Drug-induced oral pigmentation can be caused by a variety of medications through multiple different mechanisms. Common culprit medications include minocycline, antimalarials, clofazimine, and oral contraceptives. Other implicated medications include zidovudine (azidothymidine; AZT), chlorpromazine, ketoconazole, busulfan, doxorubicin, bleomycin, cyclophosphamide, 5-fluorouracil, nicotine, heroin, nitrogen mustard, phenothiazines, arsenic, silver, gold, lead, mercury, progesterone, and imatinib mesylate.
The pathogenesis of oral pigment changes depends primarily on the causative drug. The drug or drug metabolites may be pigmented substances that can be identified lying free or chelated to iron or melanin within the hard and/or soft tissues. Minocycline complexes with iron and deposits in the mucosa. Hyperproduction of melanin through melanocyte stimulation has been implicated as the mechanism for antimalarial medications (chloroquine, hydroxychloroquine, amodiaquine, and quinacrine) as well as oral contraceptive pills. Amiodarone-induced oral pigmentation is thought to result from increased production of lipofuscin.
Other drugs may lead to oral pigmentation when a lichenoid drug eruption resolves with post-inflammatory hyperpigmentation (such as from nonsteroidal anti-inflammatory drugs or a number of antihypertensive medications) or when there is direct damage to the mucosa (such as from chemotherapeutic agents). An oral fixed drug eruption appears as one or more well-demarcated, round or oval, slate-brown colored macules. The most common offending agents are cotrimoxazole and tetracycline.
For a discussion addressing multiple possible etiologies of oral mucosal pigmentation (physiologic, exogenous and endogenous substances, systemic disease), see Multifocal or diffuse mucosal pigmentation.
Drug-induced oral pigmentation - Oral Mucosal Lesion
Alerts and Notices
Synopsis
Codes
ICD10CM:
T50.995A – Adverse effect of other drugs, medicaments and biological substances, initial encounter
SNOMEDCT:
403663003 – Drug-induced oral pigmentation
T50.995A – Adverse effect of other drugs, medicaments and biological substances, initial encounter
SNOMEDCT:
403663003 – Drug-induced oral pigmentation
Look For
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Diagnostic Pearls
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Differential Diagnosis & Pitfalls
Causes of diffuse oral pigmentation:
- Physiologic pigmentation – Diffuse and bilateral, childhood onset (see multifocal or diffuse mucosal pigmentation).
- Peutz-Jeghers syndrome (periorificial lentiginosis) – Multiple diffuse and bilateral macules on the lips, oral / intranasal / conjunctival / rectal mucosa; childhood onset.
- Cronkhite-Canada syndrome – Nonfamilial gastrointestinal polyposis syndrome with associated cutaneous hyperpigmented macules, onychodystrophy, and alopecia.
- Laugier-Hunziker syndrome – Rare, benign condition of macular hyperpigmentation of mucocutaneous surfaces and nails.
- McCune-Albright syndrome – Polyostotic fibrous dysplasia, café-au-lait spots, and gonadotropin independent precocious puberty.
- Carney complex – Lentigines of the lips and intraoral pigmentation may be present.
- Primary hypoadrenalism (Addison disease) – Diffuse blue-black streaks or patches on oral mucosa and tongue in addition to hyperpigmentation, particularly in sun-exposed areas and flexural creases; also with fatigue, hypotension, electrolyte abnormalities.
- Other endocrine disorders: hyperthyroidism, Cushing disease
- Post-inflammatory pigmentation – Hyperpigmented lesions at sites of previous inflammatory or traumatic lesions or adjacent to active lesions (eg, lichen planus, pemphigus, pemphigoid).
- Smoker's melanosis – Brown-black lesions on the anterior labial and buccal mucosa in smokers.
- Scurvy – Ecchymosis, sometimes dusky purple discoloration of the gingiva with intraoral swelling and hemorrhage.
- Kaposi sarcoma – Bilateral brown to purple plaques / nodules in human immunodeficiency virus (HIV)-positive individuals; ulcerative and necrotic in advanced stages.
- Melanotic macule – Usually less than 1 cm, well demarcated, light or dark brown; more common in women and young adults. Though benign, should consider biopsy to rule out melanoma.
- Pigmented nevi – Brown or blue macule or papule commonly on the palate. Though benign, should consider biopsy to rule out melanoma.
- Melanoma – Brown or black patch with irregular borders, rapidly growing and more ulcerated as it advances; commonly on the palate, followed by the gingiva.
- Hemangioma – Red-bluish / purple lesion, flat or slightly raised, blanches with pressure, most commonly on tongue.
- Varix – Bluish / purple, irregular elevation, blanches with pressure, commonly on ventral tongue; if it does not blanch with pressure, it may contain a thrombus.
- Hemorrhage – Nonblanching macule, papule, or petechiae; may be ecchymotic.
Best Tests
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Management Pearls
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Therapy
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Drug Reaction Data
Below is a list of drugs with literature evidence indicating an adverse association with this diagnosis. The list is continually updated through ongoing research and new medication approvals. Click on Citations to sort by number of citations or click on Medication to sort the medications alphabetically.
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References
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Last Reviewed:05/24/2018
Last Updated:11/05/2019
Last Updated:11/05/2019
Drug-induced oral pigmentation - Oral Mucosal Lesion