Medications causing drug induced gingival overgrowth (DIGO).
Periodontal tissue is susceptible to a range of adverse effects of several medications used in daily medical practice. Phenytoin, cyclosporine, and calcium-channel blockers are the most commonly used drugs related to gingival disease. Several other medications can also have an adverse effect on the periodontium, especially in the presence of compromised oral hygiene. These medications act on periodontal tissues by triggering the inflammatory pathways involved in the pathogenesis of periodontal disease or by potentially compromising the management of patients with these conditions. Gingival overgrowth is probably the mostly widely recognized and investigated type of adverse drug reaction in the periodontal tissues. Since many patients are on such medications, dental practitioner should take a thorough medical history and be aware of medication-related problems and their potential effects on diagnosis and treatment planning. The chapter reviews the commonly prescribed medications that can affect the periodontium either in its healthy or inflamed condition.
- adverse effects
- calcium channel blockers
- gingival overgrowth
Medications are chemical substances used to treat, cure, prevent, or diagnose a disease or to promote well-being. An adverse drug reaction is defined by WHO as a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, therapy of diseases or for the modification of physiological function. Several medications can cause adverse effects in the periodontium. The most common are the gingival enlargement, inflammation, pigmentations, gingival bleeding and osteonecrosis . Gingival overgrowth (GO) or enlargement is a condition is characterized by an increase in the size of gingiva subsequent to the increase in extracellular tissue volume. Gingival overgrowth is a side effect of several medications used by patients have the capability to cause adverse effects in the oral cavity and periodontal tissues . Though many medications have marked effects on the periodontal tissues and these adverse reactions are well documented, many have been described only as isolated case series or reports . It is important for the clinician to obtain a complete record of the medications the patient takes, including prescription drugs and over-the-counter drugs. This will help the clinician to diagnose and manage the adverse effects in the periodontal tissues.
2. Drug induced gingival overgrowth (DIGO)
The main drugs associated with GO can be divided into three categories such as anticonvulsants, calcium channel blockers, and immunosuppressants. Few isolated incidences of GO associated with antibiotics and sulphonamides were also reported. Though these drugs have different pharmacologic effect and targets, all of them seem to act similarly on the gingival connective tissue as a secondary target, leading to common clinical and histopathological changes. The gingival overgrowth (GO) is consequent to the alteration of the host tissue response, resulting in an increase in collagen synthesis and cellular changes within the connective tissue. The prevalence of gingival overgrowth varies with different medications, with a reported rate of 50% for phenytoin (anticonvulsant), 25–30% for cyclosporine (immunosuppressant), 5–20% for nifedipine and 3% for amlodipine (CCBs) . The drug associated gingival overgrowth is three times more prevalent among men and can be attributed to the effect of testosterone on fibroblast proliferation and collagen stimulus .
The GO appears normally within 1–3 months after administration of these medications (Table 1). The gingival enlargement may appear inflamed or more fibrotic depending on the degree of inflammation. Normally the GO is confined to the attached gingiva which might occasionally extend coronally. The enlarged gingiva produces esthetic changes and its clinical symptoms include tenderness, bleeding, interference with speech, dental occlusion problems, and enhanced susceptibility to periodontal diseases [4, 5, 6].
Histologically, the drug-induced gingival overgrowth is indistinguishable from other types of gingival enlargement. The enlargement of the gingival tissue occurs as a result of accumulation of extracellular matrix (ECM), although the pathogenesis remains multifactorial. Age, genetic predisposition, pharmacokinetic variables, drug-induced alterations in gingival connective tissue homeostasis, inflammatory changes, drug-induced action on growth factors, etc. are some of the factors that influences the occurrence and severity of the gingival overgrowth.
Genetic factors are important in the pathogenesis of drug associated gingival overgrowth. The drugs are metabolized by cytochrome p450 enzymes, which are characterized by high genetic variability. Research on genes responsible for HLA leukocyte antigen coding confirmed the theory of HLA-DR2 antigen influence, which is found much more commonly in patients with moderate or severe drug-induced gingival overgrowth than HLA-DR1 . The drug variables such as dosage, duration of therapy and concentration of drug in plasma and local fluids, like gingival crevicular fluid and saliva, play an important role in DIGO .
