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BMJ Clin Evid. 2008; 2008: 1714.
Published online 2008 May 15.
PMCID: PMC2907987

Acne vulgaris

Sarah Purdy, MD MPH MRCGP, Consultant Senior Lecturer in Primary Health Care# and David DeBerker, Consultant Dermatologist#

Abstract

Introduction

Acne vulgaris affects over 80% of teenagers, and persists beyond the age of 25 years in 3% of men and 12% of women. Typical lesions of acne include comedones, inflammatory papules, and pustules. Nodules and cysts occur in more severe acne and can cause scarring and psychological distress.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of topical and oral treatments in people with acne vulgaris? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 67 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: topical treatments (adapalene, azelaic acid, benzoyl peroxide, clindamycin, erythromycin (alone or plus zinc), isotretinoin, tetracycline, tretinoin), and oral treatments (doxycycline, isotretinoin, lymecycline, minocycline, oxytetracycline, tetracycline).

Key Points

Acne vulgaris affects over 80% of teenagers, and persists beyond the age of 25 years in 3% of men and 12% of women.

  • Typical lesions of acne include comedones, inflammatory papules, and pustules. Nodules and cysts occur in more severe acne, and can cause scarring and psychological distress.

Topical benzoyl peroxide should be considered as first-line treatment in mild acne.

  • Topical benzoyl peroxide and topical azelaic acid reduce inflammatory and non-inflammatory lesions compared with placebo, but can cause itching, burning, stinging, and redness of the skin.

Topical antibiotics such as clindamycin and erythromycin (alone or with zinc) reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions. Tetracycline may reduce overall acne severity.

  • Antimicrobial resistance can develop with use of topical or oral antibiotics, and their efficacy may decrease over time.
  • Tetracyclines may cause skin discoloration, and should be avoided in pregnant or breastfeeding women.
  • Topical preparations of tretinoin, adapalene, and isotretinoin may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.

Oral antibiotics (doxycycline, erythromycin, lymecycline, minocycline, oxytetracycline, and tetracycline) are considered useful for people with more severe acne, although we don't know for sure whether they are effective.

  • Oral antibiotics can cause adverse effects such as contraceptive failure.
  • Minocycline has been associated with an increased risk of systemic lupus erythematosus, and of liver disorders.
  • Oral isotretinoin has been associated with skin problems, change in liver function, teratogenesis, and psychiatric disorders.

About this condition

Definition

Acne vulgaris is a common inflammatory pilosebaceous disease characterised by comedones, papules, pustules, inflamed nodules, superficial pus-filled cysts, and (in extreme cases) canalising and deep, inflamed, sometimes purulent sacs. Lesions are most common on the face, but the neck, chest, upper back, and shoulders may also be affected. Acne can cause scarring and considerable psychological distress. It is classified as mild, moderate, or severe. Mild acne is defined as non-inflammatory lesions (comedones), a few inflammatory (papulopustular) lesions, or both. Moderate acne is defined as more inflammatory lesions, occasional nodules, or both, and mild scarring. Severe acne is defined as widespread inflammatory lesions, nodules, or both, and scarring, moderate acne that has not settled with 6 months of treatment, or acne of any "severity" with serious psychological upset. This review does not cover acne rosacea, acne secondary to industrial occupations, and treatment of acne in people under 13 years of age.

Incidence/ Prevalence

Acne is the most common skin disease of adolescence, affecting over 80% of teenagers (aged 13-18 years) at some point. Estimates of prevalence vary depending on study populations and the method of assessment used. Prevalence of acne in a community sample of 14- to 16-year-olds in the UK has been recorded as 50%. In a sample of adolescents from schools in New Zealand, acne was present in 91% of males and 79% of females, and in a similar population in Portugal the prevalence was 82%. It has been estimated that up to 30% of teenagers have acne of sufficient severity to require medical treatment. Acne was the presenting complaint in 3.1% of people aged 13-25 years attending primary care in a UK population. Overall incidence is similar in both men and women, and peaks at 17 years of age. The number of adults with acne, including people over 25 years, is increasing; the reasons for this increase are uncertain.

Aetiology/ Risk factors

The exact cause of acne is unknown. Four factors contribute to the development of acne: increased sebum secretion rate, abnormal follicular differentiation causing obstruction of the pilosebaceous duct, bacteriology of the pilosebaceous duct, and inflammation. The anaerobic bacterium Propionibacterium acnes plays an important role in the pathogenesis of acne. Androgen secretion is the major trigger for adolescent acne.

Prognosis

In 3% of men (95% CI 1.2% to 4.8%) and 12% of women (95% CI 9% to 15%), facial acne persists after the age of 25 years, and in a few people (1% of men and 5% of women) acne persists into their 40s.

Aims of intervention

To reduce the number of non-inflammatory and inflammatory lesions and scarring, with minimal adverse effects of treatment.

Outcomes

Number of non-inflammatory lesions (comedones); number of inflammatory lesions (papules, pustules, and nodules); severity scores and scales; patient perception of improvement; quality of life; psychological distress; adverse effects of treatment. Commonly used severity scores and scales include: Leeds Acne Grading Technique, which involves counting and categorising lesions into inflammatory and non-inflammatory; Cook's acne grading scale method, which uses photographs to document severity of acne and grades severity from 0 (least severe) to 8 (most severe); and the Pillsbury Scale, which classifies acne from 1 (mildest) to 4 (severe).

Methods

BMJ Clinical Evidence search and appraisal June 2007. The following databases were used to identify studies for this review: Medline 1966 to June 2007, Embase 1980 to June 2007, and The Cochrane Library 2007, Issue 2. Additional searches were carried out using the websites: NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE guidance. Abstracts of the studies retrieved were assessed independently by two information specialists using predetermined criteria to identify relevant studies. Design criteria included: systematic reviews and RCTs, in any language, that were at least single blind, containing more than 20 individuals, and with a follow-up of more than 80%. There was no minimum length of follow-up. We excluded individual RCTs described as "open", "open label", or non-blinded. However, if open-label RCTs were included in systematic reviews, we have included these, and have stated that they were open-label studies where this was reported by the review. The review by Lehmann et al included both randomised and non-randomised controlled trials, and did not state in all cases whether trials were randomised. We have focused on reporting results for RCTs only and, where necessary, have analysed original papers to ascertain whether trials were randomised. None of the reviews we identified were able to perform a meta-analysis owing to heterogeneity among the trials identified. We have described the results of each RCT identified by the reviews and, where we found numerous RCTs on an intervention, we have tabulated results. We compared all listed oral treatments versus each other and included all RCTs of sufficient quality that we retrieved. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for acne vulgaris

Glossary

Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Sarah Purdy, University of Bristol, Bristol, UK.

David DeBerker, Bristol Dermatology Centre, Bristol, UK.

