of the concerned area leading to progressive reduction of the inflammation.
Figure 4: (a) Implant-retained porcelain-fused-to-metal bridge immediately post fit in. (b) 2 years postoperative exhibiting healthy gingiva.

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On subsequent observation of the patient at 1 month, 3 months, 6 months, 1 year, and 2 years [Figure 4]b, no untoward inflammatory enlargement was ever seen again.

  Discussion Top

Literature abundantly documents the potential of CCBs in the causation of gingival enlargement. Most of the cross-sectional studies have recognized plaque accumulation as an important risk factor while establishing a positive correlation between oral hygiene status, gingival inflammation, and prevalence and severity of gingival overgrowth.[13] The presence of plaque-retaining areas in susceptible patients with poor brushing habits is contributory toward gingival enlargement. Institution of oral hygiene measures in such patients has exhibited remarkable resolution in the enlargement due to inhibition of inflammatory changes occurring in the lesion.[14]

Previous periodontal status has also been reported by a few authors as a causal factor for gingival enlargement. However, there still remains a legion of patients with impeccable oral hygiene and periodontal condition who develop gingival overgrowth, for which the presence of other risk factors may provide an explanation.

On a more histological level, a variable fibroblast response to similar drug dose challenge has been observed in overgrowth patients ascribed to genetic fibroblast heterogeneity.[9] These subsets of fibroblasts exhibit a differential expression of function in regard to collagenase, which is a matrix metalloproteinase (MMP) responsible for normal and pathological turnover of connective tissue, and tissue inhibitors of MMPs, which selectively and reversibly binds and inactivates MMPs, thereby decreasing the collagen breakdown resulting in gingival overgrowth.

Seymour et al.[15] additionally observed dose-dependent elevated levels of protein synthesis, primarily collagen, by this cohort. On further histometric analysis, Goultschin and Shoshan [16] discovered it to be type IV collagen which being inherently resistant to bacterial collagenase and tissue MMPs contributed to the elevated extracellular matrix proteins.

Tissue culture experiments on human gingival tissues have supplemented the vital evidence suggesting an increased rate of emigration of “fibroblastoid” cells, following the administration of the offending drug.[17]

Yet another genetic polymorphism that has been widely acknowledged by authors is pertaining to drug metabolizing enzymes namely hepatic cytochrome P450 with ensuing variation in inter-individual drug levels.[18] A consequential disparity in serum and tissue drug concentrations therefore accounts for the inconsistent gingival response.

Pernu et al.[19] furthered our knowledge on genetic markers by establishing a linear relationship between the human lymphocyte antigen (HLA) expression and gingival overgrowth delineating the patients expressing HLA-DR2 phenotype as more susceptible in contrast to the ones with HLA-DR1 phenotype which imparted some degree of “protection” against the untoward side effects.

On auxiliary analysis, HLA-A19 phenotype expression has revealed an increased susceptibility while individuals with HLA-B37 expression were conceded to be at a significant risk for developing the enlargement.[20]

Although the exact underlying pathophysiology remains ambiguous, HLA gene expression has been hypothesized to have an effect on the lymphocyte function.[21]

Brown et al.[22] redirected our attention toward a noninflammatory pathway to elucidate the mechanism which includes defective collagenase activity due to diminished folic acid uptake, blockage of aldosterone synthesis in the adrenal cortex, consequent feedback increase in adrenocorticotropic hormone level, and upregulation of keratinocyte growth factor.

Alternately, the inflammatory pathway as discussed by Van der Vleuten et al.[23] entails inflammation attributable to toxic levels of concentrated drug in the gingival crevicular fluid, leading to upregulation of cytokine factors such as transforming growth factor-β1 and consequent synthesis of a fibrous scaffold culminating in the vertical growth of gingiva and pseudopocket development.

