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. 2011 Jan 5;2011:1714.

Acne vulgaris

Sarah Purdy 1,#, David de Berker 2,#
PMCID: PMC3275168  PMID: 21477388

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 February 2010 (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 69 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 liver disorders.

  • Oral isotretinoin has been associated with skin problems, change in liver function, teratogenesis, and psychiatric disorders.

Clinical context

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.[1] 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.[2] It is classified as mild, moderate, or severe.[1] 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.[3] 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%.[4] 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%.[5] [6] It has been estimated that up to 30% of teenagers have acne of sufficient severity to require medical treatment.[7] Acne was the presenting complaint in 3.1% of people aged 13 to 25 years attending primary care in a UK population.[8] Overall incidence is similar in both men and women, and peaks at 17 years of age.[7] The number of adults with acne, including people over 25 years, is increasing; the reasons for this increase are uncertain.[9]

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.[10] The anaerobic bacterium Propionibacterium acnes plays an important role in the pathogenesis of acne. Androgen secretion is the major trigger for adolescent acne.[11]

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,[12] and in a few people (1% of men and 5% of women) acne persists into their 40s.[9]

Aims of intervention

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

Outcomes

Acne severity: as measured by number of non-inflammatory lesions (comedones), number of inflammatory lesions (papules, pustules, and nodules), severity scores and scales; patient perception of improvement; psychological distress; quality of life; and 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;[13] 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);[14] and the Pillsbury Scale, which classifies acne from 1 (mildest) to 4 (severe).[15]

Methods

Clinical Evidence search and appraisal February 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to February 2010, Embase 1980 to February 2010, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. The review by Lehmann et al[16] 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. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Acne vulgaris.

Important outcomes Acne severity, Patient perception of improvement, Psychological distress, Quality of life
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of topical treatments in people with acne vulgaris?
5 (less than 875) Acne severity Topical benzoyl peroxide versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for assessing different outcomes and for no direct comparison between groups in one RCT
7 (less than 1284) Acne severity Topical clindamycin versus placebo 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and methodological flaws (no intention-to-treat analysis, or poor follow-up)
3 (less than 750) Patient perception of improvement Topical clindamycin versus placebo 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and methodological flaws (no intention-to-treat analysis, poor follow-up)
8 (less than 1108) Acne severity Topical erythromycin versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for assessing different outcomes
1 (less than 160) Patient perception of improvement Topical erythromycin versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for no direct comparison between groups
4 (less than 999) Acne severity Topical tretinoin versus placebo 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and no intention-to-treat analysis
1 (60) Patient perception of improvement Topical tretinoin versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for no direct comparison between groups
4 (1343) Acne severity Topical adapalene versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (453) Patient perception of improvement Topical adapalene versus placebo 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and no statistical comparison between groups in one RCT.
2 (132) Acne severity Azelaic acid versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for uncertainty about duration and severity of acne in one RCT
2 (less than 222) Acne severity Topical erythromycin plus zinc versus placebo 4 0 0 –2 0 Low Directness points deducted for uncertainty about severity of acne in one RCT and for assessing different outcomes
4 (less than 632) Acne severity Topical isotretinoin versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between groups
1 (less than 160) Patient perception of improvement Topical isotretinoin versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for no direct comparison between groups
4 (less than 344) Acne severity Topical tetracycline versus placebo 4 –3 0 0 0 Very low Quality points deducted for incomplete reporting of results and for methodological flaws (no intention-to-treat analysis, uncertainty about method of analysis of results)
1 (55) Patient perception of improvement Topical tetracycline versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
What are the effects of oral treatments in people with acne vulgaris?
1 (56) Acne severity Oral erythromycin versus oral doxycycline 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
3 (300) Acne severity Oral erythromycin versus oral tetracycline 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between groups in one RCT
1 (200) Patient perception of improvement Oral erythromycin versus oral tetracycline 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (113) Acne severity Oral doxycycline versus placebo 4 –3 0 –2 0 Very low Quality points deducted for sparse data, incomplete reporting of results, and poor follow-up. Directness points deducted for no direct comparison between groups in one RCT and for low dose of doxycycline used in treatment arm of another RCT
1 (51) Patient perception of improvement Oral doxycycline versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for low dose of doxycycline used in treatment arm
1 (28) Acne severity Oral doxycycline versus oral oxytetracycline 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
4 (1081) Acne severity Oral minocycline versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for no direct comparison between groups
1 (64) Acne severity Oral minocycline versus oral doxycycline 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (64) Patient perception of improvement Oral minocycline versus oral doxycycline 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
3 (less than 348) Acne severity Oral minocycline versus oral lymecycline 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
2 (278) Patient perception of improvement Oral minocycline versus oral lymecycline 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting
1 (261) Patient perception of improvement Oral minocycline versus oral oxytetracycline 4 0 0 –1 0 Moderate Directness point deducted for uncertainty about clinical relevance of results
2 (144) Acne severity Oral minocycline versus oral tetracycline 4 –1 0 0 0 Moderate Quality point deducted for sparse data
2 (144) Patient perception of improvement Oral minocycline versus oral tetracycline 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for assessing different outcomes
7 (less than 621) Acne severity Oral tetracycline versus placebo 4 –2 0 –1 0 Very low Quality points deducted for incomplete reporting of results and methodological weaknesses (no intention-to-treat analysis and blinding flaws). Directness point deducted for no direct comparison between groups
2 (less than 392) Patient perception of improvement Oral tetracycline versus placebo 4 0 0 –1 0 Moderate Directness point deducted for uncertainty about definitions of assessments
1 (33) Acne severity Oral isotretinoin versus placebo 4 –1 0 0 0 Moderate Quality point deducted for sparse data
1 (29) Acne severity Oral isotretinoin versus oral tetracycline 4 –1 0 0 0 Moderate Quality point deducted for sparse data
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