References

1. Healy E, Simpson N. Acne vulgaris. BMJ 1994;308:831–833. [PMC free article] [PubMed]
2. Mallon E, Newton JN, Klassen A, et al. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 1999;140:672–676. [PubMed]
3. Chu TC. Acne and other facial eruptions. Medicine 1997;25:30–33.
4. Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol 2001;145:274–279. [PubMed]
5. Pearl A, Arroll B, Lello J, et al. The impact of acne: a study of adolescents' attitudes, perception and knowledge. N Z Med J 1998;111:269–271. [PubMed]
6. Amado JM, Matos ME, Abreu AM, et al. The prevalence of acne in the north of Portugal. J Eur Acad Dermatol Venereol 2006;20:1287–1295. [PubMed]
7. Garner S. Acne vulgaris. In: Williams H. Evidence-based dermatology. London: BMJ, 2003.
8. Purdy S, Langston J, Tait L. Presentation and management of acne in primary care: a retrospective cohort study. Br J Gen Pract 2003;53:525–529. [PMC free article] [PubMed]
9. Cunliffe WJ. Management of adult acne and acne variants. J Cutan Med Surg 1998;2(suppl 3):7–13. [PubMed]
10. Brown SK, Shalita AR. Acne vulgaris. Lancet 1998;351:1871–1876. [PubMed]
11. Webster GF. Acne vulgaris: state of the science. Arch Dermatol 1999;135:1101–1102. [PubMed]
12. Goulden V, Stables G, Cunliffe W. Prevalence of facial acne in adults. J Am Acad Dermatol 1999;578:577–580. [PubMed]
13. Burke BM, Cunliffe WJ. The assessment of acne vulgaris � the Leeds technique. Br J Dermatol 1984;111:83–92. [PubMed]
14. Cook CH, Centner RL, Michaels SE. An acne grading method using photographic standards. Arch Dermatol 1979;115:571–575. [PubMed]
15. Pillsbury DM, Shelley WB, Kligman AM. A manual of cutaneous medicine. Philadelphia: Saunders, 1961.
16. Lehmann HP, Andrews JS, Robinson KA, et al. Management of acne (Evidence Report/Technology Assessment No 17). Agency for Healthcare Research and Quality Publication No 01-E019. Rockville, MD. Agency for Healthcare Research and Quality, 2001. Search date 1999, primary sources Central, Pubmed, Medline, Healthstar, Psycinfo, Cinahl, hand searches; inclusion criteria: management of acne, English language, human data, prospective controlled, randomised/quasi-randomised allocation.
17. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004;292:726–735. Search date 2004, primary sources Medline, Embase, and The Cochrane Library. [PubMed]
18. Ede M. A double-blind comparative study of benzoyl peroxide, benzoyl peroxide�chlorhydroxyquinolone, benzoyl peroxide�chlorhydroxyquinolone�hydrocortisone, and placebo lotions in acne. Curr Ther Res Clin Exp 1973;15:624–629. [PubMed]
19. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol 1997;37:590–595. [PubMed]
20. Hunt MJ, Barnetson RS. A comparative study of gluconolactone versus benzoyl peroxide in the treatment of acne. Australas J Dermatol 1992;33:131–134. [PubMed]
21. Hughes BR, Norris JF, Cunliffe WJ. A double-blind evaluation of topical isotretinoin 0.05%, benzoyl peroxide gel 5% and placebo in patients with acne. Clin Exp Dermatol 1992;17:165–168. [PubMed]
22. Smith EB, Padilla RS, McCabe JM, et al. Benzoyl peroxide lotion (20 percent) in acne. Cutis 1980;25:90–92. [PubMed]
23. Braathen LR. Topical clindamycin versus oral tetracycline and placebo in acne vulgaris. Scand J Infect Dis Suppl 1984;43:71–75. [PubMed]
24. Ellis CN, Gammon WR, Stone DZ, et al. A comparison of Cleocin T Solution, Cleocin T Gel, and placebo in the treatment of acne vulgaris. Cutis 1988;42:245–247. [PubMed]
25. Lucchina LC, Kollias N, Gillies R, et al. Fluorescence photography in the evaluation of acne. J Am Acad Dermatol 1996;35:58–63. [PubMed]
26. Gratton D, Raymond GP, Guertin-Larochelle S, et al. Topical clindamycin versus systemic tetracycline in the treatment of acne. Results of a multiclinic trial. J Am Acad Dermatol 1982;7:50–53. [PubMed]
27. Becker LE, Bergstresser PR, Whiting DA, et al. Topical clindamycin therapy for acne vulgaris. A cooperative clinical study. Arch Dermatol 1981;117:482–485. [PubMed]
28. Kuhlman DS, Callen JP. A comparison of clindamycin phosphate 1 percent topical lotion and placebo in the treatment of acne vulgaris. Cutis 1986;38:203–206. [PubMed]
29. Noble WC, Naidoo J. Evolution of antibiotic resistance in Staphylococcus aureus: the role of the skin. Br J Dermatol 1978;98:481–489. [PubMed]
30. Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol 2005;153:395–403. [PubMed]
31. Kellett N, West F, Finlay AY. Conjoint analysis: a novel, rigorous tool for determining patient preferences for topical antibiotic treatment for acne. A randomised controlled trial. The Br J Dermatol 2006;154:524–532. [PubMed]
32. Glass D, Boorman GC, Stables GI, et al. A placebo-controlled clinical trial to compare a gel containing a combination of isotretinoin (0.05%) and erythromycin (2%) with gels containing isotretinoin (0.05%) or erythromycin (2%) alone in the topical treatment of acne vulgaris. Dermatology 1999;199:242–247. [PubMed]
33. Lesher JL Jr, Chalker DK, Smith JG Jr, et al. An evaluation of a 2% erythromycin ointment in the topical therapy of acne vulgaris. J Am Acad Dermatol 1985;12:526–531. [PubMed]
34. Pochi PE, Bagatell FK, Ellis CN, et al. Erythromycin 2% gel in the treatment of acne vulgaris. Cutis 1988;41:132–136. [PubMed]
35. Jones EL, Crumley AF. Topical erythromycin vs blank vehicle in a multiclinic acne study. Arch Dermatol 1981;117:551–553. [PubMed]
36. Dobson RL, Belknap BS. Topical erythromycin solution in acne. Results of a multiclinic trial. J Am Acad Dermatol 1980;3:478–482. [PubMed]
37. Rivkin L, Rapaport M. Clinical evaluation of a new erythromycin solution for acne vulgaris. Cutis 1980;25:552–555. [PubMed]
38. Hellgren L, Vincent J. Topical erythromycin for acne vulgaris. Dermatologica 1980;161:409–414. [PubMed]
39. Prince RA, Busch DA, Hepler CD, et al. Clinical trial of topical erythromycin in inflammatory acne. Drug Intell Clin Pharm 1981;15:372–376. [PubMed]
40. Christiansen JV, Gadborg E, Ludvigsen K, et al. Topical tretinoin, vitamin A acid (Airol) in acne vulgaris: a controlled clinical trial. Dermatologica 1974;148:82–89. [PubMed]
41. Christiansen J, Holm P, Reymann F. The retinoic acid derivative Ro 11-1430 in acne vulgaris: a controlled multicenter trial against retinoic acid. Dermatologica 1977;154:219–227. [PubMed]
42. Krishnan G. Comparison of two concentrations of tretinoin solution in the topical treatment of acne vulgaris. Practitioner 1976;216:106–109. [PubMed]
43. Lucky AW, Cullen SI, Jarratt MT, et al. Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter double-blind, parallel study. J Am Acad Dermatol 1998;38:S17–S23. [PubMed]
44. Lucky AW, Cullen SI, Funicella T, et al. Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol 1998;38:S24–S30. [PubMed]
45. Pinnock CB, Alderman CP. The potential for teratogenicity of vitamin A and its congeners. Med J Aust 1992;157:805–809. [PubMed]
46. Thiboutot DM, Shalita AR, Yamauchi PS, et al. Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study. Arch Dermatol. 2006;142:597–602. [PubMed]
47. Thiboutot D, Pariser DM, Egan N, et al. Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. J Am Acad Dermatol 2006;54:242–250. [PubMed]
48. Lucky A, Jorizzo JL, Rodriguez D, et al. Efficacy and tolerance of adapalene cream 0.1% compared with its cream vehicle for the treatment of acne vulgaris. Cutis 2001;68:34–40. [PubMed]
49. Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Derm Venereol Suppl (Stockh) 1989;143:31–34. [PubMed]
50. Katsambus A, Graupe K, Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Comparison with vehicle and topical tretinoin. Acta Derm Venereol Suppl (Stockh) 1989;143:35–39. [PubMed]
51. Graupe K, Cunliffe WJ, Gollnick HP, et al. Efficacy and safety of topical azelaic acid (20% cream): an overview of results from European clinical trials and experimental reports. Cutis 1996;57(suppl 1):20–35. [PubMed]
52. Feucht CL, Allen BS, Chalker DK, et al. Topical erythromycin with zinc in acne. A double-blind controlled study. J Am Acad Dermatol 1980;3:483–491. [PubMed]
53. Schachner L, Eaglestein W, Kittles C, et al. Topical erythromycin and zinc therapy for acne. J Am Acad Dermatol 1990;22:253–260. [PubMed]
54. Chalker DK, Lesher JL Jr, Smith JG Jr, et al. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol 1987;17:251–254. [PubMed]
55. Langner A, Boorman GC, Stapor V, et al. Isotretinoin cream 0.05% and 0.1% in the treatment of acne vulgaris. J Dermatol Treat 1994;5:177–180.
56. Blaney DJ, Cook CH. Topical use of tetracycline in the treatment of acne: a double-blind study comparing topical and oral tetracycline therapy and placebo. Arch Dermatol 1976;112:971–973. [PubMed]
57. Anderson RL, Cook CH, Smith DE. The effect of oral and topical tetracycline on acne severity and on surface lipid composition. J Invest Dermatol 1976;66:172–177. [PubMed]
58. Smith JG Jr, Chalker DK, Wehr RF. The effectiveness of topical and oral tetracycline for acne. South Med J 1976;69:695–697. [PubMed]
59. Burton J. A placebo-controlled study to evaluate the efficacy of topical tetracycline and oral tetracycline in the treatment of mild to moderate acne. Dermatology Research Group. J Int Med Res 1990;18:94–103. [PubMed]
60. Ochsendorf F. Systemic antibiotic therapy of acne vulgaris. J Deutschen Dermatologischen Gesellschaft 2006;4:828–841. [PubMed]
61. Bleeker J, Hellgren L, Vincent J. Effect of systemic erythromycin stearate on the inflammatory lesions and skin surface fatty acids in acne vulgaris. Dermatologica 1981;162:342–349. [PubMed]
62. Brandt H, Attila P, Ahokas T, et al. Erythromycin acistrate � an alternative treatment for acne. J Dermatol Treat 1994;5:3–5.
63. Gammon WR, Meyer C, Lantis S, et al. Comparative efficacy of oral erythromycin versus oral tetracycline in the treatment of acne vulgaris. A double-blind study. J Am Acad Dermatol 1986;14:183–186. [PubMed]
64. Al-Mishari MA. Clinical and bacteriological evaluation of tetracycline and erythromycin in acne vulgaris. Clin Ther 1987;9:273–280. [PubMed]
65. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust 1998;169:259–261. Search date 1998, primary sources Medline, Embase, hand searches; inclusion criteria: English language, Propionibacterium acnes resistance patterns. [PubMed]
66. Plewig G, Petrozzi JW, Berendes U. A double-blind study of doxycycline in acne vulgaris. Arch Dermatol 1970;101:435–438. [PubMed]
67. Juhlin L, Liden S. A quantitative evaluation of the effect of oxytetracycline and doxycycline in acne vulgaris. Br J Dermatol 1969;81:154–158. [PubMed]
68. The National Prescribing Centre. The treatment of acne vulgaris: an update. MeReC Bulletin 1999;10:29–32.
69. Sanchez AR, Rogers RS, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity. Int J Dermatol 2004;43:709–715. [PubMed]
70. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne vulgaris: efficacy and safety. In: The Cochrane Library: Issue 2, 2006. Chichester, UK: John Wiley & Sons, Ltd. Search date 2002, primary sources Medline, Embase, Biosis, Biological abstracts, International Pharmaceutical Abstracts, Cochrane Skin Group's Trial Register, Theses Online, Bids, and hand searches.
71. Fleischer AB,Jr, Dinehart S, Stough D, et al. Safety and efficacy of a new extended-release formulation of minocycline. Cutis 2006;78:21–31. [PubMed]
72. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet 2004;364:2188–2197. [PubMed]
73. Schlienger RG, Bircher AJ, Meier CR. Minocycline-induced lupus. A systematic review. Dermatology 2000;200:223–231. Search date 1999, primary sources Medline, Embase, hand searches; inclusion criteria: participants to have developed minocycline induced systemic lupus erythematosus. [PubMed]
74. Lawrenson RA, Seaman HE, Sundstrom A, et al. Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Saf 2000;23:333–349. Search date 1998, primary sources Medline, Cinahl, The Cochrane Library, Embase, Current Contents, Toxline, Bids, hand searches, pharmaceutical and WHO adverse events databases; inclusion criteria: participants to have developed liver damage from taking minocycline for acne. [PubMed]
75. Goulden V, Glass D, Cunliffe WJ. Safety of long-term high-dose minocycline in the treatment of acne. Br J Dermatol 1996;134:693–695. [PubMed]
76. Sturkenboom MC, Meier CR, Jick H, et al. Minocycline and lupuslike syndrome in acne patients. Arch Intern Med 1999;159:493–497. [PubMed]
77. Heslett C, Chilvers ER, Boon NA, et al. Davidson's principals and practices of medicine. London: Churchill Livingstone, 2002.
78. British National Formulary. http://www.bnf.org/bnf/ (last accessed 10 April 2008).
79. Lane P, Williamson DM. Treatment of acne vulgaris with tetracycline hydrochloride: a double-blind trial with 51 patients. BMJ 1969;2:76–79. [PMC free article] [PubMed]
80. Wong RC, Kang S, Heezen JL, et al. Oral ibuprofen and tetracycline for the treatment of acne vulgaris. J Am Acad Dermatol 1984;11:1076–1081. [PubMed]
81. Lester RS, Schachter GD, Light MJ. Isotretinoin and tetracycline in the management of severe nodulocystic acne. Int J Dermatol 1985;24:252–257. [PubMed]
82. Peck GL, Olsen TG, Butkus D. Isotretinoin versus placebo in the treatment of cystic acne. J Am Acad Dermatol 1982;6:735–745. [PubMed]
83. Goulden V, Clark SM, McGeown C, et al. Treatment of acne with intermittent isotretinoin. Br J Dermatol 1997137:106–108. [PubMed]
84. Barth JH, Macdonald-Hull SP, Mark J, et al. Isotretinoin therapy for acne vulgaris: A re-evaluation of the need for measurements of plasma lipids and liver function tests. Br J Dermatol 1993;129:704–707. [PubMed]
85. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in women of childbearing age receiving isotretinoin. New Engl J Med 1995;333:101–106. [PubMed]
86. Berard A, Azoulay L, Koren G, et al. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. B J Clin Pharmacol 2007;63:196–205. [PubMed]
87. Strahan JE, Raimer S. Isotretinoin and the controversy of psychiatric adverse effects. Int J Dermatol 2006;45:789–799. [PubMed]
88. Hull PR, D'Arcy C, Hull PeterR, et al. Isotretinoin use and subsequent depression and suicide: presenting the evidence. Am J Clin Dermatol 2003;4:493–505. [PubMed]
89. Jick SS, Kremers HM, Vasilakis-Scaramozza C, et al. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000;136:1231–1236. [PubMed]
90. Rubinow DR, Peck GL, Squillace KM, et al. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987;17:25–32. [PubMed]
91. Chia CY, Lane W, Chibnall J, et al. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch Dermatol 2005;141:557–560. [PubMed]
92. Magin P, Pond D, Smith W, et al. Isotretinoin, depression and suicide: a review of the evidence. Br J Gen Pract 2005;55:134–138. [PMC free article] [PubMed]
2008; 2008: 1714.
Published online 2008 May 15.

