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Am Fam Physician. 2020;102(9):613-621

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial affiliations.

Drugs are being prescribed with more frequency and in higher quantities. A serious adverse drug event from prescribed medications constitutes 2.4% to 16.2% of all hospital admissions. Many of the adverse drug events present intraorally or periorally in isolation or as a clinical symptom of a systemic effect. Clinical recognition and treatment of adverse drug events are important to increase patient adherence, manage drug therapy, or detect early signs of potentially serious outcomes. Oral manifestations of commonly prescribed medications include gingival enlargement, oral hyperpigmentation, oral hypersensitivity reaction, medication-related osteonecrosis, xerostomia, and other oral or perioral conditions. To prevent dose-dependent adverse drug reactions, physicians should prescribe medications judiciously using the lowest effective dose with minimal duration. Alternatively, for oral hypersensitivity reactions that are not dose dependent, quick recognition of clinical symptoms associated with time-dependent drug onset can allow for immediate discontinuation of the medication without discontinuation of other medications. Physicians can manage oral adverse drug events in the office through oral hygiene instructions for gingival enlargement, medication discontinuation for oral pigmentation, and prescription of higher fluoride toothpastes for xerostomia.

Drugs are being prescribed with more frequency and in higher quantities per patient, with an estimated prevalence of 59% of the U.S. population taking at least one prescription medication and 15% taking five or more prescription drugs.1 A serious adverse drug event from prescribed medications constitutes 2.4% to 16.2% of all hospital admissions with an estimated treatment cost of $1.6 to $5.6 billion.2 Increased usage of medications leads to increased adverse drug reactions, particularly in vulnerable elderly populations.3 All of the 10 most commonly filled prescription medications4 have adverse effects associated with the orofacial complex, including hypersensitivity type reactions, xerostomia, paresthesia, and dysgeusia5 (Table 135 ). Other adverse reactions, such as vomiting, can cause secondary oral symptoms of tooth erosion, oral mucosal erythema or edema, and subsequent increase in dental caries. Adverse effects can present as severe systemic disease, for example Stevens-Johnson syndrome. Close attention is warranted even in seemingly mild adverse effects, such as xerostomia, because these might decrease patient compliance with prescribed drug therapies or have negative effects on quality of life.6 A high suspicion for medication adverse effects as a source of oral complaints can thus lead to appropriate interventions, such as stopping the causative medication, finding appropriate substitutes, and identifying serious reactions in a timely manner. The main categories of oral or perioral manifestations attributable to prescribed medications are gingival enlargement, oral hyperpigmentation, oral hypersensitivity reaction, osteonecrosis, xerostomia, and other oral or perioral conditions such as angioedema and chemical burns (Table 2).