2.1 Pathogenesis of DIGO
The exact mechanism behind the pathogenesis of drug-induced gingival overgrowth is not yet fully understood. Each medication has got separate impacts on the range of cytokines and growth factors involved in connective tissue metabolism. Studies revealed that the molecular markers and clinical features of gingival overgrowth differ depending on the drugs. The cytokine and growth factor balances are altered in tissues with GO, including connective tissue growth factor (CTGF), a member of the interesting CCN (cysteine-rich angiogenic protein 61) family of factors [3, 9, 10].
Cytokine dependent alterations in extracellular matrix metabolism appear to be of functional importance to gingival overgrowth. Abnormal differentiation of cells, resulting in accumulation of fibroblasts with a pathologic range of proliferative and synthetic phenotypes, could result from deregulated cytokines. The unique metabolic aspects of gingival extracellular matrix metabolism; and a greater understanding of interactions between and among medications, the innate and acquired immune response, cytokines and growth factors, and gingival epithelial and connective tissue cells providing more detailed molecular and mechanistic information need to be elucidated [3, 11].
2.2 Histological features
Histologically, slight to moderate hyperkeratosis, thickening of the spinous layer, fibrosis of underlying connective tissue with fibroblastic proliferation, increase in the number of capillaries with slight chronic perivascular inflammation is seen. Excessive accumulation of extracellular matrix like collagen with varying amounts of inflammatory infiltrates, predominantly plasma cells are seen. Fibroblastic proliferation may not be evident. Plasma cells are the principal type of infiltrating inflammatory cell. Parakeratinized epithelium of variable thickness covers the connective tissue stroma. The epithelial ridges may penetrate deep into the connective with columns of interspersed collagen fibers .
2.3 Management of drug induced DIGO
The management of medication induced gingival overgrowth depends on the degree of progression of the disease. Withdrawal or substitution of medication is one of the methods that might resolve the gingival overgrowth. However, not all patients respond to this mode of treatment especially those with long standing gingival enlargement. Professional debridement with scaling and root planning as needed has been shown to offer some remission of the gingival overgrowth in patients. Since the anterior labial gingiva is frequently involved, surgery is commonly performed for esthetic reasons. The classical surgical approach has been the external bevel gingivectomy. However, a total or partial internal gingivectomy approach has been suggested as an alternative. This approach has the benefit of limiting the large denuded connective tissue wound and thereby minimizing postoperative pain and bleeding .
The surgical methods include traditional scalpel gingivectomy and periodontal flap surgery. Electrocautery may be used in difficult cases, children, or where the gingiva is fragile and likely to bleed. Excision using laser provides a superior incision margin and improved wound healing due to a coagulated layer along the incision, as well as a reduced incidence of scarring. CO2 laser is very effective in surgery of soft tissues with high water content like the gingiva. Blood vessels up to a diameter of 0.5 mm can be sealed effectively and provides a dry field for better visibility of the surgical field. A laser is preferred over the scalpel as it has strong bactericidal and hemostatic effects [14, 15]. A combined non-surgical and surgical therapy with drug substitution is the most common treatment approach in the management of medication induced gingival overgrowth . In most cases, conservative methods such as professional oral hygiene maintenance, topical anti-inflammatory and antibacterial drugs and a meticulous oral hygiene measures by the patient. Surgical excision is used in cases of where the gingival overgrowth interferes with food intake, causing difficulties in speech and maintaining oral hygiene. Surgical excision is more reliable as it eliminates the hyperplastic tissue and promotes plaque control as well as improves the esthetics.
Phenytoin is an anticonvulsant prescribed for the control of epilepsy and neuralgias. In the present day, phenytoin is not usually prescribed as a first line drug for the management of epilepsy due to the availability of a wide range of newer, more effective anticonvulsant drugs with fewer side effects. The prevalence of drug-induced gingival overgrowth in patients taking phenytoin is reportedly between 15% and 60% . Phenytoin, or its metabolites, probably acts directly on high activity fibroblasts leading to the high levels of production of collagen in the presence of inflammation. This results in gingival enlargement, characteristically originating principally from the interdental papillae (Figure 1). The amount or degree of severity of the overgrowth is not related to the dose of the drug. Presence of plaque and gingival inflammation, serum concentrations of the drug are factors which increases the risk of phenytoin-induced gingival overgrowth .