Benzoyl peroxide (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical benzoyl peroxide may be more effective at reducing the total lesion count or the number of inflammatory and non-inflammatory lesions at 4–12 weeks in people with moderate acne ( low-quality evidence ).

Benefits

Topical benzoyl peroxide versus placebo:

We found two systematic reviews comparing topical benzoyl peroxide acid versus placebo (vehicle) (see table 1 ). The first review (search date 1999, 5 RCTs, 875 people with mild to moderate acne) did not perform a meta-analysis owing to heterogeneity among the trials in methods of outcome assessment. The second review (search date 2004), which had more stringent inclusion criteria than the earlier review, included one RCT, which was also identified by the earlier review. Four of the identified RCTs, primarily in people with moderate acne, found that topical benzoyl peroxide significantly reduced either total lesion count or the number of inflammatory and non-inflammatory lesions at 4–12 weeks compared with vehicle. A fifth RCT found more limited evidence from within-group comparisons that benzoyl peroxide reduced total lesion count and the number of inflammatory and non-inflammatory lesions from baseline at 12 weeks. None of the RCTs assessed patient perception of improvement.

Table 1
RCTs comparing benzoyl peroxide versus vehicle.

Harms

Topical benzoyl peroxide versus placebo:

One of the RCTs found that benzoyl peroxide 5% significantly increased the proportion of people who had adverse effects compared with vehicle, including dryness, scaling, burning, tingling, and redness; a second RCT found that more people using benzoyl peroxide 5% had peeling compared with vehicle (see table 1 ). A third RCT found that benzoyl peroxide 5% was associated with erythema, dryness, soreness, and burning; another RCT found that benzoyl peroxide 20% and vehicle were associated with similar rates of local adverse effects, including redness and peeling. One of the RCTs gave no quantitative information about adverse effects.

Comment

Clinical guide:

Benzoyl peroxide is indicated as an effective first-line treatment for mild acne. It has both anti-microbial and anti-comedonal properties, it also has an anti-inflammatory effect. It is recommended to start with a lower strength and increase gradually. Reducing frequency of application or temporarily discontinuing treatment helps with irritation.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Clindamycin (topical)

Summary

SYMPTOM SEVERITY Compared with placebo/vehicle: Topical clindamycin may be more effective at reducing the number of inflammatory lesions at 8–12 weeks in people with mild to severe acne ( very low-quality evidence ). PATIENT PERCEPTION OF IMPROVEMENT Compared with placebo/vehicle: Topical clindamycin may be more effective at increasing the proportion of people with mild to severe acne who rate their acne as markedly improved or improved (very low-quality evidence).

Benefits

Topical clindamycin versus placebo:

We found two systematic reviews. The first review (search date 1999, 7 RCTs, 1502 people with mild to severe acne) compared topical clindamycin 1% (phosphate or hydrochloride) one to four times daily versus placebo or vehicle for 8–12 weeks (see table 2 ). The review did not perform a meta-analysis owing to heterogeneity among the trials in comparisons and outcomes assessed. The second systematic review (search date 2004), which had more stringent inclusion criteria, identified two RCTs, both of which were included by the earlier review. Three of the RCTs identified by the first systematic review found inconclusive evidence about the effects of clindamycin compared with placebo on non-inflammatory lesions; the other RCTs did not assess non-inflammatory lesions. Four RCTs found that clindamycin significantly reduced the number of inflammatory lesions compared with placebo, and a fifth found no significant difference in the number of inflammatory lesions. A sixth RCT found that clindamycin significantly reduced the number of pustules, but not papules. The seventh RCT did not compare clindamycin versus placebo directly, although within-group comparisons found that clindamycin significantly reduced the number of inflammatory lesions from baseline. Three RCTs found that clindamycin increased the proportion of people who perceived that their acne was “markedly improved” or “improved”; in two of these RCTs the difference between groups was significant, whereas the third RCT did not conduct between-group comparisons.

Table 2
RCTs comparing topical clindamycin versus placebo or vehicle.

Harms

Topical clindamycin versus placebo:

Five of the RCTs identified by the first review found that clindamycin was associated with diarrhoea and burning in a small proportion of people, although none of these studies performed significance tests (see table 2 ). The sixth RCT found no significant difference in adverse effects between clindamycin and placebo. The seventh RCT gave no information on adverse effects.

Comment

Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance to Propionibacterium acnes. One systematic review (search date 2003) analysed the efficacy of topical antibiotics in clinical trials (randomised and non-randomised) conducted between 1966 and 2003 using linear regression. It found no significant change in the efficacy of 12 weeks' treatment with topical clindamycin 1.0–1.2% for inflammatory or non-inflammatory lesion count over this period (inflammatory lesions: 8 studies, change in efficacy [regression coefficient]: +0.2%/year, P = 0.7; non-inflammatory lesions: 7 studies, change in efficacy: –0.3%/year, P = 0.7).

Clinical guide:

Topical antibiotics or topical retinoids are indicated as treatments for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical clindamycin or erythromycin than with erythromycin plus zinc or tetracycline. A conjoint analysis study of patient preference for different topical antibiotic characteristics found that acne patients preferred a gel formulation that could be applied with the fingers once daily and stored at room temperature for up to 18 months.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Erythromycin (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical erythromycin may be more effective at reducing inflammatory lesions at 8–12 weeks in people with mild to severe acne ( low-quality evidence ). PATIENT PERCEPTION OF IMPROVEMENT Compared with placebo: We don’t know whether topical erythromycin is more effective at increasing the proportion of people with mild to moderate acne who perceive their acne as improved at 12 weeks ( very low-quality evidence ).

Benefits

Topical erythromycin versus placebo:

We found two systematic reviews. The first review (search date 1999, 8 RCTs, 347 people with mild to moderate acne, 555 people with moderate to severe acne) compared topical erythromycin 1–2% versus vehicle for 4–12 weeks (see table 3 ). The review did not perform a meta-analysis owing to heterogeneity among the trials in outcomes assessed. The second systematic review (search date 2004), which had more stringent inclusion criteria, included three RCTs, all of which were identified by the earlier review. Five RCTs identified by the first review found that erythromycin significantly reduced the number of inflammatory lesions at 8–12 weeks compared with vehicle. The sixth RCT found that, in most people, erythromycin was more effective than vehicle at reducing the number of inflammatory lesions at 4–8 weeks, but it did not assess the significance of the difference between treatments. The seventh RCT found no significant difference in the proportion of people who had a greater than 50% reduction in the number of inflammatory lesions at 12 weeks. The eighth RCT did not report direct comparisons of erythromycin alone versus placebo; it reported changes from baseline within the erythromycin and the placebo groups. Few of the RCTs assessed effects on non-inflammatory lesions, and those that did found inconclusive results. One RCT found that a similar proportion of people using erythromycin compared with vehicle perceived that their acne had improved from baseline at 12 weeks; the other RCTs did not assess patient perception of improvement.

Table 3
RCTs comparing topical erythromycin versus vehicle.

Harms

Topical erythromycin versus placebo:

The RCTs identified by the reviews found no significant difference in adverse effects between topical erythromycin and placebo or vehicle (see table 3 ).

Comment

Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance in Propionibacterium acnes. One systematic review (search date 2003) analysed the efficacy of topical antibiotics in clinical trials (randomised and non-randomised) conducted between 1966–2003 using linear regression. It found that the efficacy of 12 weeks' treatment with topical erythromycin 1.5–2% for inflammatory and non-inflammatory lesion count decreased significantly over this period (inflammatory lesions, 8 studies, change in efficacy [regression coefficient]: –2.1%/year, P = 0.001; non-inflammatory lesions, 6 studies, change in efficacy: –2.0%/year, P = 0.001).

Clinical guide:

Topical antibiotics or topical retinoids are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical erythromycin or clindamycin than with erythromycin plus zinc or tetracycline. However, there is some evidence that topical erythromycin may be less effective now than in the past, owing to increasing P acnes resistance.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Tretinoin (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical tretinoin may be more effective at 8–12 weeks at reducing the number of inflammatory and non-inflammatory lesions in people with mild to severe acne ( low-quality evidence ). PATIENT PERCEPTION OF IMPROVEMENT Compared with placebo: We don’t know whether topical tretinoin is more effective at increasing patient perception of improvement in people with mild to moderate acne ( very low-quality evidence ). NOTE Topical tretinoin has been associated with erythema, peeling, burning, and pruritus. Topical retinoids are not recommended in women of childbearing age not taking adequate contraceptive precautions, or during pregnancy.

Benefits

Topical tretinoin versus placebo:

We found one systematic review (search date 1999, 5 RCTs, 802 people with mild to moderate acne, 257 people with moderate to severe acne) comparing topical tretinoin 0.02%, 0.025%, or 0.05% versus vehicle twice daily for 8–12 weeks (see table 4 ). The review did not perform a meta-analysis because of heterogeneity among the RCTs in methods of outcome assessment. Four RCTs found that topical tretinoin 0.025 to 0.05% significantly reduced the number of inflammatory and non-inflammatory lesions at 8–12 weeks compared with vehicle. The fifth RCT did not assess lesion count, but found that tretinoin 0.025% increased patient perception of improvement compared with vehicle (significance of difference between groups not assessed). The other RCTs did not assess patient perception of improvement.

Table 4
RCTs comparing topical tretinoin versus vehicle.

Harms

Topical tretinoin versus placebo:

The RCTs found that topical tretinoin 0.02%, 0.025%, or 0.05% significantly increased erythema, peeling, burning, and pruritus compared with vehicle (see table 4 ).

Birth defects:

We found no RCTs assessing the risk of birth defects in women using topical retinoids. One non-systematic review found that oral retinoids were teratogenic in case reports and case series in humans, and in experimental studies in animals. In the absence of data regarding the risk of birth defects, it is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.

Comment

Two of the RCTs used weak methods of assessing outcomes (see table 4 ).