Studies have revealed an augmented collagenous protein synthesis by gingival fibroblasts when simultaneously exposed to nifedipine and pro-inflammatory cytokines namely interleukin (IL)-1b and IL-6.[10]

Apoptosis or programmed cell death involves a rise in the intracellular calcium levels which then triggers a series of specific biochemical steps for its culmination. The pharmacokinetic profile of CCBs divulges a mechanism entailing the inhibition of intracellular calcium influx, thereby preventing apoptosis with subsequent enlargement of the gingival.[11]

Concomitant administration of CCBs with cyclosporine in organ transplant patients is yet another acclaimed etiologic feature evincing an increase in the prevalence of the condition attributable to analogous mechanisms of action though the severity of the lesion may remain unaltered.[12]

Despite the similarity in the pharmacokinetic profile, the incidence and prevalence of gingival enlargement are not very well recognized with amlodipine as compared to nifedipine which is of considerable interest. Structurally, amlodipine is more polar with a pKa value of 8.7 than nifedipine which is strongly lipophilic and hence dissolves readily within the cell membrane and passes in the cytoplasm. Amlodipine on the other hand remains tissue bound therefore largely “inactive,” hence generating minimal untoward tissue responses.

Besides the cardiovascular system, CCBs have been indicted for instigating a diminished bone metabolism as ascertained by Duarte et al.[24] in their histometric study on bone metabolism. As previously mentioned, the CCBs inhibit the intracellular calcium influx while the osteoclasts activity depends on calcium concentration, thereby leading to a discernible dose-dependent fall in the cell spread area and osteoclast bone resorption.

Kapitan-Malinowska et al.[25] in fact reported temporary increase in bone mineral density in elderly patients treated for coronary heart disease for over 2 years with nifedipine.

Owing to the ambiguity of the role played by the interplay of diverse etiological and risk factors in instigating the disease, a streamlined comprehensive treatment plan is difficult to establish. In our case report, the patient is suspected to have had the gingival enlargement only in the vicinity of the healing abutments because of the inability of the patient to maintain oral hygiene in the particular sites. Once the hypertrophied area was surgically removed and oral hygiene maintenance improved after the fixation of the prosthesis, the lesion never recurred again even after 2 years. Professional debridement with scaling and root planing has been shown to offer relief in gingival overgrowth patients, particularly in short-term gingival lesion as was in our case. Withdrawal or substitution of medication though is a valuable treatment option; however, long-standing cases of gingival lesion have continually shown resistance in such cases. Impediment of esthetics or function may thrust a patient toward elective surgical treatment with a partial or total gingivectomy approach. A 3-month interval for periodontal maintenance therapy has been recommended for patients taking drugs associated with gingival enlargement.[26]

