Drug-Induced Gingival Overgrowth: More than a Cosmetic Issue

Drug-induced gingival overgrowth affects about 1 million North Americans.

The medications that Americans take daily, both over the counter and prescription, have a major impact on dental health.¹ In addition, physicians often fail to discuss the oral adverse effects (AEs) with patients.¹ One woman thought nothing of having her blood pressure medication changed until a few weeks later when her gums seemed to be growing over her teeth.¹ Gingival overgrowth (also referred to as gingival enlargement or gingival hyperplasia) from drugs is widespread, with children and adolescents being more susceptible than adults.² Although not officially tracked,³ estimates are that drug-induced gingival overgrowth affects about 1 million North Americans.⁴ Men account for nearly 60% of patients.⁵

Most (86%) drug-induced gingival overgrowth is neither serious⁵ nor painful.⁶ Overgrowth can be localized or affect all teeth, including implants, with front teeth more affected than back teeth; toothless areas are usually not affected.⁷ Overgrowth varies from mild (such as a single nodule or only affecting the gums in the areas between the teeth) to severe, potentially covering the entire tooth. Presentation varies from noninflamed, firm, and fibrous to swollen, red, and bleeding.⁷ The increased tissue is primarily a drug-induced connective tissue response (increasing the matrix of the gingival connective tissue by affecting fibroblast function)5 rather than cell overgrowth.⁷ Although several possibilities have been proposed, the actual mechanism of pathogenesis is unclear.⁷

Causative Agents

Anticonvulsants, immunosuppressives, and calcium channel blockers are known to cause gingival overgrowth.^3,8-10 Other implicated drug classes include those for attention-deficit/hyperactivity disorder, obesity, and hypertension.³ Calcium channel blockers are the most common offenders (20%-30% of patients on calcium channel blockers are affected),^1,5 followed by immunosuppressants (15%), and anticonvulsants (10%).⁵ Gingival overgrowth is the most common dental AE of antiepileptics.⁶

Phenytoin, phenobarbital, valproate, cyclosporine, tacrolimus, nifedipine, verapamil, and amlodipine are known to cause gingival overgrowth^3,5,6,8-11; these drugs affect fibroblast function, increasing the matrix of the gingival connective tissue.⁵ Gingival overgrowth has also been reported with mycophenolate mofetil, valproic acid, clarithromycin, and estradiol.⁵ Calcium channel blocker—induced gingival overgrowth is especially seen with dihydropyridines (eg, amlodipine, nifedipine, felodipine, nicardipine) and benzothiazepines (eg, diltiazem)¹²; combining calcium channel blockers with cyclosporine potentiates overgrowth.³

Approximately half of patients on phenytoin or nifedipine will also develop gingival overgrowth, and cyclosporineinduced gingival overgrowth estimates range from 25% to 80% of patients.^3,4,8 Gingival overgrowth from phenytoin or nifedipine is inflammatory and highly fibrotic, whereas cyclosporine-induced overgrowth is inflammatory with little fibrosis.⁴

Drug type, dosage, concomitant medications, and existing dental disease all play a role in gingival overgrowth.^3,5 Examples include greater severity of overgrowth with increased duration of antiepileptic drug use⁶ and a higher rate of overgrowth due to high-dose calcium channel blockers.¹² Gingival overgrowth from calcium channel blockers, anticonvulsants, and immunosuppressants usually develops early (within 3 months) or late (after more than a year).^5,6,11-13 In older children (between 8 and 13 years), overgrowth usually occurs within 6 months of starting phenytoin.³

Effects of Gingival Overgrowth

Gingival overgrowth causes both physical and psychological distress.³ Drug-induced gingival overgrowth is usually limited to the gingiva; severe cases, however, can completely cover the teeth, interfering with chewing and speaking.^6-8 Overgrowth of the front teeth is common in transplant patients and can displace and destroy affected teeth.³ Overgrown tissue creates pockets that are difficult to reach with brushing or flossing, leading to plaque buildup, infection,^3,7,8,14 cavities, periodontal disease, halitosis and systemic infections^7,14; all of these contribute to deteriorating dental health.^6,11,14 Alveolar bone loss has occurred with phenytoin and carbamazepine.⁶

Gingival overgrowth can lead to depression, anxiety, fear, and pain,³ especially when it causes aesthetic problems on the front teeth,⁷ affecting smiling and facial expressions.^3,13 The media’s high value on physical appearance lessens the acceptance of those who look different,³ as exemplified by 2 sisters who had surgery to correct severe gingival hyperplasia; they were thrilled with their new smiles, partly because they had been bullied and made fun of because of the overgrowth.¹⁵ In addition to physical benefits, healthy teeth also provide psychological comfort.³