Clinical guide:

Topical retinoids or topical antibiotics are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the retinoid class, there is more evidence of benefit with topical tretinoin than with isotretinoin or adapalene. It is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Adapalene (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical adapalene is more effective at reducing the number of non-inflammatory and inflammatory lesions at 12 weeks in people with mild to moderate acne, and at maintaining improvement of lesions at 16 weeks in people who have responded to previous treatment with oral doxycycline with or without adapalene gel ( moderate-quality evidence ). NOTE Topical retinoids are not recommended in women of childbearing age not taking adequate contraceptive precautions, or during pregnancy.

Benefits

Topical adapalene versus placebo:

We found one systematic review (search date 2004; 1 RCT) and two subsequent RCTs. The RCT identified by the systematic review compared adapalene 0.1% daily versus placebo (vehicle). It found that adapalene significantly reduced total lesion count at 12 weeks compared with vehicle (237 people with moderate acne; mean reduction in total lesion count: 40% with adapalene v 20% with vehicle; P less than 0.01). It also found that, compared with vehicle, adapalene significantly reduced the number of non-inflammatory lesions (mean reduction: 38% with adapalene v 20% with vehicle; P less than 0.01) and the number of inflammatory lesions (mean reduction: 35% with adapalene v 19% with vehicle; P less than 0.01). The RCT assessed quality of life at 12 weeks through a patient questionnaire that evaluated self-perception, social and emotional status, and acne symptoms, and found similar scores in both groups (no further data reported). The first subsequent RCT compared adapalene gel 0.1% daily versus placebo as maintenance treatment in people with severe acne vulgaris who had experienced at least 50% improvement in total lesion count after 12 weeks' treatment with oral doxycycline plus adapalene 0.1% gel or oral doxycycline plus placebo (vehicle). It found that adapalene 0.1% significantly improved maintenance of at least 50% of the improvement in total lesion count compared with placebo at 16 weeks (253 people; AR for maintenance of 50% of improvement: 75% with adapalene v 54% with placebo; P less than 0.001; absolute numbers not reported). It also found that, at 16 weeks, adapalene significantly reduced lesion counts compared with placebo (absolute data reported graphically; significance for adapalene v placebo: total lesions P = 0.005, inflammatory lesions P = 0.01, non-inflammatory lesions P = 0.02). Adapalene significantly increased participant satisfaction with maintenance treatment compared with placebo (details of satisfaction scale not reported; proportion reporting being “satisfied” or “very satisfied”: 76% with adapalene v 65% with placebo; P = 0.01; absolute numbers not reported).The second subsequent RCT (653 people with mild to moderate acne vulgaris) compared adapalene gel 0.3% or 0.1% daily versus placebo. It found that, compared with placebo, adapalene 0.1% significantly reduced the total number of lesions (mean reduction: 48% with adapalene 0.1% v 36% with vehicle; P less than 0.001, no absolute figures reported), number of non-inflammatory lesions (mean reduction: 43% with adapalene 0.1% v 29% with vehicle; P less than 0.001, no absolute figures reported) and the number of inflammatory lesions (mean reduction: 58% with adapalene 0.1% v 47% with vehicle; P less than 0.001, no absolute figures reported) at 12 weeks. It also found that adapalene 0.1% significantly increased success rate as assessed by the Investigators Global Assessment (clear or almost clear) compared with vehicle (17% success rate with adapalene 0.1% v 10% success rate with vehicle; P = 0.02, no absolute figures reported). Adapalene 0.3% is not available in the UK.

Harms

Topical adapalene versus placebo:

The RCT identified by systematic review found that adapalene significantly increased erythema, dryness, scaling, stinging/burning, and pruritus compared with vehicle (P less than 0.01), with the highest incidence at 2 weeks. By 12 weeks of follow-up, no significant difference in adverse effects was found between the groups. Two people taking adapalene withdrew, one because of adverse effects. The first subsequent RCT found similar rates of mild adverse events (erythema, scaling, dryness, stinging, burning) with adapalene and placebo (25% with adapalene v 23% with placebo; significance not reported).The second subsequent RCT found low rates of mild adverse effects (dry skin and skin discomfort) with adapalene and placebo (12% with adapalene 0.1% v 5% with placebo; significance not reported).

Birth defects:

We found no RCTs assessing the risk of birth defects in women using topical retinoids. One non-systematic review found that oral retinoids were teratogenic in case reports and case series in humans, and in experimental studies in animals. In the absence of data regarding the risk of birth defects, it is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.

Comment

Clinical guide:

Topical retinoids or topical antibiotics are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the retinoid class, there is more evidence of benefit with topical tretinoin than with isotretinoin or adapalene. It is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.

Substantive changes

Adapalene (topical) One RCT added comparing adapalene with placebo. The RCT found that, at 16 weeks, adapalene 0.1% improved maintenance of at least 50% of the improvement in total lesion count, and reduced lesion counts compared with placebo. Categorised as Likely to be beneficial.

2008; 2008: 1714.
Published online 2008 May 15.

Azelaic acid (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical azelaic acid may be more effective at 8–12 weeks at reducing the number of comedones and inflammatory lesions in people with moderate acne ( low-quality evidence ). ADVERSE EFFECTS Topical azelaic acid has been associated with itching, stinging, burning, and erythema.

Benefits

Topical azelaic acid versus placebo:

We found two systematic reviews, which compared topical azelaic acid 20% versus placebo. The first review (search date 1999) identified two RCTs. The second review (search date 2004), which had more stringent inclusion criteria than the earlier review, included one RCT also identified by the earlier review. The RCT identified by both reviews found that, compared with placebo (vehicle), azelaic acid significantly reduced the number of comedones and inflammatory lesions (92 people with moderate acne; % reduction in comedones: 56% with azelaic acid v 0% with placebo; P = 0.05 [reported as significant]; % reduction in inflammatory lesions: 72% with azelaic acid v 47% with vehicle; P = 0.05 [reported as significant]). It also found that azelaic acid significantly increased the proportion of people who had a physician rating of response to treatment of “excellent” or “good” after 12 weeks of treatment compared with placebo (reduction in total lesion count by 75–100% rated as “excellent” and 50–75% as “good”; AR for ”excellent/good” rating: 28/43 [65%] with azelaic acid v 18/49 [37%] with vehicle; P = 0.05 [reported as significant]). These results should be treated with caution because the RCT did not perform an intention-to-treat analysis, and 13% of people did not complete the trial. The RCT did not assess patient perception of improvement. The second RCT identified by the first review found that, compared with placebo, azelaic acid significantly reduced the number of inflammatory lesions and of non-inflammatory lesions after 8 weeks' treatment (40 people, severity of acne unclear; % reduction in inflammatory lesions: 50% with azelaic acid v 12% with placebo; P = 0.001; % reduction in non-inflammatory lesions: 50% with azelaic acid v 25% with placebo; P = 0.027). These results should be treated with caution because it is unclear whether people taking azelaic acid and placebo had comparable duration and severity of acne. The RCT did not assess patient perception of improvement.

Harms

Topical azelaic acid versus placebo:

The RCT identified by both reviews found that a higher proportion of people using azelaic acid than placebo (vehicle) had burning (4/43 [9%] with azelaic acid v 1/49 [2%] with vehicle), itching (2/43 [5%] with azelaic acid v 0/49 [0%] with vehicle), and erythema (2/43 [5%] with azelaic acid v 1/49 [2%] with vehicle; P values not reported for any outcome). The second RCT (40 people) found that two people taking azelaic acid (10%) had itching and stinging compared with one person taking placebo (5%). One non-systematic review of RCTs and uncontrolled studies found that 0–5% of people taking azelaic acid had scaling, 5–23% had burning, and 13–29% had itching.

Comment

Clinical guide:

Azelaic acid is a similar type of treatment to benzoyl peroxide, but there is less evidence of benefit for azelaic acid than for benzoyl peroxide. It can also cause irritation which is helped by reducing the frequency of application or temporarily discontinuing treatment.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Erythromycin plus zinc (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical erythromycin plus zinc may be more effective at reducing inflammatory and non-inflammatory lesions and at reducing overall acne severity at 10–12 weeks ( low-quality evidence ).

Benefits

Topical erythromycin plus zinc versus placebo:

We found one systematic review (search date 1999, 2 RCTs, 222 people with mild to severe acne), which compared topical erythromycin 4% plus zinc acetate 1.2% versus placebo. The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed. The first RCT compared four interventions for 10 weeks: erythromycin 4% plus zinc acetate 1.2% gel twice daily plus oral placebo; erythromycin 4% plus zinc octoate 1.2% liquid twice daily plus oral placebo; oral tetracycline 250 mg twice daily plus topical vehicle; and topical vehicle plus oral placebo. It found that erythromycin plus zinc (liquid or gel) significantly reduced overall acne severity at 10 weeks compared with topical vehicle plus oral placebo (149 men, severity of acne unclear; reduction in severity measured by Cook's acne grading scale: 46% with topical erythromycin plus zinc liquid v 7% with topical vehicle plus oral placebo, P less than 0.001; reduction in severity: 33% with topical erythromycin plus zinc gel v 7% with topical vehicle plus oral placebo, P less than 0.01). It also found that erythromycin plus zinc significantly reduced papules compared with placebo (reduction in papules measured by Cook's acne grading scale: 58% with topical erythromycin plus zinc liquid v 25% with topical vehicle plus oral placebo, P less than 0.001; reduction in papules: 45% with topical erythromycin plus zinc gel v 25% with topical vehicle plus oral placebo, P less than 0.05). It found no significant difference in pustules between treatments (reported as non-significant, no further data reported). The RCT did not assess patient perception of improvement. The second RCT compared topical erythromycin 4% plus zinc acetate 1.2% twice daily versus vehicle. It found that topical erythromycin plus zinc acetate significantly reduced both non-inflammatory and inflammatory lesions at 12 weeks compared with vehicle (73 women with Cook's acne grade score 3 or more in non-inflammatory lesions: 61% with topical erythromycin plus zinc acetate v 48% with vehicle, P less than 0.01; reduction in inflammatory lesions: 73% with topical erythromycin plus zinc acetate v 46% with vehicle, P less than 0.01). The RCT did not assess patient perception of improvement.

Harms

Topical erythromycin plus zinc versus placebo:

One person in the first RCT withdrew from the trial because of irritation with topical erythromycin plus zinc acetate liquid plus oral placebo. The second RCT reported that no one withdrew from the trial owing to irritation or other adverse effects of treatment; it gave no further information on adverse effects.

Comment

Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance in Propionibacterium acnes. One systematic review (search date 2003) has found evidence that the efficacy of topical erythromycin 1.5–2% has decreased over the period 1966–2003, which may be as a result of increasing bacterial resistance (see comment on topical erythromycin).

