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. [1-3]

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]

References:

[1] Livada R, Shiloah J. Calcium channel blocker-induced gingival enlargement. J Hum Hypertens. 2014;28(1):10-14. doi:10.1038/jhh.2013.47
[2] Nyska A, Shemesh M, Tal H, Dayan D. Gingival hyperplasia induced by calcium channel blockers: mode of action. Med Hypotheses. 1994 Aug;43(2):115-8. doi: 10.1016/0306-9877(94)90061-2. PMID: 7990738.
[3] Tungare S, Paranjpe AG. Drug Induced Gingival Overgrowth. [Updated 2021 Sep 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538518/
[4] Meraw SJ, Sheridan PJ. Medically induced gingival hyperplasia. Mayo Clin Proc. 1998;73(12):1196-1199. doi:10.4065/73.12.1196
[5] Steele RM, Schuna AA, Schreiber RT. Calcium antagonist-induced gingival hyperplasia. Ann Intern Med. 1994;120(8):663-4. doi: 10.7326/0003-4819-120-8-199404150-00006.

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