Drug nameTotal prescriptions4 Oral adverse effects3
Levothyroxine114,344,324Vomiting, dysgeusia (< 1%)
Lisinopril110,611,324Dysgeusia (≥ 1%), Stevens-Johnson syndrome (≥ 1%), toxic epidermal necrolysis (≥ 1%), xerostomia (≥ 1%), angioedema (< 1%)
Atorvastatin (Lipitor)96,942,508Anaphylaxis (< 1%), angioedema (< 1%), dysgeusia (< 1%), erythema multiforme (< 1%), hypoesthesia/paresthesia (< 1%), Stevens-Johnson syndrome (< 1%), toxic epidermal necrolysis (< 1%), vomiting (< 1%)
Metformin81,305,415Infection (21%), nausea and vomiting (7% to 26%), taste disorder (1% to 10%)
Amlodipine (Norvasc)75,201,622Angioedema (< 1%), dysphagia (< 1%), erythema multiforme (< 1%), gingival enlargement (< 1%), hypersensitivity reaction (< 1%), hypoesthesia/paresthesia (< 1%), increased thirst (< 1%), vomiting (< 1%), xerostomia (< 1%)
Metoprolol74,019,645Xerostomia (1%), vomiting (frequency undefined), paresthesia (< 1%), taste disorder (< 1%)
Omeprazole (Prilosec)70,626,980Vomiting (3%), acid regurgitation (2%), allergic reactions/anaphylaxis/hypersensitivity reaction (< 1%), angioedema (< 1%), dysgeusia (< 1%), erythema multiforme (< 1%), Stevens-Johnson syndrome (< 1%), tongue mucosal atrophy (< 1%), toxic epidermal necrolysis (< 1%), xerostomia (< 1%)
Simvastatin (Zocor)65,144,488Anaphylaxis (< 1%), angioedema (< 1%), dry mucous membranes (< 1%), dysgeusia (< 1%), erythema multiforme (< 1%), hypersensitivity reaction (< 1%), paresthesia (< 1%), Stevens-Johnson syndrome (< 1%), toxic epidermal necrolysis (< 1%), vomiting (< 1%)
Losartan (Cozaar)49,281,054Paresthesia (< 2%), vomiting (< 2%), anaphylaxis (< 1%), angioedema (< 1%), dysgeusia (< 1%), lip edema (< 1%), tongue edema (< 1%)
Albuterol47,109,711Application site reaction (6%), oropharyngeal pain (≤ 5%), unpleasant taste at inhalation site (4%), vomiting (3% to 7%), hypersensitivity reaction (3% to 6%), glossitis (< 3%), infection (< 3%), oropharyngeal edema (< 3%), xerostomia (< 3%), anaphylaxis (< 1%), angioedema (< 1%), dysgeusia (< 1%), oropharyngeal irritation (< 1%), tongue ulcer (< 1%)
ManifestationPresentationCommonly associated medicationPrevention/treatment
Gingival enlargementEnlarged gumsAnticonvulsants (e.g., carbamazepine [Tegretol], phenytoin [Dilantin]), calcium channel blockers (e.g., amlodipine [Norvasc], nifedipine), cyclosporine (e.g., Sandimmune), erythromycin, oral contraceptivesPrescribe lowest dose for shortest time needed or use substitutes; promote personal oral hygiene through flossing and twice daily brushing with fluoridated toothpaste; reversible with drug discontinuation/substitution; excision of gums if not reversed after three to six months
HyperpigmentationDiscoloration of oral/perioral tissuesAmiodarone, antibiotics (e.g., minocycline [Minocin], tetracycline), anticancer drugs (e.g., bleomycine, busulfan [Busulfex], tacrolimus [Prograf]), antimalarials (e.g., chloroquine [Aralen], hydroxychloroquine [Plaquenil]), antiretrovirals (e.g., zidovudine [Retrovir]), chlorhexidine gluconate (Peridex), clofazimine, heavy metals (e.g., arsenic, bismuth), hormone replacement therapy, ketoconazole, methyldopa, oral contraceptives, quinidineLimit duration of medications; discontinuation of medication; surgical stripping (laser, cryotherapy, or scalpel) if normalization does not occur (repigmentation after surgical stripping may occur)
AngioedemaEnlarged lipAngiotensin-converting enzyme inhibitors (e.g., enalapril [Vasotec], lisinopril), nonsteroidal anti-inflammatory drugs, selective cyclooxygenase inhibitors (e.g., celecoxib [Celebrex], rofecoxib, thiazolidinedione)Antihistamines and corticosteroids; avoidance of drugs if they caused a past reaction
Chemical burnsWhite to yellow wrinkled lesions, sloughing of mucosal tissuesAngiotensin-receptor blockers (e.g., captopril, losartan [Cozaar]), nonsteroidal anti-inflammatory drugs (e.g., aspirin, naproxen, piroxicam [Feldene])Removal of causative agent; topical corticosteroid and/or benzocaine; one- to two-week follow-up
Osteonecrosis of the jawExposure of necrotic bone through oral mucosaAntiangiogenic drugs (e.g., bevacizumab [Avastin], sunitinib [Sutent]), bisphosphonates (e.g., alendronate [Fosamax], zoledronic acid [Reclast]), denosumab (Prolia)Limit duration of bisphosphonate treatment; recommend good oral hygiene and routine dental visits; necessary dental work is recommended before initiation of treatment; hold bisphosphonates for two to three months before and up to three months after invasive dental treatment
XerostomiaDry mouth, ropey saliva, glossy tongue, mucositisAmphetamines, analgesics (e.g, morphine), anticholinergics (e.g., atropine), antidepressants (e.g., amitriptyline), antiemetics (e.g, metoclopramide [Reglan]), antihistamines (e.g., loratadine [Claritin], chlorpheniramine), anxiolytics (e.g., alprazolam [Xanax]), bronchodilators (e.g., albuterol), decongestants (e.g., pseudoephedrine, phenylephrine), diuretics (e.g., hydrochlorothiazide), skeletal muscle relaxants (e.g., orphenadrine [Norflex])Encourage water drinking habits, sialagogues, oral lubricants, prevention of caries-forming habits (e.g., drinking sugary soda, sucking on sugary hard candies), oral hygiene instructions (e.g., twice daily brushing, flossing, show proper brushing technique); keep doses as low as possible for causative agents; can prescribe cevimeline (30 mg three times daily)
Oral candidiasisWhite coating on dorsal tongue that wipes offAntimicrobials, inhaled corticosteroid aerosol (beclomethasone, fluticasone)Rinse mouth with water after use; prescribe swish-and-swallow antifungal; rinse mouth after use of inhaled corticosteroids