Clinical guide:

Topical antibiotics or topical retinoids are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical clindamycin or erythromycin than with erythromycin plus zinc or tetracycline. However, there is some evidence that topical erythromycin may be less effective now than in the past, owing to increasing P acnes resistance. Erythromycin plus zinc is available as a formulated combination topical solution.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Isotretinoin (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical isotretinoin may be more effective at reducing the number of inflammatory and non-inflammatory lesions at 12 weeks in people with mild to moderate acne ( low-quality evidence ). PATIENT PERCEPTION OF IMPROVEMENT Compared with placebo: We don’t know whether topical isotretinoin is more effective at increasing the proportion of people who perceive their acne as improved at 12 weeks ( very low-quality evidence ). NOTE Topical isotretinoin has been associated with severe erythema, dryness, soreness, and burning. Topical retinoids are not recommended in women of childbearing age who taking adequate contraceptive precautions, or during pregnancy.

Benefits

Topical isotretinoin versus placebo:

We found one systematic review (search date 1999, 3 RCTs, 472 people with mild to moderate acne) and one subsequent RCT (160 people with mild to moderate acne) comparing isotretinoin versus placebo (vehicle). The review did not perform a meta-analysis because of heterogeneity among the trials in methods of outcome assessment. The first RCT identified by the review found that isotretinoin significantly reduced the number of inflammatory lesions (313 people with moderate acne; mean reduction: 55% with isotretinoin v 25% with vehicle), the number of non-inflammatory lesions (46% with isotretinoin v 14% with vehicle), and severity scores (measured by Cook's acne grading scale method: 40% with isotretinoin v 20% with vehicle; differences reported as significant for all outcomes, CI not reported) compared with vehicle. The RCT did not assess patient perception of improvement. The second RCT identified by the review compared three interventions: isotretinoin, benzoyl peroxide, and vehicle. It found that, at 12 weeks, isotretinoin significantly reduced the number of inflammatory lesions (77 people with mild to moderate acne; mean change: –33% with isotretinoin v +9% with vehicle; P = 0.01), the number of non-inflammatory lesions (mean change: –47% with isotretinoin v +6% with vehicle; P = 0.01), and severity scores compared with vehicle (measured using the Leeds score where 0 = no acne and 10 = severest acne; mean score: 0 with isotretinoin v 1 with vehicle; P less than 0.05). The RCT did not assess patient perception of improvement. The third RCT identified by the review did not assess the effects of isotretinoin on the number of inflammatory or non-inflammatory lesions. It assessed effects on comedones and papules but did not compare isotretinoin versus vehicle directly; rather, it assessed within-group differences from baseline in each group. It found that isotretinoin 0.05% or 0.1% significantly reduced the number of whiteheads or papules from baseline at 12 weeks (82 people with mild to moderate acne; mean change in whiteheads from baseline with isotretinoin 0.05%: –9.6, P less than 0.01; mean change in papules with isotretinoin 0.05%: –7.6, P less than 0.01; mean change in whiteheads from baseline with isotretinoin 0.1%: –9.4, P less than 0.01; mean change in papules with isotretinoin 0.1%: –13.3, P less than 0.01; mean change in whiteheads with placebo from baseline: –2.6, reported as not significant; mean change in papules with placebo: –7.3, P less than 0.01). The RCT did not assess patient perception of improvement. The subsequent RCT compared isotretinoin 0.05% alone, erythromycin 2% alone, isotretinoin plus erythromycin, or vehicle for 12 weeks' treatment. The RCT did not report direct comparisons of isotretinoin alone versus vehicle; it reported changes from baseline within the isotretinoin alone and the vehicle groups. It found a significant reduction in total lesion count from baseline at 12 weeks with isotretinoin, but not with vehicle (160 people with mild to moderate acne; mean change in total lesion count: –21.52%, 95% CI –32.44% to –10.60% with isotretinoin v –10.82%, 95% CI –24.29% to +2.65% with vehicle). It also found significant reductions in the number of non-inflammatory and inflammatory lesions from baseline to 12 weeks with isotretinoin, but not with vehicle (mean change in non-inflammatory lesion count: –18.49, 95% CI –35.5 to –1.63 with isotretinoin v –7.07, 95% CI –28.31 to +14.16 with vehicle; mean change in inflammatory lesion count: –15.66, 95% CI –27.71 to –3.62 with isotretinoin v –9.58, 95% CI –24.51 to +5.36 with vehicle). However, the RCT found that a similar proportion of people using isotretinoin compared with vehicle perceived that their acne had improved from baseline at 12 weeks (66% with isotretinoin v 53% with vehicle; P value not reported).

Harms

Topical isotretinoin versus placebo:

The first RCT identified by the review found that more people using isotretinoin had peeling or erythema compared with vehicle cream (peeling: 71% with isotretinoin v 51% with vehicle; erythema: 76% with isotretinoin v 62% with vehicle). The second RCT identified by the review found that isotretinoin was associated with severe erythema (2 people), dryness (3 people), redness (10 people), soreness (4 people), and burning (4 people). One person taking isotretinoin withdrew because of erythema. The third RCT identified by the review found that isotretinoin (0.05% and 0.1%) significantly increased peeling at 12 weeks compared with vehicle (P less than 0.01, no further data reported). The subsequent RCT found no significant difference among treatments in “overall tolerance” over 12 weeks (reported as non-significant, P value not reported). This RCT is likely to have been underpowered to detect a clinically important difference in adverse effects among treatments.

Birth defects:

In the absence of data regarding the risk of birth defects, it is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.

Comment

Clinical guide:

Topical retinoids or topical antibiotics are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the retinoid class, there is more evidence of benefit with topical tretinoin than with isotretinoin or adapalene. It is recommended that topical retinoids are not used during pregnancy, or by women of childbearing age not taking adequate contraceptive precautions.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Tetracycline (topical)

Summary

SYMPTOM SEVERITY Compared with placebo: Topical tetracycline may be more effective at reducing severity of acne at 12–16 weeks in people with mild to moderate acne ( very low-quality evidence ). PATIENT PERCEPTION OF IMPROVEMENT Compared with placebo: Topical tetracycline may be no more effective at increasing the proportion of people who consider their condition better than before treatment ( low-quality evidence ). NOTE Topical tetracycline has been associated with skin discoloration.

Benefits

Topical tetracycline versus placebo:

We found one systematic review (search date 1999, 4 RCTs, 355 people with moderate to severe acne). The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed. The first RCT identified by the review compared three interventions for 13 weeks: topical tetracycline 0.5% plus oral placebo, oral tetracycline 250 mg twice daily plus topical placebo, and topical plus oral placebo. It found that topical tetracycline significantly reduced acne severity at 12 weeks compared with placebo (75 people; mean reduction in severity measured by Cook's acne grading scale : 1.43 with topical tetracycline v 0.62 with placebo; P less than 0.05). The results of the RCT should be interpreted with caution, as it did not perform an intention-to-treat analysis of results, and 11/75 (15%) people withdrew from the trial. The RCT did not assess patient perception of improvement. The second RCT identified by the review also compared three interventions: topical tetracycline plus oral placebo, topical vehicle plus oral tetracycline, and topical vehicle plus oral placebo. It found that more people taking topical tetracycline had reduced acne severity compared with people taking placebo (60 male adolescents; AR for improvement of at least 1 on a scale from 0 [least improvement] to 8 [most improvement]: 14/19 [74%] with topical tetracycline v 6/17 [35%] with placebo). The RCT did not assess the significance of the difference among groups, and did not assess patient perception of improvement. The third RCT identified by the review compared three interventions for 12 weeks: topical tetracycline 0.22% plus oral placebo, oral tetracycline plus topical vehicle, and topical vehicle plus oral placebo. It found that topical tetracycline significantly reduced acne severity at 7, 10, and 12 weeks compared with placebo (135 people aged 18–25 years with mild to moderate acne, Cook's acne grades 0–8, P less than 0.05; absolute results presented graphically). The RCT did not assess patient perception of improvement. The fourth RCT compared topical tetracycline 2.2% versus placebo for 16 weeks. All participants took oral tetracycline for 8 weeks before beginning treatment with topical tetracycline or placebo. The RCT found that topical tetracycline significantly increased the proportion of people who had improved acne at 16 weeks (85 people with mild to moderate acne; proportion with improvement measured on a scale from 0 to 8: 29/31 [94%] with topical tetracycline v 13/23 [57%] with placebo; P = 0.035). It is unclear how the authors dichotomised results to calculate the proportion of people who had improved acne severity. The RCT found that a similar proportion of people taking topical tetracycline compared with placebo “considered that their condition was better than before treatment” (25/31 [81%] with topical tetracycline v 18/24 [75%] with placebo; P value not reported).

Harms

Topical tetracycline versus placebo:

Three of the RCTs identified by the review found that some people using topical tetracycline had skin discoloration. In one RCT, the difference between groups was significant (proportion with skin discoloration: 17/43 [40%] with tetracycline v 4/42 [10%] with placebo; P less than 0.005). One RCT gave no information on adverse effects.

Comment

Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance in Propionibacterium acnes.

Clinical guide:

Topical antibiotics or topical retinoids are indicated as treatment for mild acne that does not respond to benzoyl peroxide. Within the antibiotic class, there is more evidence of benefit with topical clindamycin or erythromycin than with erythromycin plus zinc, or with tetracycline.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Erythromycin (oral)

Summary

SYMPTOM SEVERITY Compared with oral doxycycline: We don’t know whether oral erythromycin is more effective at reducing the number of papules and pustules at 6 weeks in people with moderate acne ( low-quality evidence ). Compared with oral tetracycline: We don’t know whether oral erythromycin is more effective at improving inflammation scores at 6 months, or at reducing the number of pustules, papules, or open or closed comedones at 12 weeks in people with moderate to severe acne (low-quality evidence). PATIENT PERCEPTION OF IMPROVEMENT Compared with oral tetracycline: Oral erythromycin and oral tetracycline are equally effective at increasing the proportion of people with moderate to severe acne who perceive their acne as markedly improved or improved at 12 weeks ( moderate-quality evidence ). NOTE We found no direct information about whether oral erythromycin is better than no active treatment in people with acne. Oral erythromycin may cause contraceptive failure during the initial weeks of treatment.

Benefits

Oral erythromycin versus placebo:

We found two systematic reviews (search date 2004)and (no search date given) which identified no RCTs comparing oral erythromycin versus placebo. We found no subsequent RCTs.

Oral erythromycin versus oral doxycycline:

We found one RCT (56 people with moderate acne) comparing oral doxycycline (100 mg daily for 2 weeks, then on alternate days for 4 weeks) versus oral erythromycin (500 mg twice daily for 2 weeks, then 250 mg twice daily for 4 weeks). Before treatment, people taking doxycycline had a mean of 38 inflammatory lesions, and people taking erythromycin had a mean of 46 inflammatory lesions (significance not reported). The RCT found no significant difference in the number of papules and pustules after 6 weeks between doxycycline and erythromycin (mean number per person: 16 with doxycycline v 15 with erythromycin; P greater than 0.1). The RCT did not assess patient perception of improvement.

