Is there data on the incidence of gingival hyperplasia as an adverse event of calcium channel blockers (e.g., amlodipine or nifedipine)? is it more prevalent with a particular CCB?

Is there data on the incidence of gingival hyperplasia as an adverse event of calcium channel blockers (e.g., amlodipine or nifedipine)? is it more prevalent with a particular CCB?

Comment by InpharmD Researcher

The prevalence of CCB-induced gingival hyperplasia greatly varies depending upon the reporting study and review articles. In general, nifedipine may have a higher risk of gingival overgrowth, followed by diltiazem, verapamil, and amlodipine in a descending order. However, the data mainly involves older studies and comparison between all CCB agents within a single, recent study has not been performed.

Background

Gingival hyperplasia (GH) is a known side effect of calcium antagonism although the reported incidence rate for calcium channel blockers (CCBs) seems to be low. The pathogenesis of gingival hyperplasia from the use of CCB is poorly understood but may be related to the proliferation of collagen fibers. Inhibition of calcium cell influx may lead to reduced production of collagenase, proliferation of inflammatory cytokines, or genetic involvement which alters enzyme activity or fibroblast vulnerability to CCBs. Risk factors that predispose patients to greater risk of GH may include poor oral hygiene and male gender. Evidence is not clear on whether patient age or dose of CCB correlates to increased risk of GH. [1], [2], [3]

A 1998 article discusses the prevalence of CCB-induced GH, stating that the most commonly reported agent is nifedipine (38%) followed by diltiazem (20%), verapamil (4 to 19%), and amlodipine (3%). However, reported incidence rates can greatly vary based on the individual studies with reports for nifedipine ranging from 0.5% to 83% and diltiazem being as high as 74%. Episodes of GH typically occur 1 to 3 months after initiating CCB. At the time of publication, the authors did not report a specific dose or plasma level relationship between CCB and GH. [4], [5]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Is there data on the incidence of gingival hyperplasia as an adverse event of calcium channel blockers (e.g., amlodipine or nifedipine)? is it more prevalent with a particular CCB?

Please see Tables 1-4 for your response.

Gingival hyperplasia: a side effect of nifedipine and diltiazem
Design	Prospective, cross-sectional study N= 89
Objective	To study the effects of the calcium channel blockers (CCBs) on gingivae
Study Groups	Control (n= 31) Diltiazem (n= 35) Nifedipine (n= 23)
Inclusion Criteria	Treated in the outpatient geriatric medicine clinic, treated inpatient, were referred to the outpatient dental clinic, taking CCB for at least 6 months, not taking any other medications that may cause gingival hyperplasia, not having any medical condition where premedication might be required because time constraints were a factor, not received periodontal therapy within the past 6 months
Exclusion Criteria	Switching CCB treatment during the study
Methods	Patients were initially identified via medical charts. Then patients were sent to the staff periodontist for oral examination for grading of gingival hyperplasia. The periodontist was blinded as to whether the patients were receiving CCBs or not.
Duration	February 1989 to September 1989
Outcome Measures	Presence and grade of gingival hyperplasia were defined as: Grade 0: No hyperplasia; normal gingiva Grade 1: The hyperplastic gingiva covered the cervical third or less of the anatomic crowns Grade 2: The hyperplastic gingiva extended anywhere into the middle third of the anatomic crowns Grade 3: The hyperplastic gingiva covered more than 213 of the anatomic crowns
Baseline Characteristics		Control (n= 31)	Diltiazem (n= 35)	Nifedipine (n= 23)
	Age, years	57	65	62
	Months on medication	11	14	12
Results	Endpoint	Control (n= 31)	Diltiazem (n= 35)	Nifedipine (n= 23)
	Presence of gingival hyperplasia Grade 0 Grade 1 Grade 2 Grade 3 Average grade	27 4 0 0 0.1	74% 9 19 7 0 0.9	83% 4 10 8 1 1.3
Study Author Conclusions	Future studies will undoubtedly show how best to manage patients on calcium channel blockers who develop gingival hyperplasia. Perhaps good oral hygiene and regular dental checkups will control this gingival overgrowth the same as they do with Dilantin. For some patients, perhaps other antihypertensive medications may be more suitable than the calcium channel blockers.
InpharmD Researcher Critique	This is an older study that may not reflect the current healthcare landscape regarding gingival grading and diagnosis. The authors attempted to assess for verapamil but only 4 patients were involved in the baseline analysis and were left unreported in the results.