The management of this overgrowth is based on obtaining optimal control of plaque. Where the enlargement is unsightly and disfiguring, or even interfering with chewing, the over-growths should be removed. Gingivectomy appears to be the simplest and best way of achieving good gingival contour as a post-operative result. But optimal plaque control post-operatively is the most important determinant of success. Recent research work suggests that the use of chlorhexidine, especially brushing daily using the gel, can be of valuable assistance in controlling plaque and hence in controlling the overgrowths in the post-surgical phase.
Cyclosporin (CsA) is a cyclic polypeptide with potent immunosuppressive activity used widely to prevent organ transplant rejection and also in the treatment of autoimmune diseases [38, 39]. CsA selectively suppresses helper T-cell function and modulates the network of inflammatory cytokines. However, cyclosporin is associated with several untoward effects like nephrotoxicity, hepatotoxicity, hirsutism and gingival overgrowth [40, 41]. Gingival overgrowth is one of the common side effects of CsA treatment, observed in 13–81% of the patients [6, 39]. The prevalence of gingival overgrowth associated with CsA averages around 30%, with reported rates ranging from 10 to 85% . Studies have shown certain degree of association between GO and potential risk factors, such as age, genetic susceptibility, pharmacokinetic variables, plaque-related inflammation and immunological changes [42, 43, 44]. Epidemiological studies have reported wide variation of its occurrence and it accounts for more than 70% of the transplant recipients [4, 45]. The severity of gingival overgrowth is often associated with its prolonged use and further influenced by bacterial plaque and local irritants (Figure 2) . The use of other medication, such as calcium channel blockers along with CsA increases the prevalence of gingival overgrowth and subsequently the risks . The condition can interfere with the mastication, speech and oral hygiene maintenance and has a psychological impact in the affected individual .
The most prominent pathologic manifestation of the gingival overgrowth is an excessive accumulation of extracellular matrix, predominantly type I collagen. Many studies have shown increased transcriptional and translational levels of type I collagen in both tissue and fibroblast cultures derived from CsA-induced gingival overgrowth [9, 10, 47]. Though the exact mechanism is not clearly understood, studies also have shown increased expression of specific cytokines, especially transforming growth factor-beta (TGF-β), in drug-induced gingival overgrowth. This suggests that TGF-β, an inflammatory mediator that regulates cell proliferation and differentiation, plays a role in enlarging the extracellular matrix in hyperplastic gingival tissue .
The management of cyclosporin associated gingival overgrowth includes removal of local irritants and plaque and maintenance of adequate oral hygiene. Invasive procedures, such as gingivectomy is done in severe cases . Currently the use of antibiotics has shown reduction in the GO associated with the drug usage. Azithromycin, a semi synthetic antibiotic, derived from the macrolide erythromycin has shown reduction in gingival overgrowth . Roxithromycin, a macrolide antibiotic with similar characteristics of azithromycin, is also found to be effective in the reduction of gingival overgrowth in renal transplant recipients on CsA . Gingival overgrowth can be prevented by intensive plaque-control practices including meticulous brushing, although critically ill patients receiving CsA may not be the ideal candidates for such intensive procedures. A combination of chlorhexidine or normal saline mouth rinses and mechanical cleaning was found to be effective in controlling the management of such patients [51, 52].
2.6 Calcium channel blockers
Drugs including diuretics, alpha and beta blockers, angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers and calcium channel blockers (CCBs) have been used to manage hypertension . They are administered either alone or in combination, depending on the needs of the patient. The calcium channel blockers are the most frequently prescribed antihypertensive agents which is comprised of two subclasses, dihydropyridines and non-dihydropyridines. Although their mechanism of action is the same, they have varied pharmacological effects. While the dihydropyridines are potent vasodilators, the non-dihydropyridines produce more negative inotropic effects. The dihydropyridines such as nifedipine, amlodipine and felodipine are significantly associated with gingival overgrowth. The non-dihydropyridines such as diltiazem and verapamil are less commonly associated with gingival enlargement .