Oral erythromycin versus oral tetracycline:

We found two systematic reviews. The first review (search date 1999) identified three RCTs (300 people), which compared oral erythromycin versus oral tetracycline in people with mild, moderate, or severe acne. The second review (search date 2004), which had more stringent inclusion criteria, included one RCT identified by the first review. The first RCT included in the first review found no significant difference in cure or total inflammation scores between erythromycin 200–400 mg daily and tetracycline 250–400 mg daily for 6 months (60 people with moderate to severe acne; proportion symptom free: 9/21 [43%] with erythromycin v 7/21 [33%] with tetracycline; inflammation score on face: 1 in both groups; reported as non-significant, P value not reported). The RCT did not assess patient perception of improvement. The second RCT compared erythromycin (333 mg three times daily for 4 weeks, then once daily for 8 weeks) versus tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks). It found no significant difference between erythromycin and tetracycline at 12 weeks in the number of pustules, papules, open comedones, or closed comedones (200 people with moderate to severe acne; % change, pustules: –73% with erythromycin v –65% with tetracycline; papules: –60% with erythromycin v –62% with tetracycline; open comedones: –26% with erythromycin v –31% with tetracycline; closed comedones: –17% with erythromycin v –36% with tetracycline; P value reported as non-significant for all outcomes, CI not reported). It also found no significant difference between erythromycin and tetracycline in the proportion of people who perceived that their acne had improved (proportion who reported acne as “markedly improved” or “improved”: 77% with erythromycin v 89% with tetracycline; difference reported as non-significant, P value and CI not reported). The third RCT compared erythromycin 250 mg twice daily versus tetracycline 250 mg twice daily for 16 weeks. It did not compare the two treatments directly, but found that fewer people in the erythromycin group than in the tetracycline group had a “good” or “very good” response as assessed by their physician (40 people with mild, moderate, or severe acne; AR for “good” or “very good” response: 65% with erythromycin v 90% with tetracycline). It did not assess patient perception of improvement.

Harms

Oral erythromycin versus placebo:

We found no RCTs.

Oral erythromycin versus oral doxycycline:

The RCT reported no withdrawals due to adverse effects, but gave no further information.

Oral erythromycin versus oral tetracycline:

The RCTs found that oral erythromycin and oral tetracycline were associated with similar rates of adverse effects, mostly gastrointestinal. In the first RCT, one person in each treatment group discontinued treatment in the first week because of diarrhoea, and 14% of people in the trial had adverse effects, mostly gastrointestinal. In the second RCT, 12 people taking erythromycin and seven taking tetracycline had adverse effects, again mostly gastrointestinal. One person taking oral tetracycline developed a pseudotumour cerebri, but later recovered. In the third RCT, one person taking erythromycin had nausea and vomiting, and one person taking tetracycline had mild diarrhoea, one had nausea, and one had pruritus. Both oral erythromycin and oral tetracycline may cause contraceptive failure during the initial weeks of treatment.

Comment

Propionibacterium acnes are becoming increasingly resistant to systemic antibiotics. One systematic review (search date 1998, 12 studies) found an increase in the prevalence of P acnes resistance from 20% in 1978 to 62% in 1996. Resistance to systemic antibiotics varied, but was most commonly reported in people taking erythromycin, clindamycin, tetracycline, doxycycline, and trimethoprim. Resistance to minocycline was rare.

Clinical guide:

Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and can be supplemented by non-antibiotic topical treatment (e.g. benzoyl peroxide) if needed. There is evidence that erythromycin is effective, but there are some concerns about bacterial resistance. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

Erythromycin (oral) Two systematic review added comparing oral erythromycin versus placebo. The systematic reviews identified no RCTs. Categorisation unchanged (Beneficial).

2008; 2008: 1714.
Published online 2008 May 15.

Doxycycline (oral)

Summary

SYMPTOM SEVERITY Compared with placebo: We don’t know whether oral doxycyline is more effective at reducing the number of inflammatory lesions at 4 weeks in people with mild acne ( very low-quality evidence ). Compared with oral erythromycin: We don’t know whether oral doxycycline is more effective at reducing the number of papules and pustules at 6 weeks in people with moderate acne ( low-quality evidence ). Compared with oral minocycline: We don’t know whether oral doxycline is more effective at increasing the proportion of people with mild to moderate or inflammatory acne with at least 50% reduction in inflammatory lesions, and in total lesion count (very low-quality evidence). Compared with oral oxytetracycline: We don’t know whether oral doxycycline is more effective at reducing the number of lesions at 8 weeks in people with moderate to severe acne (low-quality evidence). NOTE Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Benefits

Oral doxycycline versus placebo:

We found two systematic reviews. The first review (search date 1999) identified one crossover RCT (62 people with mild acne), which compared oral doxycycline 100 mg daily versus placebo for 8 weeks. The RCT did not report direct comparisons of oral doxycycline with placebo, but reported changes from baseline within the doxycycline and the placebo groups. Comparing changes from baseline within the oral doxycycline group before crossover, it found that oral doxycycline significantly reduced the number of inflammatory lesions from baseline at 4 weeks compared with placebo (% change from baseline: –36% with doxycycline, P = 0.001; +12% with placebo, change reported as non-significant, P value and CI not reported). It found no significant difference in the number of comedones and cysts from baseline within the doxycycline group. The RCT had major losses to follow-up (no further data reported). It did not assess patient perception of improvement.

Oral doxycycline versus oral erythromycin:

See benefits of oral erythromycin.

Oral doxycycline versus oral minocycline:

See benefits of oral minocycline.

Oral doxycycline versus oral oxytetracycline:

We found one double blind crossover RCT comparing oral doxycycline (100 mg daily for 8 weeks) versus oral oxytetracycline (250 mg three times daily for 4 weeks then once daily for 4 weeks). Before crossover, it found no significant difference in mean number of lesions between oral doxycycline and oxytetracycline (28 people with moderate to severe acne; mean number per person at 8 weeks: 62 with doxycycline v 32 with oxytetracycline; reported as non-significant, P value not reported). The RCT did not assess patient perception of improvement.

Harms

Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Oral doxycycline versus placebo:

The RCT identified by the review found no adverse effects in people taking doxycycline or placebo, but may have been underpowered to detect adverse effects.

Oral doxycycline versus oral erythromycin:

The RCT (56 people) comparing doxycycline with erythromycin reported that no one withdrew from treatment because of adverse effects after 6 weeks with either treatment.

Oral doxycycline versus minocycline:

See harms of oral minocycline.

Oral doxycycline versus oral oxytetracycline:

The RCT reported no “significant adverse effects”.

Comment

See comment on oral erythromycin regarding antibiotic resistance.

Clinical guide:

Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and can be supplemented by non-antibiotic topical treatment (e.g. benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) offer benefits, but have differing adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Lymecycline (oral)

Summary

SYMPTOM SEVERITY Compared with oral minocycline: Oral lymecycline and oral minocycline seem equally effective at 12 weeks at increasing the proportion of people with 50% or greater reduction in inflammatory or non-inflammatory lesions ( moderate-quality evidence ). PATIENT PERCEPTION OF IMPROVEMENT Compared with oral minocycline: Oral lymecycline and oral minocycline seem equally effective at 12 weeks at increasing the proportion of people who perceive an overall improvement in their acne (moderate-quality evidence). NOTE We found no direct information about whether oral lymecycline is more effective than no active treatment in people with acne vulgaris. NOTE Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Benefits

Oral lymecycline versus placebo:

We found one systematic review (search date 1999), which identified no RCTs comparing oral lymecycline versus placebo. We found no subsequent RCTs.

Oral lymecycline versus oral minocycline:

See benefits of oral minocycline.

Harms

Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Oral lymecycline versus placebo:

We found no RCTs.

Oral lymecycline versus oral minocycline:

See harms of oral minocycline.

Comment

See comment on oral erythromycin regarding antibiotic resistance.

Clinical guide:

Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g. benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Minocycline (oral)

Summary

SYMPTOM SEVERITY Compared with placebo: We don’t know whether oral minocycline is more effective at reducing the number of inflammatory lesions and total number of lesions at 12 weeks ( low-quality evidence ). Compared with oral doxycycline: We don’t know whether oral minocycline is more effective at increasing the proportion of people with mild to moderate or inflammatory acne with 50% or greater reduction in inflammatory lesions, and at decreasing total lesion count ( very low-quality evidence ). Compared with oral lymecycline: Oral minocycline and oral lymecyline seem equally effective at 12 weeks at increasing the proportion of people with 50% or greater reduction in inflammatory or non-inflammatory lesions ( moderate-quality evidence ). Compared with oral oxytetracyline: We don’t know whether oral minocycline is more effective at increasing the proportion of people who report moderate improvement, or whose acne improves by at least two grades on the Cook’s acne grading severity scale at 12–24 weeks (very low-quality evidence). Compared with oral tetracycline: We don’t know whether oral minocycline is more effective at improving overall acne severity assessed on a variety of scales (including the Samuelson Lesion and Pillsbury Scale), or at increasing the proportion of people who report an overall improvement or rate response as satisfactory in people with moderate to severe acne (very low-quality evidence). PATIENT PERCEPTION OF IMPROVEMENT Compared with placebo: We don’t know whether oral minocycline is more effective at improving patient perception of overall efficacy (very low-quality evidence). Compared with oral lymecycline: Oral minocycline and oral lymecycline seem equally effective at 12 weeks at increasing the proportion of people who perceive an overall improvement in their acne (moderate-quality evidence). NOTE Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may also cause contraceptive failure during the initial weeks of treatment.

Benefits

Oral minocycline versus placebo:

We found one systematic review (search date 2002), which identified one crossover RCT comparing oral minocycline versus placebo for 5 weeks. The RCT did not compare minocycline versus placebo directly, but assessed within-group differences from baseline in each group. Before crossover, it found that minocycline significantly reduced total lesion score from baseline (P less than 0.05), whereas placebo did not (no further data reported). It found no significant change in patient perception of overall efficacy of minocycline compared with baseline (43 people; perceived efficacy measured on a 10 cm visual analogue scale: WMD –1.25, 95% CI –7.22 to +4.72). The RCT was of insufficient duration to adequately assess the effects of minocycline. The review did not report on results post-crossover because there was no washout period before crossover, which could have affected results in the placebo group.We found one subsequent RCT (924 people with moderate or severe facial acne) comparing extended-release minocycline (1 mg/kg daily) versus placebo. The RCT found that, compared with placebo, extended-release minocyline significantly reduced the number of inflammatory lesions (reduction from baseline to day 84: 46% with extended-release minocyline v 32% with placebo, P less than 0.001; absolute figures not reported) and total number of lesions (reduction from baseline to day 84: 33% with extended-release minocycline v 22 %, P less than 0.001; absolute figures not reported) at 12 weeks.

