Rosacea Awareness Month on April, 2018: teeth staining?

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teeth staining?

Minocycline: Stain Devil?

M.L. Good, D.L. Hussey

Br J Dermatol 149(2):237-239, 2003. © 2003 Blackwell Publishing

Posted 10/03/2003

Summary and Introduction

Summary

Minocycline is the treatment of choice for acne vulgaris, the most common form of inflammatory acne, despite the increase in awareness of rare but significant side-effects. This paper discusses the undesirable side-effect of minocycline staining in permanent teeth.

Introduction

Minocycline is the treatment of choice for acne vulgaris, the most common form of inflammatory acne,[1] despite the increase in awareness of rare but significant side-effects[2] such as tissue hyperpigmentation,[3-5] serious hypersensitivity reactions[6] and autoimmune disorders.[6] This paper discusses the undesirable side-effect of minocycline staining in permanent teeth.

Background

Tetracycline was first introduced in 1947, with its semisynthetic second-generation derivative minocycline being introduced in 1967. Minocycline is a broad-spectrum antibiotic which inhibits protein synthesis, causing bacteriostasis. It also reduces fatty acids in sebum,[7] and exhibits an anti-inflammatory effect. Its structure contains the same basic ring as tetracycline but it is chemically different in that there is substitution of a dimethylamino group at C7 and it lacks a functional group at C6, making it more lipophilic. This increases the drug's distribution and half-life, and enables it to cross bacterial lipid membranes. Minocycline, unlike tetracycline, poorly chelates calcium and so is completely absorbed from the gastrointestinal tract even when administered with dairy products. The drug can, however, chelate some divalent metal ions, especially iron, forming insoluble complexes. Minocycline is highly plasma-protein bound and reaches its maximum concentration in 2-3 h, with a half-life of approximately 16 h. Its concentration in saliva reaches 30-60% of that in serum but its concentration in gingival crevicular fluid is five times greater than that found in serum.[4] Minocycline is deposited in tissues rich in collagen.

The most common clinical indication for prescribing minocycline is moderate to severe acne vulgaris,[7] and the commonest indication for prescribing minocycline for long-term treatment is rosacea.[8] It is also used in the management of certain sexually transmitted diseases such as those caused by Mycoplasma, Chlamydia and Treponema. Other indications include chronic respiratory disease, rheumatoid arthritis,[9] and as an adjunct in the management of periodontal disease.[10] The most common side-effects are gastrointestinal symptoms, dizziness and vertigo. Less commonly, tissue hyperpigmentation can occur, affecting tissues such as the oral mucosa, sclera, skin, thyroid, nails, bone and teeth.[3-5] Generalized intrinsic staining of the permanent dentition most commonly occurs during tooth development, between the ages of 4 months and 12 years, and therefore the discoloration is evident on eruption. With minocycline, however, the generalized intrinsic staining occurs posteruption in previously normal-coloured fully mineralized adult teeth. This staining is distinctly different to that caused by tetracycline (Table 1). Other rare but severe side-effects do exist, including serious hypersensitivity reactions[6] and autoimmune disorders such as autoimmune hepatitis[6] and systemic lupus erythematosus.[6]

Staining of the adult dentition appears to occur in 3-6% of patients taking long-term minocycline at > 100 mg daily.[4,11] The onset of discoloration can occur any time from 1 month to many years after the initiation of treatment.[3,11] However, other drugs are also known to cause intrinsic staining of teeth, such as oral contraceptives and phenothiazines and therefore a full medical and drug history is needed to determine if minocycline is the causative agent.

Mechanisms of Tooth Staining

Tetracycline staining of permanent teeth takes place during tooth development, and the mechanism by which this occurs is well documented. Tetracycline forms a complex with calcium orthophosphate during tooth calcification which then darkens with exposure to light.[12,13]

Four theories exist on the mechanism of tooth discoloration by minocycline, but further research is required. The first is the 'extrinsic theory'[4] where it is thought that minocycline attaches to the acquired pellicle's glycoproteins. This in turn etches the enamel and demineralization/remineralization cycles occur. It oxidizes on exposure to air or as a result of bacterial activity and so causes degradation of the aromatic ring, forming insoluble black quinone. The second is the 'intrinsic theory'[5,14] where the minocycline bound to plasma proteins is deposited in collagen-rich tissues such as pulp, teeth and bone. This then oxidizes slowly over time with exposure to light. The third possibility is that haemosiderin, a breakdown product of minocycline, chelates with iron to form an insoluble complex.[3,13] The fourth and last suggestion is that minocycline could be deposited in dentine during dentinogenesis, and the process of dentinogenesis can be accelerated in bruxists.

Prevention

It is said that prevention is better than cure, and in patients with moderate to severe acne the importance of avoiding minocycline staining of teeth cannot be overemphasized as these patients are already prone to negative psychological effects.[15] Various ways of preventing and treating minocycline staining have been put forward. It has been suggested that there may be a relationship with thyroid function and that this should be checked prior to prescribing minocycline and reviewed during long-term treatment.[14] Vitamin C, or an alternative antioxidant, taken together with minocycline has been shown to prevent the formation of the quinone ring, which is part of the degradation product and a component of the stain pigment.[14,16] Alternatively, reducing the therapeutic dose of minocycline to below 100 mg daily for long-term therapy may in itself prevent dental staining: an effective therapeutic regimen for acne is 100 mg daily initially, reducing to 50 mg daily after 15 days.[17] Alternative drugs to minocycline should also be considered in the management of acne[18] such as other systemic and topical antimicrobials, e.g. lymecycline, systemic and topical retinoids, systemic hormonal therapy and zinc gluconate used singly or in combination.