Nifedipine, a drug that belongs to a pharmacological agent group known as calcium channel blocker was introduced in 1972 and has been used widely in the management of hypertension and angina pectoris. Lederman et al.  was the first to describe nifedipine-induced gingival overgrowth in patients treated with this drug. The prevalence of nifedipine-induced gingival overgrowth is between 30 and 50% and was found to be 3 times likely to develop in males . The overgrowth appears 1–9 months after administration of the drug and the most common sites affected included the labial anterior gingiva of both jaws [56, 57]. A multifactorial pathogenesis has been suggested including environmental, genetic, immunological and inflammatory factors . The interdental papilla becomes more grossly enlarged followed by the marginal and the attached gingiva (Figure 3). Presence of gingival periodontal disease and dental plaque has been reported as significant risk factors in the development of gingival enlargement. Several hypotheses have been put forward to explain the phenomena of the gingival overgrowth. The interaction between nifedipine and gingival fibroblasts contain increased sulfated mucopolysaccharides which are precursors of ground substance, leading to the overproduction of collagen and extracellular ground substance . A genetically specific predetermined subpopulations of fibroblasts are identified which are sensitive to nifedipine and cause an increase in the production of collagen . The dose of nifedipine is important and it was found that its presence in gingival crevicular fluid is 15–316 times higher than plasma. The higher concentration of nifedipine in the gingival crevicular fluid could increase the severity of gingival enlargement.
Amlodipine is a third-generation dihydropyridine calcium channel blockers (CCB) that is used in the management of both hypertension and angina. The prevalence of gingival overgrowth associated with amlodipine is between 1.7% and 3.3% . Though the etiopathology of this adverse reaction is not clearly understood, mechanisms such as inflammatory and non-inflammatory pathways have already been hypothesized. The non-inflammatory mechanisms involves a defective collagenase activity due to decreased uptake of folic acid, blockage of aldosterone synthesis in the adrenal cortex and consequent increase in Adrenocorticotropic hormone level, and up-regulation of keratinocyte growth factor . The inflammatory pathway develops as a result of direct toxic effects of concentrated drug in gingival crevicular fluid and bacterial plaques leading to the up-regulation of several cytokine factors such as transforming growth factor-beta (TGF-β) .
The gingival overgrowth normally begins at the interdental papillae and is more frequently found in the anterior segment of the labial surfaces. Subsequently gingival lobulations that develop might appear as inflamed or fibrotic in nature depending on the degree of contributing factors (Figure 4). Normally the fibrotic enlargement is confined to the attached gingiva which might advance coronally and interfere with esthetics, mastication, or speech . Management of amlodipine induced gingival overgrowth includes substitution of the drug and controlling the other risk factors with meticulous mechanical and chemical plaque control. Surgical management of the overgrowth is advised in cases to accomplish an esthetic and functional outcome .
Verapamil is an effective preventive agent in both episodic and chronic cluster headache. Gingival overgrowth is an infrequent adverse effect of Verapamil and a prevalence rate of around 4.2% has been reported . Histologically, verapamil induced gingival enlargement shows a highly vascular connective tissue, acanthotic and thickened epithelium with long rete pegs containing dyskeratotic pearls, and varying amounts of subepithelial inflammatory infiltrate which is similar to other group of drugs . The histological appearance is similar to that caused by phenytoin, cyclosporin, and other calcium channel antagonists. Discontinuation of the drug usually results in complete regression of the gingival overgrowth.
3. Other effects of medications on periodontal tissues
Minocycline, a semi-synthetic broad-spectrum antimicrobial agent, is mainly used for the treatment of acne, chronic respiratory diseases, and rheumatoid arthritis. It is lipid soluble and therefore can easily penetrate into body fluids, such as saliva and gingival crevicular fluid, and into various body tissues including bone and soft tissues . Minocycline-induced pigmentation of oral mucous membranes including the buccal mucosa, gingiva, palatal area, lips and tongue has been reported [67, 68, 69]. The pathophysiology of minocycline staining is not clearly understood. It has been suggested that either a minocycline-metabolite complex or melanin, iron and calcium-containing granules are the source of the pigment . The pigmentation of oral soft tissues appears as distinctive blue-gray or brown in color and occurs as a result of pigmented black bone visible through the thin overlying mucosa without any actual involvement of the soft tissue itself (Figure 5) . The pigmentation appears to be related to the duration of minocycline therapy or the cumulative dose, and resolves once the drug is discontinued [69, 72]. Intraoral pigmentation can be managed with lasers .