What We Can Do

Frequent dental checkups and good oral hygiene are the first line of defense against drug-induced dental complications.¹ Surgery is commonly used for control, but is only recommended for overgrowth interfering with function or appearance^2,3,8; however, the recurrence rate is high and surgery is a less than ideal option for immunocompromised patients.⁸ Nonsurgical treatments are symptomatic, rather than curative,⁸ and include continual reinforcement of good dental care, individually tailored orthodontia, and working with other providers, perhaps to switch medications.² Gingival overgrowth can often be reversed by stopping medication⁶; it usually resolves within 6 months of stopping phenytoin.²

Other control methods include electrocautery and CO₂ lasers—but these are expensive and have similar risks as surgery.⁸ Lack of apoptosis and cell clearance, which are needed for the constant tissue remodeling that occurs in the mouth, contribute to gingival overgrowth; the results of studies inducing apoptosis with cytochrome C show promise for controlling gingival overgrowth, but evidence is preliminary.⁸ Apoptosis, in which a cell “commits suicide,” shrinks, and is cleared without an inflammatory response, is preferred to necrosis, where lysis and inflammation occurs.⁸ Lovastatin-attenuated, phenytoin- induced gingival overgrowth has taken place in a mouse model, but human studies have not yet been conducted.⁹

For patients at risk, prevention of gingival overgrowth is essential and can best be achieved by practicing good oral hygiene and an interdisciplinary approach^2,6,10,11,14; cavities are preventable and gingivitis reversible with good oral hygiene.¹⁴ One dentist describes her work as a spiritual calling, strongly encouraging cross-clinical conversations with other providers.¹⁶ She wants people to know that poor dental health is more than a cosmetic problem; it can lead to other health problems, which are “100% preventable.”¹⁶

Debra Freiheit has been a practicing pharmacist and human services professional for over 25 years. Specializing in medical information, she has compiled a broad spectrum of experience obtained through research for companies including Cerner and PPD, Inc. With an emphasis on clear and concise information transfer, she has built a career communicating data to medical professionals and patients. Education and knowledge have been the motivation behind her career rich in caregiving through research. Debra’s current project involves the creation of a multinational database of drug information.

References

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• Bondon-Guitton E, Bagheri H, Montastruc JL. Drug-induced gingival overgrowth: a study in the French Pharmacovigilance Database. J Clin Periodontol. 2012;39(6): 513-518. doi: 10.1111/j.1600-051X.2012.01878.x.
• Cornacchio AL, Burneo JG, Aragon CE. The effects of antiepileptic drugs on oral health. J Can Dent Assoc. 2011;77:b140.
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• Yu H, Chamberlain S, Wanda P, Joy A. Induction of apoptosis to control drug-induced gingival overgrowth: an in Vitro study. Trans Ill State Acad Sci. 2013;106:59-62.
• Assaggaf MA, Kantarci A, Sume SS, Trackman PC. Prevention of phenytoin-induced gingival overgrowth by Lovastatin in mice. The American Journal of Pathology website. http://ajp.amjpathol.org/article/S0002-9440(15)00136-4/abstract. Published April 2, 2015. Accessed April 25, 2015.
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• Banthia R, Gupta S, Banthia P, Singh P, Raje S, Kaur N. Is periodontal health a predictor of drug-induced gingival overgrowth? a cross-sectional study. Dent Res J (Isfahan). 2014;11(5):579-584.
• Kaur G, Verhamme KMC, Dieleman JP, et al. Association between calcium channel blockers and gingival hyperplasia. J Clin Periodontol. 2010;37(7):625-630. doi: 10.1111/j.1600-051X.2010.01574.x.
• Sorunke ME, Agbelusi GA, Savage KO, Fadeyibi IO. Gingival overgrowth and associated factors among epileptic patients of Lagos University Teaching Hospital, Lagos, Nigeria. African Journals Online website. www.ajol.info/index.php/njpsur/article/view/95030.
• Zarco MF, Vess TJ, Ginsburg GS. The oral microbiome in health and disease and the potential impact on personalized dental medicine. Oral Dis. 2012;18(2):109-120. doi: 10.1111/j.1601-0825.2011.01851.x.
• Sisters debut brand new smiles after surgery for rare condition. NBC 6 South Florida website. www.nbcmiami.com/news/local/Sisters-Smile-for-the-First-Time-After-Surgery-for-Rare-Condition-Gingival-Fibromatosis-262712491.html. Published June 11, 2014. Accessed April 26, 2015.
• Bourg A. Marriottsville dentist out to ensure all receive comprehensive dental care. ABC 2 WMAR Baltimore website. www.abc2news.com/news/health/marriottsville-dentist-out-to-ensure-all-receives-proper-dental-care. Published April 22, 2015. Accessed April 26, 2015.