Treatment

In cases where minocycline staining of permanent teeth has already occurred (Fig. 1) the staining is not removable by dental polishing.[3] The treatment options are therefore no intervention, bleaching, composite or porcelain veneers, or crowns. Veneer and crown preparations involve the removal of at least 0·7 mm of sound tooth substance, allowing sufficient depth of porcelain in each restoration to mask the discoloration. These restorations produce reasonable results but are quite destructive. The preferred treatment option is vital bleaching as it avoids any tissue removal and has no known damaging effects on enamel or dentine.[19] Bleaching causes extensive structural changes in both enamel and dentine which can either alter or liberate the pigment (Fig. 2). Research carried out on rats demonstrated that hydrogen peroxide breaks down the quinone ring in tetracycline-stained teeth, although repeated maintenance is required and the results are best for more uniform grey/brown stains.[16]

Figure 1. This appearance is typical of a patient with minocycline staining in the permanent dentition.

Figure 2. Following the application of a vital bleaching system for 17 weeks there has been a satisfactory resolution of the stained teeth seen in Figure 1.

In conclusion, patients who have suffered moderate to severe acne are generally conscious of their appearance and it would be adding insult to injury for them to then experience greying of their permanent teeth following minocycline therapy. Before minocycline is prescribed it is important to evaluate whether the benefits outweigh the risks as the management of dental staining may be destructive, expensive and in the case of bleaching unpredictable, not forgetting the possible medicolegal considerations.

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Tables

Table 1. Comparison Between Tetracycline-and Minocycline-Stained Teeth

Tetracycline (parent drug) Minocycline hydrochloride (semisynthetic derivative)

Colour of staining Bright yellow to brown/grey[12] Green/grey, blue/grey[3,13]

Pattern Gingival margin or cervical third of crown[12] or band relating to duration and timing of drug administration Incisal edge and most intensely the middle third of crown[3,13]

Severity Severe Less severe

Fluorescence Yellow fluorescence None clinically[13] but will fluoresce in an acid medium

Resolution with drug stoppage None Resolution rare in teeth[3]

References

Pierard-Franchimont C, Goffin V, Arrese JE et al. Lymecycline and minocycline in inflammatory acne, a randomised, double-blind intent-to-treat study on clinical and in vivo antibacterial efficacy. Skin Pharmacol Appl Skin Physiol 2002; 15: 112-19.

Hoefnagel JJ, Leeuwen RL, Mattie H, Bastiaens MT. Side effects of minocycline in the treatment of acne vulgaris. Ned Tijdschr Geneeskd 1997; 19(141): 1424-7.

Poliak SC, DiGiovanna JJ, Gross EG et al. Minocycline-associated tooth discoloration in young adults. JAMA 1985; 254: 2930-2.

Berger RS, Mandel EB, Hayes TJ, Grimwood RR. Minocycline staining of the oral cavity. J Am Acad Dermatol 1989; 21: 1300-1.

Bowles WH, Bokmeyer TJ. Staining of adult teeth by minocycline: binding of minocycline by specific proteins. J Esthet Dent 1997; 9: 30-4.

Gough A, Chapman S, Wagstaff K et al. Minocycline-induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. Br Med J 1996; 312: 169-72.

Hubbell CG, Hobbs ER, Rist T, White JW Jr. Efficacy of minocycline compared with tetracycline in treatment of acne vulgaris. Arch Dermatol 1982; 118: 989-92.

Rebora A. The management of rosacea. Am J Clin Dermatol 2002; 3: 489-96.

Tilley BS, Alarcon GS, Heyse SP et al. Minocycline in rheumatoid arthritis. Ann Intern Med 1995; 122: 81-9.

Seymour RA, Heasman PA. Pharmacologic control of periodontal disease. II. Antimicrobial agents. J Dent 1995; 23: 5-14.

Westbury LW, Najera A. Minocycline-induced intraoral pharmacogenic pigmentation: case reports and review of the literature. J Periodontol 1997; 68: 84-91.

Wallman IS, Hilton HB. Teeth pigmented by tetracycline. Lancet 1962; i: 827-9.

Rosen T, Hoffman TJ. Minocycline-induced discoloration of the permanent teeth. J Am Acad Dermatol 1989; 21: 569.

Bowles WH. Protection against minocycline pigment formation by ascorbic acid (vitamin C). J Esthet Dent 1998; 100: 182-6.

Aktan S, Ozmen E, Sanli B. Anxiety, depression, and nature of acne vulgaris in adolescents. Int J Dermatol 2000; 39: 354-7.

Ledoux WR, Malloy RB, Hurst RVV et al. Structural effects of bleaching on tetracycline-stained vital rat teeth. J Prosthet Dent 1985; 54: 55-9.

Bernier C, Dreno B. Minocycline. Ann Dermatol Venereol 2001; 128: 627-37.

Stein RH, Lebwohl M. Acne therapy: clinical pearls. Semin Cutan Med Surg 2001; 20: 184-9.

Kelleher MGD, Roe FJC. The safety-in-use of 10% carbamide peroxide (Opalescence) for bleaching teeth under the supervision of a dentist. Br Dent J 1999; 187: 190-4.

Reprint Address

Correspondence: Melissa Good. E-mail: m.l.good@qub.ac.uk

M.L. Good, D.L. Hussey

Department of Restorative Dentistry, Royal Victoria Hospital, Belfast BT12 6BA, U.K.

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