References:

Fattore L, Stablein M, Bredfeldt G, Semla T, Moran M, Doherty-Greenberg JM. Gingival hyperplasia: a side effect of nifedipine and diltiazem. Spec Care Dentist. 1991;11(3):107-109. doi:10.1111/j.1754-4505.1991.tb00828.x

Prevalence of Amlodipine-Related Gingival Hyperplasia
Design	Prospective cross-sectional study N= 150
Objective	To examine a large random sampling of dentate patients who had been taking amlodipine for at least 6 months and to determine the prevalence of gingival hyperplasia
Study Groups	Study participants (N= 150)
Inclusion Criteria	Received amlodipine, had at least 10 natural teeth, no other medication associated with gingival hyperplasia, no antibiotic premedication required for dental treatment, no periodontal treatment within the previous 6 months
Exclusion Criteria	N/A
Methods	Patients recruited were on amlodipine 5 mg per day for at least 6 months and were prospectively interviewed while receiving oral examination.
Duration	N/A
Outcome Measures	Average plaque index, patients who exhibit gingival hyperplasia
Baseline Characteristics		Study participants (N= 150)
	Age range, years	33 to 87
	Female	76 (50.7%)
	Smoking status Never Former Current	73 (48.7%) 69 (46.0%) 8 (5.3%)
Results	Endpoint	Study participants (N= 150)
	Average plaque index	38% (10% to 85%)
	Exhibiting gingival hyperplasia	5 (3.3%)*
	*This is significantly less than rates reported for nifedipine (p< 0.001), and not significantly different from rates reported for control groups who were not taking any drugs known to cause gingival hyperplasia.
Study Author Conclusions	The results from this group of patients indicated that amlodipine, 5 mg per day, did not induce gingival hyperplasia.
InpharmD Researcher Critique	There were limited discussions regarding the methods and analysis of the study.

References:

Jorgensen MG. Prevalence of amlodipine-related gingival hyperplasia. J Periodontol. 1997;68(7):676-678. doi:10.1902/jop.1997.68.7.676

Prevalence of gingival overgrowth among elderly patients under amlodipine therapy at a large Indian teaching hospital
Design	Cross-sectional study N= 157
Objective	To determine the prevalence of amlodipine-induced gingival overgrowth (GO) among elderly subjects attending an Indian teaching hospital and find any association with demographic factors, drug variables, oral hygiene status and gingival inflammation
Study Groups	Study participants (N= 157)
Inclusion Criteria	Age ≤ 60 years, taking amlodipine for at least 3 months
Exclusion Criteria	Taking any other medications known to induce GO, undergoing periodontal therapy in the last 6 months, medicated with antibiotics in the past 6 months, systemic disease that could significantly affect the periodontal condition.
Methods	Medical records, questionnaires, and oral examinations were collected for analysis. All patients were examined by a single examiner. Periodontal examination included oral hygiene via plaque index and gingival inflammation.
Duration	N/A
Outcome Measures
Baseline Characteristics		Study participants (N= 157)
	Age, years	66.55 ± 10.27
	Female	40.1%
	Drug dosage, mg 2.5 5 10	21 (13.4%) 77 (49.0%) 59 (37.6%)
	Duration of therapy, months 3 to 4 4 to 6 6 to 12 12 to 24 > 24	13 (8.3%) 19 (12.1%) 22 (14.0%) 24 (15.3%) 79 (50.3%)
Results	Endpoint	Study participants (N= 157)
	Patients with GO	8 (5.09%)
		Patients with GO (N= 8)	Patients without GO (N= 149)	p-Value
	Mean plaque index score	2.95 ± 0.48	1.97 ± 0.52	0.001
	Mean gingival index score	1.71 ± 0.31	0.97 ± 0.31	0.001
	Mean probing depth	5.13 ± 1.01	3.28 ± 0.86	0.001
Study Author Conclusions	Prevalence of amlodipine-associated GO in the sample of elderly Indian patients was noted higher than that previously reported. Plaque and gingival inflammation were highly correlated with this condition, while demographic characteristics and drug dosage did not relate significantly.
InpharmD Researcher Critique	Only elderly patients age 60 years or older from India represented the study population which may not reflect the U.S. prevalence rate.