  Conclusion Top

In view of the upsurge witnessed in cardiovascular ailments, there is an increased likelihood of utilizing medication implicated in gingival overgrowth in near future. Drug substitution in conjunction with efficient plaque control though remains the treatment of choice, yet the patient's esthetic stipulations, failure of enlargement's resolution, or hindrance in the elective therapeutic protocol, as was in our case, might necessitate surgical intervention.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lindquist LW, Carlsson GE. Long-term effects on chewing with mandibular fixed prostheses on osseointegrated implants. Acta Odontol Scand 1985;43:39-45.  Back to cited text no. 1
Silverstein LH, Melkonian R. Periodontal considerations of dental implantology. In: Clark's Dentistry. Ch. 62. Philadelphia: J. B. Lippincott; 1993. p. 1-5.  Back to cited text no. 2
Rees TD, Levine RA. Systematic drugs as a risk factor for periodontal disease initiation and progression. Compendium 1995;16:20, 22, 26.  Back to cited text no. 3
Sakellari D, Vouros ID, Aristodemou E, Konstantinidis AB, Socransky S, Goodson M. Tetracycline fibers as an adjunct in the treatment of nifedipine-induced gingival enlargement. J Periodontol 2005;76:1034-9.  Back to cited text no. 4
Ellis JS, Seymour RA, Steele JG, Robertson P, Butler TJ, Thomason JM. Prevalence of gingival overgrowth induced by calcium channel blockers: A community-based study. J Periodontol 1999;70:63-7.  Back to cited text no. 5
Seymour RA. Effects of medications on the periodontal tissues in health and disease. Periodontol 2000 2006;40:120-9.  Back to cited text no. 6
Thomason JM, Seymour RA, Ellis JS, Kelly PJ, Parry G, Dark J, et al. Determinants of gingival overgrowth severity in organ transplant patients. An examination of the rôle of HLA phenotype. J Clin Periodontol 1996;23:628-34.  Back to cited text no. 7
Nishikawa S, Tada H, Hamasaki A, Kasahara S, Kido J, Nagata T, et al. Nifedipine-induced gingival hyperplasia: A clinical and in vitro study. J Periodontol 1991;62:30-5.  Back to cited text no. 8
Romanos GE, Strub JR, Bernimoulin JP. Immunohistochemical distribution of extracellular matrix proteins as a diagnostic parameter in healthy and diseased gingiva. J Periodontol 1993;64:110-9.  Back to cited text no. 9
Johnson RB, Zebrowski EJ, Dai X. Synergistic enhancement of collagenous protein synthesis by human gingival fibroblasts exposed to nifedipine and interleukin-1-beta in vitro. J Oral Pathol Med 2000;29:8-12.  Back to cited text no. 10
Fay AA, Satheesh K, Gapski R. Felodipine-influenced gingival enlargement in an uncontrolled type 2 diabetic patient. J Periodontol 2005;76:1217.  Back to cited text no. 11
Pernu HE, Pernu LM, Knuuttila ML. Effect of periodontal treatment on gingival overgrowth among cyclosporine A-treated renal transplant recipients. J Periodontol 1993;64:1098-100.  Back to cited text no. 12
Tavassoli S, Yamalik N, Caglayan F, Caglayan G, Eratalay K. The clinical effects of nifedipine on periodontal status. J Periodontol 1998;69:108-12.  Back to cited text no. 13
Seymour RA, Smith DG. The effect of a plaque control programme on the incidence and severity of cyclosporin-induced gingival changes. J Clin Periodontol 1991;18:107-10.  Back to cited text no. 14
Seymour RA, Thomason JM, Ellis JS. The pathogenesis of drug-induced gingival overgrowth. J Clin Periodontol 1996;23(3 Pt 1):165-75.  Back to cited text no. 15
Goultschin J, Shoshan S. Inhibition of collagen breakdown by diphenylhydantoin. Biochim Biophys Acta 1980;631:188-91.  Back to cited text no. 16
Hassell TM, Page RC, Narayanan AS, Cooper CG. Diphenylhydantoin (dilantin) gingival hyperplasia: Drug-induced abnormality of connective tissue. Proc Natl Acad Sci U S A 1976;73:2909-12.  Back to cited text no. 17
Seymour RA, Ellis JS, Thomason JM. Risk factors for drug-induced gingival overgrowth. J Clin Periodontol 2000;27:217-23.  Back to cited text no. 18
Pernu HE, Knuuttila ML, Huttunen KR, Tiilikainen AS. Drug-induced gingival overgrowth and class II major histocompatibility antigens. Transplantation 1994;57:1811-3.  Back to cited text no. 19
Margiotta V, Pizzo I, Pizzo G, Barbaro A. Cyclosporin– and nifedipine-induced gingival overgrowth in renal transplant patients: Correlations with periodontal and pharmacological parameters, and HLA-antigens. J Oral Pathol Med 1996;25:128-34.  Back to cited text no. 20
Bökenkamp A, Bohnhorst B, Beier C, Albers N, Offner G, Brodehl J. Nifedipine aggravates cyclosporine A-induced gingival hyperplasia. Pediatr Nephrol 1994;8:181-5.  Back to cited text no. 21
Brown RS, Sein P, Corio R, Bottomley WK. Nitrendipine-induced gingival hyperplasia. First case report. Oral Surg Oral Med Oral Pathol 1990;70:593-6.  Back to cited text no. 22
Van der Vleuten CJ, Trijbels-Smeulders MA, van de Kerkhof PC. Telangiectasia and gingival hyperplasia as side-effects of amlodipine (Norvasc) in a 3-year-old girl. Acta Derm Venereol 1999;79:323-4.  Back to cited text no. 23
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Kapitan-Malinowska B, Talalaj M, Marcinowska-Suchowierska E. The influence of calcium channel blockers on Ca-P-Mg homeostasis and bone mass in patients with coronary heart disease and hypertension. Osteoporos Int 1996;6:184-6.  Back to cited text no. 25
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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