Oral minocycline versus oral doxycycline:

We found one systematic review (search date 2002, 5 RCTs, 419 people with mild to moderate or inflammatory acne) comparing oral minocycline versus oral doxycycline. The review did not perform a meta-analysis because of heterogeneity among the trials in methods, outcomes assessed, and drug doses. All of the RCTs found no significant difference in outcomes between minocycline and doxycycline. Outcomes assessed included proportion of people with at least a 50% reduction in inflammatory lesions, total lesion count, patient perception of improvement, and overall efficacy. The review found problems with the methods used in all of the RCTs: three were open label, and the two double blind RCTs reported insufficient information to allow calculation of effect sizes.

Oral minocycline versus oral lymecycline:

We found one systematic review (search date 2002), which identified one multicentre RCT comparing oral minocycline versus oral lymecycline. It found no significant difference between minocycline and lymecycline in the proportion of people with at least a 50% reduction in inflammatory or non-inflammatory lesions at 12 weeks (144 people with at least 20 inflammatory lesions on the face; AR for at least 50% reduction in inflammatory lesions: 46/73 [63%] with minocycline v 41/71 [58%] with lymecycline, RR 1.09, 95% CI 0.84 to 1.42; AR for at least 50% reduction in non-inflammatory lesions: 22/73 [30%] with minocycline v 33/71 [46%] with lymecycline, RR 0.65, 95% CI 0.42 to 1.00). The RCT also found no significant difference between minocycline and lymecycline in the proportion of people who perceived that there had been “overall improvement” in their acne (59/71 [83%] with minocycline v 55/65 [85%] with lymecycline; RR 0.98, 95% CI 0.91 to 1.24).

Oral minocycline versus oral oxytetracycline:

We found one systematic review (search date 2002), which identified one open-label RCT comparing oral minocycline versus oral oxytetracycline, and one subsequent RCT. The RCT identified by the review found that minocycline significantly increased the proportion of people whose acne had improved by at least two grades on the Cook's acne grading severity scale over 12–24 weeks' treatment compared with oxytetracycline (237 people with at least grade 4 acne on Cook's scale; AR for at least 2 grades' improvement: 90/104 [87%] with minocycline v 64/90 [71%] with oxytetracycline; RR 1.22, 95% CI 1.05 to 1.42; completer analysis). The results of the RCT should be interpreted with caution, as they are not analysed by intention to treat, and 43 people (18%) were excluded from the analysis. The clinical relevance of the results is also unclear, because the RCT did not state acne grades after treatment. The RCT did not assess patient perception of improvement. The subsequent double-blind RCT compared five treatments: oral minocycline 100 mg once daily plus topical placebo; oral oxytetracycline 500 mg twice daily plus topical placebo; oral placebo plus topical benzoyl peroxide twice daily; oral placebo plus topical benzoyl peroxide plus topical erythromycin twice daily; and oral placebo plus topical erythromycin in the morning plus topical benzoyl peroxide in the evening. It found no significant difference in the proportion of people reporting moderate improvement in facial acne at 18 weeks between oral minocycline and oral oxytetracycline (5-arm RCT, 649 people with mild to moderate acne [Leeds acne grade 3 or less]; improvement assessed using a 6-point Likert scale; AR for at least moderate improvement: 70/130 [54%] with minocycline v 72/131 [55%] with oxytetracycline; OR 0.95, 95% CI 0.58 to 1.55).

Oral minocycline versus oral tetracycline:

We found one systematic review (search date 2002, 6 RCTs, 693 people with moderate to severe acne) comparing oral minocycline versus oral tetracycline. The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed. Five RCTs identified by the review found no significant difference between minocycline and tetracycline in overall acne severity assessed on a variety of scales, including the Samuelson Lesion and Pillsbury Scale. Two RCTs identified by the review found no significant difference between oral minocycline and oral tetracycline in the proportion of people who perceived overall improvement in their acne, or felt that their response was “satisfactory”; the other RCTs did not assess patient perception of improvement. One open-label RCT identified by the review reported a difference in outcomes between minocycline and tetracycline, but the methods used had serious flaws sufficient to question the validity of the result.

Harms

We found three systematic reviews assessing the adverse effects of minocycline. The first review (search date 2002) identified 21 studies assessing the adverse effects of minocycline. It found that 137/1230 (11%) people had an adverse reaction attributed to minocycline, 36/1230 (3%) of whom withdrew because of adverse effects. It also found that 17/700 (2%) people taking minocycline had abnormal pigmentation. One prospective cohort study identified by the review (700 people) assessed adverse effects in people taking minocycline 100–200 mg daily for a mean 10.5 months. It found that adverse effects were reported in 13.6% of people. They included vestibular disturbance, candida infection, gastrointestinal disturbance, cutaneous symptoms (pigmentation, pruritus, photosensitive rash, and urticaria), and benign intracranial hypertension. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Oral minocycline versus placebo:

The subsequent RCT of extended-release (ER) minocycline found similar rates of adverse effects in the minocycline and placebo groups during the 12 weeks of follow-up (56% with minocyline v 54% with placebo, significance not reported). The most commonly reported adverse effects in the minocycline group were headaches (22.6%), nausea (9.5%), fatigue (9.2%), dizziness (8.8%), diarrhoea (5.2%) and pruritis (4.6%).

Oral minocycline versus oral oxytetracycline:

The subsequent RCT found that adverse events were more common in the first 6 weeks of treatment, and occurred with similar frequency in the minocycline and oxytetracycline groups (skin adverse event: 4% in both groups; gastrointestinal adverse event: 9% with minocycline v 8% with oxytetracycline; central nervous system adverse event: 11% with minocycline v 17% with oxytetracycline; significance assessments not performed). In the minocycline group, 2% of participants experienced musculoskeletal symptoms at week 12, and 4% experienced musculoskeletal symptoms at week 18 (figures not reported for other groups).

Systemic lupus erythematosus:

We found two systematic reviews. The first review identified one case control study (27,688 people aged 15–19 years with acne) assessing the risk of systemic lupus erythematosus (SLE) in people taking tetracyclines compared with matched controls. Women had a significantly higher risk of developing SLE compared with men (RR 14, 95% CI 1.8 to 111). The case control study found that 29 people (27 women) taking tetracyclines had an SLE-like syndrome. It found that current minocycline use significantly increased the risk of developing SLE (AR 52.8 cases per 100,000 prescriptions; RR 8.5, 95% CI 2.1 to 35). It found no significant difference in the risk of developing SLE with tetracyclines other than minocycline, although use of tetracyclines was associated with an increased risk (RR 1.7, 95% CI 0.4 to 8.1). Cumulative minocycline dose and prolonged exposure (more than 100 days) to minocycline may also be risk factors, but no quantitative data were reported. The second review (search date 1999) identified 57 case reports of SLE in people taking minocycline. It suggested that minocycline may induce SLE, but did not quantify its conclusions. Evidence about adverse effects should be interpreted with caution because of wide variation between studies in numbers of reported adverse events. The prevalence of SLE in the general population is 30/100,000 in white people, rising to 200/100,000 in Afro-Caribbean people.

Liver damage:

We found one systematic review (search date 1998) of case reports and case series, which found 65 cases of liver damage in people taking minocycline. The review did not quantify the increased risk in people taking minocycline. It suggested that minocycline was associated with severe hepatic dysfunction, including hypersensitivity, within a few weeks of taking minocycline (16 cases), autoimmune hepatitis within 1 year or more of taking minocycline (29 cases), or unspecified hepatitis (20 cases).

Comment

See comment on oral erythromycin regarding antibiotic resistance.

Clinical guide:

Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g. benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Current clinical guidance in the UK suggests that people taking minocycline for more than 6 months should be monitored for hepatotoxicity, pigmentation, and SLE. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

Minocycline (oral) One RCT added comparing oral mynocycline with placebo. The RCT found that extended-release oral minocyline reduced the number of inflammatory lesions and total number of lesions at 12 weeks compared with placebo. The RCT reported similar rates of adverse effects between groups. Categorisation unchanged (Trade-off between benefits and harms).

2008; 2008: 1714.
Published online 2008 May 15.

Oxytetracycline (oral)

Summary

SYMPTOM SEVERITY Compared with oral minocycline: We don’t know whether oral oxytetracycline is more effective at increasing the proportion of people who report moderate improvement or whose acne improves by at least two grades on the Cook’s acne grading severity scale at 12–24 weeks ( very low-quality evidence ). Compared with oral doxycycline: We don’t know whether oral oxytetracycline is more effective at reducing the number of lesions at 8 weeks in people with moderate to severe acne ( low-quality evidence ). NOTE We found no direct information about whether oral oxytetracycline is better than no active treatment in people with acne vulgaris. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Benefits

Oral oxytetracycline versus placebo:

We found two systematic review (search date 1999) and (search date not given) which identified no RCTs comparing oral oxytetracycline versus placebo. We found no subsequent RCTs.

Oral oxytetracycline versus oral minocycline:

See benefits of oral minocycline.

Oral oxytetracycline versus oral doxycycline:

See benefits of oral doxycycline.

Harms

Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Oral oxytetracycline versus oral minocycline:

See harms of oral minocycline.

Oral oxytetracycline versus oral doxycycline:

See harms of oral doxycycline.

Comment

See comment on oral erythromycin regarding antibiotic resistance.

Clinical guide:

Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g. benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

No new evidence

2008; 2008: 1714.
Published online 2008 May 15.

Tetracycline (oral)

Summary

SYMPTOM SEVERITY Compared with placebo: Oral tetracycline may be more effective at reducing severity of acne at 8–12 weeks in people with mild to moderate acne ( very low-quality evidence ). Compared with oral erythromycin: We don’t know whether oral tetracycline is more effective at improving inflammation scores at 6 months, or at reducing the number of pustules, papules, or open or closed comedones at 12 weeks in people with moderate to severe acne ( low-quality evidence ). Compared with oral minocycline: We don’t know whether oral tetracycline is more effective at improving overall acne severity assessed on a variety of scales (including the Samuelson Lesion and Pillsbury Scale) or at increasing the proportion of people with moderate to severe acne who report an overall improvement, or who rate response as satisfactory (very low-quality evidence). Compared with oral isotretinoin: Oral tetracycline is less effective at reducing acne cysts, pustules, and comedones at 24 weeks in people with severe nodulocystic acne ( moderate-quality evidence ). PATIENT PERCEPTION OF IMPROVEMENT Compared with placebo: Oral tetracycline is more effective at increasing the proportion of people with moderate to severe acne who perceive their acne as markedly improved or improved at 8 weeks (moderate-quality evidence). Compared with oral erythromycin: Oral tetracycline and oral erythromycin are equally effective at increasing the proportion of people with moderate to severe acne who perceive their acne as markedly improved or improved at 12 weeks (moderate-quality evidence). NOTE Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may also cause contraceptive failure during the initial weeks of treatment.

