Drug-Induced Discoloration of Teeth

Mouth Rinses

Extrinsic staining of teeth is a well-known local side effect of the use of cationic antiseptic mouth rinses, particularly chlorhexidine. ⁵ Addy et al ⁶ demonstrated tooth staining after use of cetylpyridinium chloride and chlorhexidine mouth rinses. Cetylpyridinium stained comparably to chlorhexidine. A 0.1% chlorhexidine rinse stained slightly more than a 0.2% solution. A phenolic/essential oil product produced some staining but zinc, triclosan, and other essential oil rinses did not stain. Autio-Gold ⁷ reported that chlorhexidine rinses, gels, varnishes, or combinations of these with fluoride have variable effects on tooth. Staining of the teeth occurs in one third to one half of patients after several days of daily use of rinses. Stain is removable with the exception of porous restorations or in open margins, and a professional dental prophylaxis is usually required after prolonged use of chlorhexidine mouth wash. The mechanism by which cationic antiseptic cause tooth staining is still controversial. However, chlorhexidine or cetylpyridinium chloride precipitate or bind to surface food dyes and dietary chromogens in vitro. ⁸ Several clinical studies also support a dietary etiology for staining associated with cationic antiseptics, and certain beverages are particularly chromogenic in vivo. ⁵

Iron Salts/Other Metals

Extrinsic discoloration of teeth following large consumption of tannin-containing beverages is a well-known observation. Studies have shown that the presence of iron in chlorhexidine/tannic acid discolored pellicle material. Nordbo et al ⁹ demonstrated that aqueous solution of tannic acid in vivo produces brown discoloration of dental pellicle, and intake of liquid iron preparations for treatment of iron-deficiency anemia, particularly with tea consumption, may cause heavy staining of tooth surfaces. Addy et al ¹⁰ also reported tooth discoloration with certain metals, notably iron and tin. Silver nitrate stains the dentine black. Lead crosses the placenta and has potential to affect development of teeth. ¹¹ Lead has also been shown to accumulate in teeth posteruptively (black lead line on teeth). ¹²

Antimicrobials

Netherlands Pharmacovigilance Foundation reported 25 cases of yellow to brown discoloration of tooth following oral use of liquid drugs; 84% involved antibiotics of which 14 were amoxicillin. ¹³ The Dutch center for monitoring adverse reactions to drugs received 37 reports of tooth discoloration after use of amoxicillin, doxycycline, or metronidazole. Dewit et al ¹⁴ reported pseudodiscolorations caused by antimicrobials, possibly by chromogenic precipitates in the pellicle or by overgrowth with chromogenic microorganism. Garcia-López et al ¹⁵ reported 3 cases of tooth discoloration in children 3 to 6 years old after intake of 100 to 400 mg amoxicillin-clavulanic acid every 8 hours.

Linezolide

Matson and Miller ¹⁶ reported extrinsic discoloration of lower anterior teeth after linezolide therapy for 28 days in a 11-year-old immunocompromised girl with cellulitis. In an 8-year-old girl with bacterimia and polyarthritis, a 7-day course of intravenous vancomycin was given along with oral linezolide (30 mg/kg/d) for 3 weeks, and she developed brownish discoloration of teeth after 1 week of linezolide therapy. ¹⁷

Ciprofloxacin

In 13 infants (premature babies) treated with 10 to 40 mg/kg/d ciprofloxacin in 2 divided doses (slow intravenous infusion), some developed greenish discoloration of teeth, which could not be removed by mechanical means. ¹⁸ All teeth were stained uniformly with dyscalcification at cervical part. Therefore, these authors suggested that use of ciprofloxacin in newborn infants should be avoided.

Glibenclamide

Tooth discoloration is a novel side effect of sulfonylurea therapy in patients with permanent neonatal diabetes. Kumaraguru et al ¹⁹ reported tooth discoloration in 5 of the 67 patients of neonatal diabetes who received glibenclamide therapy. Discoloration was variable in severity ranging from mild discoloration or staining (n = 4) to loss of enamel (n = 1) and was seen in patients taking glibenclamide (glyburide). These authors suggested that cause of staining was precipitation of ingested chromogen onto dental surface or it may be related to decrease in blood flow to the pulp or by acting on vascular K⁺ ATP channels.

Tetracycline

Clinical evidence began to appear in the early 1960s showing that tetracycline antibiotic could cause tooth discoloration. ²⁰ The exact mechanism of tetracycline discoloration is not fully understood. However, several clinical studies have demonstrated that tetracycline becomes irreversibly bound to calcified tooth structures if taken during calcification stage of tooth development. ²¹ It is well known that discoloration is thought to be a photoinitiated reaction. ²² Tetracyclines are very well-known to cause tooth discoloration when given during second or third trimester of pregnancy; the newly born child has discolored teeth. Teeth may become bright yellow on development and after some time color of teeth may turn to gray. Jordan and Boskman ²³ classified tetracycline discoloration into 3 groups according to severity: first degree—light yellow gray or brown without banding, second degree—darker and more extensive yellow or gray staining without banding, and third degree (severe staining)—dark gray or blue discoloration with horizontal banding. Discoloration may vary depending on the type of tetracycline, doses, duration of intake, and patient’s age at the time of administration. ²⁴ In the pediatric population who have received tetracycline about one third have reported tooth staining. Incidence of this adverse effect is more during tooth development and when total daily dose exceeds more than 3 g or if treatment is continued more than 10 days. Tetracycline and oxytetracycline produce a yellow discoloration whereas chlortetracycline causes a gray-brown discoloration. ²⁴ Among all tetracyclines, oxytetracycline causes the least tooth staining. ²⁵ Tetracycline (eg, Ledermix, triamcinolone acetonide and demethylchlortetracycline) used within the tooth for endodontic therapy may also cause dark gray brown discoloration. ²⁶

