Drug-Induced Hyperpigmentation

Drug induced hyperpigmentation is skin, nail or mucosal pigmentation caused by medicines, through increased melanin, deposition of the drug or its metabolites, or iron deposition.

It accounts for 10 to 20% of acquired hyperpigmentation. Common causes are minocycline, amiodarone, antimalarial drugs (hydroxychloroquine, chloroquine), phenothiazines (chlorpromazine), cytotoxic drugs (bleomycin, busulfan, cyclophosphamide, 5-fluorouracil, hydroxyurea), clofazimine, tetracyclines, zidovudine, oral contraceptives (melasma pattern) and heavy metals.

Pigmentation is dose related and may take months or years to appear and to fade after stopping the drug. It occurs more in sun exposed skin and in people with darker skin.

Pathophysiology.

Mechanisms differ. Minocycline forms an insoluble iron chelate and pigment in the dermis. Amiodarone deposits lipofuscin like granules in dermal macrophages with photosensitisation. Antimalarials and phenothiazines bind melanin and deposit as drug melanin complexes. Cytotoxic drugs stimulate melanocytes.

• Minocycline: three types, namely blue black macules in scars or inflamed sites (type 1), blue grey on normal skin of the shins and forearms (type 2), and a muddy brown on sun exposed skin (type 3), plus nails, sclera, teeth and mucosa.
• Amiodarone: slate grey to blue grey pigment on sun exposed skin, which can develop after about a year of treatment.
• Antimalarials: blue grey on the shins, face, hard palate and nails. Chlorpromazine: blue grey in sun exposed areas.
• Bleomycin: flagellate (whip mark) streaks. Busulfan and cyclophosphamide: diffuse tanning and nail bands.

Red flags.

• Pigment with adrenal type symptoms (weakness, weight loss, low blood pressure), which suggests adrenal insufficiency.
• Rapidly changing or irregular pigmented lesion, which needs a biopsy to exclude melanoma.

• Clinical diagnosis from the pattern, the timing relative to the drug and its dose, and resolution when it is stopped.
• Biopsy when the diagnosis is unclear: pigment in dermal macrophages that stains with Perls (iron, minocycline) or Fontana-Masson (melanin), and drug specific granules.
• Exclude Addison disease (morning cortisol), haemochromatosis (ferritin, transferrin saturation) and liver disease. Review all medicines.

Differential diagnosis.

• Addison disease, haemochromatosis and chronic liver disease.
• Melasma, post-inflammatory hyperpigmentation and ochronosis.
• Argyria, other heavy metal pigmentation and acanthosis nigricans.

• Stop or change the drug when it is safe to do so. Amiodarone and cytotoxic drugs should not be stopped without discussion with the treating specialist, who can consider dose reduction.
• Strict sun protection (broad spectrum SPF 30 or more), which limits further darkening.
• Fading is slow, over months to years, and may be incomplete.
• Q-switched lasers (alexandrite 755 nm, neodymium doped yttrium aluminium garnet 1064 nm) clear minocycline type 1 and 2 pigment in most patients and may help amiodarone pigmentation. Topical bleaching agents are of limited use.
• Camouflage cosmetics.

Monitoring. Review every 3 to 6 months while the drug continues or the pigment fades.

Referral and escalation. Dermatology; discuss with the prescribing specialist before stopping amiodarone or cytotoxic drugs.