References:

Karnik R, Bhat KM, Bhat GS. Prevalence of gingival overgrowth among elderly patients under amlodipine therapy at a large Indian teaching hospital. Gerodontology. 2012;29(3):209-213. doi:10.1111/j.1741-2358.2011.00603.x

Prevalence and risk of gingival overgrowth in patients treated with diltiazem or verapamil
Design	Cross-sectional study N= 95
Objective	To determine the prevalence and risk factors for gingival enlargement in patients treated with diltiazem or verapamil
Study Groups	Cardiovascular control (n= 49) Diltiazem (n= 32) Verapamil (n= 14)
Inclusion Criteria	Age > 18 years, treated with diltiazem or verapamil, 16 permanent teeth, minimum 10 anterior teeth
Exclusion Criteria	Periodontal treatment within the last 6 months, concomitant systemic disorders known to affect the gums, taking anticonvulsant drugs, calcium antagonists other than diltiazem or verapamil, cyclosporine A, oral contraceptives, and sexual hormones
Methods	Patients in Spain included for analysis were taking diltiazem or verapamil for at least 6 months. The control group comprised of patients who were not treated with diltiazem or verapamil.
Duration	N/A
Outcome Measures	Vertical gingival enlargement (GO index), horizontal nodullary-papilla enlargement (MB index), gingival index, plaque index, probing depth
Baseline Characteristics		Cardiovascular control (n= 49)	Diltiazem (n= 32)	Verapamil (n= 14)
	Age, years	59	64	66
	Male/female	21/28	15/17	6/8
	Smokes > 20 cigarettes/day	8%	6%	0
	Bruxism	27%	19%	21%
	Oral breathing pattern	18%	9%	7%
	Dental prosthesis	29%	34%	50%
Results	Endpoint	Cardiovascular control (n= 49)	Diltiazem (n= 32)	Verapamil (n= 14)	p-Value
	GO index = 0 > 0	44 (90%) 5 (10%)	22 (69%) 11 (31%)	11 (79%) 3 (21%)	NS
	MB index = 0 > 0	42 (86%) 7 (14%)	16 (50%) 16 (50%)	9 (64%) 5 (36%)	NS
	Gingival index ≤ 1.5 ≥ 1.5	26 (53%) 23 (47%)	12 (38%) 20 (62%)	7 (50%) 7 (50%)	NS
	Plaque index ≤ 2.5 ≥ 2.5	20 (41%) 29 (59%)	8 (25%) 24 (75%)	4 (29%) 10 (71%)	NS
	Probing depth ≤ 3 ≥ 3	41 (84%) 8 (16%)	21 (66%) 11 (34%)	11 (79%) 3 (21%)	NS
	Risk of gingival enlargement, odds ratio (OR) GO index (p-value) MB index (p-value)	-- --	4.0 (1.2 to 13.1; p= 0.023) 6.0 (2.1 to 17.3; p< 0.001)	2.4 (0.5 to 11.6; NS) 3.3 (0.9 to 12.9; NS)	--
Study Author Conclusions	Patients taking diltiazem are at high risk for gingival enlargement and gingivitis has a stronger effect than the drug treatment on gingival enlargement risk.
InpharmD Researcher Critique	The study primarily took place in Spain. Patients in the verapamil group had fewer patients and half with dental prostheses. Other differences in baseline characteristics are concerning due to the low patient population despite only age being the only statistically significant difference.

References:

Miranda J, Brunet L, Roset P, Berini L, Farré M, Mendieta C. Prevalence and risk of gingival overgrowth in patients treated with diltiazem or verapamil. J Clin Periodontol. 2005;32(3):294-298. doi:10.1111/j.1600-051X.2005.00662.x