3.2 Oral contraceptives
A higher prevalence of gingival inflammation, loss of attachment and gingival enlargement in woman taking hormone based oral contraceptives [73, 74]. The gingival inflammation seems to be associated to high concentrations of sex hormones present in oral contraceptives (Figure 6) . Oral contraceptives (OCs) enhance periodontal breakdown by reducing the resistance to dental plaque and can induce gingival enlargement in otherwise healthy females [76, 77]. Oral contraceptives have pronounced effects on gingival microvasculature and it has been shown that human gingiva contains receptors for progesterone and estrogen. The dosage and duration of intake are the possible factors which influence the effect of oral contraceptives on the periodontal condition. A continued exposure of oral contraceptives for longer duration results in higher risk of periodontal disease development due to increased production of pro-inflammatory cytokines and prostaglandins as a result of elevated levels of the hormones [78, 79]. However, the currently used combined oral contraceptives showed little influence on the periodontal health, possibly related to their lower concentration of progesterone and estrogen compared to the earlier formulations [74, 80]. A critical review supports the conclusion that there is no impact of modern oral contraceptives on the periodontal and gingival tissues. Hence, it is concluded that oral contraceptives can no longer be considered to constitute a risk factor for gingivitis or periodontitis .
Bisphosphonates are used widely in the management of primary and metastatic bone cancer, as well as osteoporosis. Bisphosphonates improve bone mineral density, reduce fracture risk, and reduce hypercalcemia of malignancy. Incidents of osteonecrosis of the jaw have been reported in people on bisphosphonates and undergoing invasive dental treatment procedures, including tooth extractions, dental implants, and surgical and nonsurgical periodontal treatment . The risk for bisphosphonate-induced osteonecrosis may be influenced by the route of administration of the drug, the potency and the duration of use. Jaw osteonecrosis appears more associated with the intravenous use of bisphosphonates. A review showed that 94% of the published cases of osteonecrosis correlated with administration of intravenous, nitrogen-containing bisphosphonates .
Bisphosphonates inhibit bone resorption by acting on osteoclasts to reduce their activity or to increase the rate of apoptosis . The inhibitory effect on osteoclast function, bone formation coupled with resorption results in an overall reduction in the rate of bone remodeling . Moreover, bisphosphonates may antagonize the action of several matrix metalloproteinase involved in breakdown of structural components of periodontal connective tissue . In view of the antiresorptive properties of bisphosphonates and the ability to inhibit cytokines of periodontal tissue destruction, there has been interest in the possible use of bisphosphonates as an adjunct to scaling and root planning in the management of periodontitis [87, 88]. Although bisphosphonates claim its effectiveness in controlling periodontal destruction, clinical use warrants further evidence. A systematic review concluded that bisphosphonates may be used topically as an adjunct to scaling and root planing .
Statins, or inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), are a group of drugs, used mainly to treat hyperlipidemia. In addition to their cholesterol lowering properties they also have strong anti-inflammatory properties and may stimulate bone growth . Statins have anabolic effects on the bone by augmenting bone morphogenetic protein-2 expression and thereby contributing towards the differentiation and activity of osteoblasts . Due to their activity on bone formation statins have been considered as potential agents in improving periodontal treatment outcomes . Limited data is available on the impact of stains on periodontal tissues suggesting a reduction in periodontal destruction and tooth loss . Experimental studies on rats support the potential protective effect of statins on periodontal bone loss. Although these basic data are interesting, further research could extrapolate the use of statins as a potential adjunctive therapeutic agent in periodontal disease and bone regeneration.
3.5 Anti-platelet drugs
Anti-platelet drugs are widely used for the treatment of established cardiovascular disease, the prevention of atherothrombotic events and the treatment of myocardial infarction. The most commonly prescribed antiplatelets drugs are aspirin and clopidogrel which are often used in combination. Both of these drugs have been reported to cause increased gingival bleeding. Patients on these medications carry a risk of an increased tendency to bleeding during or following periodontal surgery and this risk is far greater when the drugs are used in combination .
Several systemic factors are known to contribute to periodontal diseases or conditions and among those are the intake of drugs. The gingival overgrowth associated with medications occur as a side effect of systemic medications. These medications include the anti-seizure drug phenytoin, the immune suppressor cyclosporin A, and certain anti-hypertensive dihydropyridine calcium-channel-blockers, most notably nifedipine. It is crucial that health professionals understand the complications that medications can have on the oral health of their patients. In order to properly diagnose and treat patients, a complete medical history including prescription medications, over the counter drugs and dietary supplements must be recorded which will enable the healthcare team to identify the causative agents.
Conflict of interest
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