Minocycline, a semisynthetic derivative of tetracycline is used as an adjunct in the treatment of periodontal diseases. Minocycline has also been reported to cause tooth discoloration. Minocycline may cause abnormal pigmentation of the skin, nails, bone, sclera, and conjunctiva in adults. It has been shown to cause tooth and bone discoloration in a few patients. ²⁷ In contrast to tetracycline, minocycline can cause generalized intrinsic tooth staining posteruption. ²⁸ This staining is quite different from that caused by tetracycline. Staining appears to occur in 3% to 6% of adult patients taking long-term minocycline in doses more than 100 mg/d. The exact mechanism by which minocycline causes tooth discoloration is still not clear. There are 4 possible theories: first, the extrinsic theory, according which minocycline combines with glycoprotein in acquired pellicles. This in turn etches the enamel, and demineralization/remineralization cycle occurs. It oxidizes on exposure to air or as a result of bacterial activity and causes degradation of the aromatic ring, forming insoluble black quinine. The second, intrinsic theory, suggested that minocycline bound to plasma protein and deposited in collagen-rich tissue such as teeth. This complex oxidizes slowly over time with exposure to light. This deposition in teeth occurs solely with dentin matrix as secondary and reparative dentin is formed; the drug or its metabolite does not affect the enamel itself. The third mechanism is that hemosidrin, a product of iron metabolism, chelates with minocycline to form an insoluble complex. ²⁹ The fourth theory is that minocycline could be deposited in dentine during dentinogenesis. ²⁸ Mozaffer et al ³⁰ reported skin and dark brown dental pigmentation in a 75-year-old man with amyotropic lateral sclerosis after 3 months of minocycline (100 mg twice daily) therapy. Kim et al ³¹ reported tooth discoloration of immature permanent incisor associated with triple antibiotic mixture of ciprofloxacine, metronidazole, and minocycline. This triple antibiotic paste was used as intracanal medication to tooth 8 of a 7-year-old child; the tooth then showed a dark discoloration. These researchers further suggested that among the component of triple antibiotic paste, only minocycline caused tooth discoloration.

In response to fears that doxycycline, like tetracycline, may stain teeth in young children, the Department of Education and Welfare in the United States and more recently, the American Academy of Pediatrics and the Committee of Infectious Disease recommend that tetracycline should not be used routinely to children younger than 8 years. However, other studies indicated that this concern may be unwarranted. Lochary et al ³² noted no clinically significant staining of permanent tooth in 10 children younger than 9 years, who were treated with doxycycline. Cale and McCarthy ³³ observed that administration of doxycycline (5 courses) in young children resulted in dental staining that was not visible to the naked eye. Volovitz et al ³⁴ reported no tooth staining or any other changes in tooth color in any of the children treated with doxycycline when 31 children, aged 2 to 8 years, were treated with up to 4 courses of doxycycline (2 mg/kg/d for 9 days for uncontrolled asthma). The better dental outcome with doxycycline may be attributed to its lower binding affinity for calcium than tetracycline.

Fluorides

Although fluoride therapy makes the tooth more resistant to dental caries, after chronic use fluorides have adverse effects on tooth. Tooth discoloration may occur when total daily intake of fluoride ion from sources such as drinking water, fluoride dentifrices, gel, foam, solution, mouthwashes, or varnishes is high during enamel formation and maturation. Dental fluorosis is the milder form of chronic toxicity, which results because of chronic ingestion of excess fluorides during the development and eruption of tooth. It is characterized by hypominerlization of enamel and is manifested as white flecks found primarily on cusp tips and on facial surfaces of permanent dentition. ³⁵ In moderate-severe form, extensive brown staining and pitting is found on tooth surfaces. ³⁵ This hypomineralized enamel appears to be directly related to a delay in the removal of amelogenin at the early maturation stage of enamel formation. The specific cause of this delay is not known, although existing evidence points to reduced proteolytic activity of proteinase that hydrolyzes amelogenin. Delay in hydrolysis of amelogenin could be because of a direct effect of fluoride on proteinase secretion or proteolytic activity, or to a reduced effectiveness of the proteinase because of other changes in the protein or mineral of the fluorosed enamel matrix. ³⁵ Dental fluorosis is a dose-dependent condition and higher the level of exposure during tooth development, the more severe the fluorosis.

Miscellaneous

Discoloration is almost impossible to eliminate if caused by silver nitrate or strongly colored iodine solutions in the root canal. Amalgam filling or root canal sealers containing iodoform or precipitated silver can also cause discoloration when contracting pulp chamber dentin. Silver points extending into the crown and corroding because of leakage will cause staining. Suge et al ³⁶ reported that diamine silver fluoride caused tooth discoloration when used for treatment of dentin hypersensitivity, and these authors prepared ammonium hexafluorosilicate to overcome tooth discoloration caused by diamine silver fluoride.