Benefits

Oral tetracycline versus placebo:

We found three systematic reviews. The first review (search date 1999, 7 RCTs, 864 people with mild, moderate, or severe acne) compared oral tetracycline 250 mg twice daily versus placebo (see table 5 ). The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed. The second review (search date 2004), which had more stringent inclusion criteria, identified one RCT included in the earlier review.The third review (search date not given), did not include any further RCTs. Four RCTs identified by the reviews found that oral tetracycline significantly reduced acne severity compared with placebo. One of these RCTs also found that oral tetracycline significantly increased the proportion of people who perceived that their acne was “markedly improved” or “improved” compared with placebo. A fifth RCT compared three interventions: topical tetracycline plus oral placebo, topical vehicle plus oral tetracycline, and topical vehicle plus oral placebo. It found that more people taking oral tetracycline had improved acne compared with people taking placebo, but did not assess the significance of the difference among groups. A sixth small RCT, which compared four interventions, found no significant difference in the number of inflammatory lesions between oral tetracycline and placebo, but may have lacked power to detect a clinically important difference among groups. The seventh RCT did not compare tetracycline versus placebo directly, although within-group comparisons found that tetracycline significantly reduced the number of inflammatory lesions from baseline, and increased the proportion of people who perceived that their acne was “markedly improved” or “improved”.

Table 5
RCTs comparing oral tetracycline versus placebo.

Oral tetracycline versus oral erythromycin:

See benefits of oral erythromycin.

Oral tetracycline versus oral minocycline:

See benefits of oral minocycline.

Oral tetracycline versus oral isotretinoin

: See benefits of oral retinoids

Harms

Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. They may cause contraceptive failure during the initial weeks of treatment.

Oral tetracycline versus placebo:

The review identified five RCTs that assessed adverse effects, and found that 15/579 [3%] people taking tetracycline had adverse effects.

Oral tetracycline versus oral minocycline:

See harms of oral minocycline.

Oral tetracycline versus oral isotretinoin

: see harms of oral retinoids.

Comment

See comment on oral erythromycin regarding antibiotic resistance.

Clinical guide:

Oral antibiotics are indicated as treatment for moderate acne that does not respond to topical treatments, and may be supplemented by non-antibiotic topical treatment (e.g. benzoyl peroxide) if needed. Oral tetracyclines (doxycycline, lymecycline, minocycline, oxytetracycline, tetracycline) are beneficial, but have different adverse-effect profiles that need to be considered in treatment decisions. Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women. Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

Tetracycline (oral) One systematic review added comparing oral tetracycline versus placebo. The systematic review added no further RCTs. One RCT added comparing oral tetracycline versus oral isotretinoin. The RCT found that, compared with tetracycline, isotretinoin reduced acne cysts, pustules, and comedones at 24 weeks; categorisation unchanged (Trade-off between benefits and harms).

2008; 2008: 1714.
Published online 2008 May 15.

Isotretinoin (oral)

Summary

SYMPTOM SEVERITY Compared with placebo: Oral isotretinoin is more effective at reducing nodules at 1 month in people with treatment-resistant cystic and conglobate acne ( moderate-quality evidence ). Compared with oral tetracycline: Oral isotretinoin is more effective at reducing acne cysts, pustules, and comdedones at 24 weeks in people with severe nodulocystic acne (moderate-quality evidence). ADVERSE EFFECTS Oral isotretinoin is teratogenic and is associated with a wide range of adverse effects, such as skin problems, changes in liver function, and development of psychiatric disorders.

Benefits

Oral isotretinoin versus placebo:

We found one RCT (33 people with treatment-resistant cystic and conglobate acne) comparing oral isotretinoin (0.5 mg/kg/day) versus placebo. The RCT found a significant mean reduction of nodules at 1 month in the isotretinoin group of 32%, compared with an increase of 33% in the placebo group (P less than 0.008, no absolute figures reported). The open phase for a further 2–4 months showed further improvement in the treatment group as dose increased to a mean of 0.9 mg/kg/day.

Oral isotretinoin versus oral tetracycline:

One small RCT (29 people with severe nodulocystic acne) compared oral isotretinoin (1–2 mg/kg/day) versus oral tetracycline (0.5–1 mg/day). The RCT found that, compared with tetracycline, isotretinoin significantly reduced acne cysts (reduction in acne cysts: 82% with isotretinoin v 52% with tetracycline; P less than 0.01) and pustules and comedones (reduction in pustules and comedones: 85% with isotretinoin v 58% with tetracycline; P less than 0.01) at 24 weeks (no absolute figures reported).

Harms

Oral isotretinoin versus placebo:

The RCT found low rates of adverse effects in the isotretinoin group, including arthralgia, decreased appetite, fatigue, cheilitis, facial dermatitis, conjunctivitis, xerosis, and dryness of the nasal mucosa with nosebleeds. No figures were reported, but no one stopped treatment owing to adverse effects.

Oral isotretinoin versus oral tetracycline:

The RCT found a higher rate of adverse effects with isotretinoin compared with tetracycline. These included xerosis (15/15 [100%] with isotretinoin v 2/15 [13%] with oral tetracycline), cheilitis/dry lips (15/15 [100%] with isotretinoin v 3/15 [20%] with oral tetracycline), dry nose (10/15 [67%] with isotretonoin v 1/15 [7%] with oral tetracycline), and dry mouth (3/15 [20%] with isotretinoin v 1/15 [7%] with oral tetracycline). The RCT also reported desquamation, alopecia, erythema, pruritis, epistaxis, dry eyes, conjunctivitis, pterygium (right eye), and photophobia in the isotretinoin group.

Skin:

Dry skin and mucosal surfaces are a well-known adverse effect of isotretinion treatment. We found one open study (80 people with a range of acne types failing to respond to oral antibiotics) of intermittent dosing with isotretinion 0.5 mg/kg/daily (1 week in 4 for 6 months), to determine the relative efficacy versus adverse effects. Although there was no control group, the authors reported modest cheilitis at the lower end of the spectrum for isotretinoin adverse effects.

Liver function:

Isotretinion treatment affects the metabolic system, and is reflected in altered liver function tests and elevated blood lipids. We found one retrospective analysis of people receiving isotretinoin for acne to determine the necessity for routine testing of lipid profiles and liver function during treatment. The 209 people in the study included 113 people treated with 1 mg/kg/day, and 96 people treated with 0.5 mg/kg/day, who had serial fasting blood samples taken at 0, 8, and 16 weeks. The study found no significant changes in any of the tests of liver function. It concluded that, if the baseline tests are normal, in the absence of clinical indicators or doses greater than 1 mg/kg it is safe to measure just once at about 4 weeks. For prolonged doses, or where there are pre-existing abnormalities or higher doses, more frequent testing may be warranted.

Pregnancy (teratogenesis):

Isotretinion is teratogenic. We found two studies evaluating the effect of isotretinoin treatment on pregnancy and unborn infants. The first study (24,503 women self-registered for a pregnancy prevention programme) found that, in 402 pregnancies, 32 went to term; 13 of the infants were examined for teratogenic effects, revealing changes in 5/32 . In the second study (8609 women), 90 women became pregnant, with nine women progressing to live birth. One of the nine infants had a congenital anomaly of the neck and face. It is not clear how many of the 76/90 terminated pregnancies had already identified anomalies by ultrasound that might have biased the results.

Psychiatric adverse effects:

There is controversy and conflicting evidence on the association of isotretinoin with a variety of adverse psychiatric effects. We found one systematic review (search date 2004) evaluating isotretinoin's association with depression, psychosis, mood swings, and violent behaviour. The review included one prospective survey and one case control studyon psychiatric adverse effects with isotretinoin. The prospective survey reported that the manufacturers had supplied 12 million treatments of isotretinoin by 2001. The data on adverse effects documented 1247 people with mood disorders. The authors also had record of 168 people with suicidal behaviour, 104 with suicide attempts, and 64 with completed suicides, at 10 years' follow-up after the completion of medication. Thirty suicides were confirmed in people while taking the medication. However, this figure should be considered in the context of a very large denominator.In addition, behavioural disorders and suicides are relatively common in the age group typically taking isotretinoin. US healthcare data reviewed in the same publication noted that 5 million people in the US are taking isotretinoin. The number of suicides expected in that group from national standardised rates would be 190, whereas the number actually reported was 37. The case control study (7195 people treated with isotretinion and 13,700 people treated with oral antibiotics) found no difference in rates of newly diagnosed psychiatric disorders between isotretinoin compared with oral antibiotics or with non-exposure to either drug (RR 0.9, 95% CI 0.3 to 2.4; P value not given).We found one additional and one subsequent cohort study. Both these studies indicated a lack of association between isotretinoin and suicidal thoughts or action. In spite of this, there remain clinical concerns that isotretinoin might be associated with idiosyncratic adverse mood and behavioural effects in a small number of people. This means that guidelines for use and the drug licence include an outline psychiatric history and assessment undertaken by the dermatologist, with relevant monitoring questions at each consultation.

Comment

Clinical guide:

Many of the studies reported here are from the 1990s, assessing data from the 1980s. At that time, the threshold for prescribing oral isotretinoin was higher, where it was typically used on more severe acne. The norms have since shifted, such that it may well be that the milder grades of acne may be effectively managed with lower doses. In addition, adverse effects (see harms, above) may warrant a trial of different regimens in order to achieve clearance with less discomfort. Clinical experience demonstrates that oral isotretinoin is an immensely valuable drug in the management of complex and aggressive acne. It shortens the duration of suffering, and typically reduces the amount of scarring. However, adverse effects are common and sometimes severe. People in their 20s or older may relapse more frequently than adolescents with similar treatment. Those with milder acne may need smaller doses, but the data on the degree of improvement is not as clear for this group as it is in classic severe nodulocystic acne. Measures to prevent pregnancy and screen for psychological factors were revised in 2005, with changes to the drug licence, effective in the US and EU. The current “pregnancy protection programme” recommends monthly pregnancy tests from 1 month before treatment to 1 month after the end of treatment, the use of two different forms of contraception, and the issue of prescriptions for only 4 weeks’ medication at a time. The oral contraceptive, or co-cyprindiol, may be commenced before treatment of women of child-bearing age with isotretinoin, and continued for at least 1 month after. This provides some additional and independent therapeutic effect in some instances. As documented in harms (see above), there remains uncertainty about the relevance of isotretinoin treatment to adverse psychological events and suicide. However, it remains important that the medical history and monitoring take close note of psychiatric history and symptoms when reviewed in clinic. A recent systematic review from primary care suggested that, although the general practitioner was best placed to undertake this, it would introduce potential for error through communication between the GP and dermatologist, where the dermatologist would be responsible for prescribing.

Substantive changes

Isotretinoin (oral) One RCT added comparing oral isotretinoin versus placebo. The RCT found a mean reduction of nodules in the oral isotretinoin group compared with an increase in the placebo group at 1 month . One RCT added comparing oral isotretinoin versus tetracycline. The RCT found that, compared with tetracycline, isotretinoin reduced acne cysts, pustules, and comedones at 24 weeks. Isotretinoin is teratogenic and is associated with a wide range of adverse effects, such as skin problems, changes in liver function, and development of psychiatric disorders. Categorised as Trade-off between benefits and harms.


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