Gingival Enlargement

Gingival enlargement (or gingival hyperplasia/hypertrophy or overgrowth) is the enlargement of gum tissue in the mouth (Figure 1). Classic drugs associated with medication-induced gingival enlargement include calcium channel blockers, anticonvulsants, and cyclosporine (Sandimmune). Erythromycin and oral contraceptives have also been implicated in gingival enlargement. The increased overgrowth of gingival tissue is related to the disruption of the degradation of collagen, which leads to a larger amount of extracellular collagen tissue within the gums. Amlodipine (Norvasc), diltiazem, nifedipine, phenytoin (Dilantin), and verapamil are most commonly implicated in gingival enlargement7 (Table 3723 ). It is well documented that the amount of plaque in the mouth is an independent risk factor in the prevalence of medication-induced gingival enlargement.7,24,25 Patients with gingival enlargement have an increased height of gingival tissue (measured from the tooth-gum connection to the top of the gums), creating a challenging environment for patients and professionals to clean plaque from the mouth. Therefore, meticulous plaque control is important to limit the extent and recurrence of the gingival enlargement. Other risk factors include being male (three times more likely), younger age (younger than 40 years),26 and taking higher daily doses of medication24 when there may be a possible genetic predisposition to gingival enlargement.27

ManifestationCausative medicationPrevalence
Gingival enlargement7,8 Phenytoin (Dilantin)20% to 57%
Diltiazem5% to 20%
Nifedipine6% to 15%
Verapamil5%
Amlodipine (Norvasc)2% to 3%
Hyperpigmentation912 Zidovudine (Retrovir)22.7% to 26.3%
Hydroxychloroquine (Plaquenil)9.8%
Minocycline (Minocin)3.7% to 5.6%
Angioedema13 Angiotensin-converting enzyme inhibitors0.1% to 0.2%
Medication-related osteonecrosis1418 Intravenous bisphosphonates (zoledronic acid [Reclast], ibandronate [Boniva])3% to 18%
Denosumab (Prolia; subcutaneous injection)0.7% to 1.9%
Oral bisphosphonates (alendronate [Fosamax], risedronate [Actonel], ibandronate)0.10% to 0.21%
Xerostomia19 Opioids25%

Gingival enlargement can present as an aesthetic concern to patients resulting in poor patient compliance with the medication.28 Tissue enlargement starts one to three months after initiation of medication,29 and discontinuation of medication with substitution can decrease effects of medication-induced gingival enlargement. Reduction of gingival size typically occurs within six months to one year after discontinuation of the causative medication. The first, most ideal step to prevent gingival enlargement is plaque control by the patient.7,24,25,30,31 Treatment options include reducing dose and/or duration of the causative medication, reviewing oral hygiene instructions to the patient, increasing frequency of professional dental cleanings with adjunctive use of chlorhexidine gluconate (Peridex), using topical folic acid, open-flap debridement (reflecting gingival tissue to clean teeth), or removing excess tissue with laser, electrosurgery, or scalpel.25,32,33 Chlorhexidine gluconate is typically prescribed under the supervision of a dentist because of the potential adverse effect of oral hyperpigmentation with prolonged use.

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