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.

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 de Berker, Bristol Dermatology Centre, Bristol, UK.

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BMJ Clin Evid. 2011 Jan 5;2011:1714.

Benzoyl peroxide (topical)

Summary

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.

Benefits and harms

Topical benzoyl peroxide versus placebo:

We found two systematic reviews comparing topical benzoyl peroxide acid versus placebo (vehicle).[16] [17] The first review (search date 1999, 5 RCTs) did not perform a meta-analysis owing to heterogeneity among the trials in methods of outcome assessment.[16] The second review (search date 2004),[17] which had more stringent inclusion criteria than the earlier review, included one RCT,[18] which was also identified by the earlier review.

Acne severity

Topical benzoyl peroxide 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 to 12 weeks in people with moderate acne (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Total lesion count/severity
[19]
RCT
4-armed trial 		196 people with moderate acne
In review [16] 		Percentage reduction in total lesion count 4 weeks
37% with benzoyl peroxide 5.5% 4 times daily
6% with vehicle
P = 0.001 for benzoyl peroxide v vehicle 		Effect size not calculated Benzoyl peroxide
[22]
RCT
3-armed trial 		150 people with mild to moderate acne
In review [16] 		Reduction in total lesion count from baseline 12 weeks
with benzoyl peroxide 5%
with vehicle
No direct comparison between benzoyl peroxide and vehicle
[20]
RCT
3-armed trial 		77 people with mild to moderate acne
In review [16] 		Leeds severity score (where 0 = no acne and 10 = severest acne) 12 weeks
0 with benzoyl peroxide 5%
1 with vehicle
P <0.05 for benzoyl peroxide v vehicle 		Effect size not calculated Benzoyl peroxide
[21]
RCT		 59 people with mild to moderate acne
In review [16] 		Proportion of people with "good" (51–75% reduction) or "excellent" (76–100% reduction) response 12 weeks
19/26 (73%) with benzoyl peroxide 20%
10/25 (40%) with vehicle
P <0.05 		Effect size not calculated Benzoyl peroxide
Non-inflammatory lesions
[18]
RCT
4-armed trial 		393 people with moderate acne
In review [16] [17] 		Percentage change in non-inflammatory lesions 11 weeks
–30% with benzoyl peroxide 5%
+11% with vehicle
P <0.005 for benzoyl peroxide v vehicle 		Effect size not calculated Benzoyl peroxide
[22]
RCT
3-armed trial 		150 people with mild to moderate acne
In review [16] 		Reduction in non-inflammatory lesions from baseline 12 weeks
with benzoyl peroxide 5%
with vehicle
No direct comparison between benzoyl peroxide and vehicle
[20]
RCT
3-armed trial 		77 people with mild to moderate acne
In review [16] 		Mean percentage change in number of non-inflammatory lesions
–52% with benzoyl peroxide 5%
+6% with vehicle
P = 0.01 for benzoyl peroxide v vehicle 		Effect size not calculated Benzoyl peroxide
Inflammatory lesions
[18]
RCT
4-armed trial 		393 people with moderate acne
In review [16] [17] 		Percentage reduction in inflammatory lesions 11 weeks
39% with benzoyl peroxide 5%
5% with vehicle
P <0.002 for benzoyl peroxide v vehicle 		Effect size not calculated Benzoyl peroxide
[22]
RCT
3-armed trial 		150 people with mild to moderate acne
In review [16] 		Reduction in inflammatory lesions from baseline 12 weeks
with benzoyl peroxide 5%
with vehicle
No direct comparison between benzoyl peroxide and vehicle
[20]
RCT
3-armed trial 		77 people with mild to moderate acne
In review [16] 		Mean percentage change in number of inflammatory lesions
–52% with benzoyl peroxide 5%
+9% with vehicle
P = 0.01 for benzoyl peroxide v vehicle 		Effect size not calculated Benzoyl peroxide
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Patient perception of improvement

No data from the following reference on this outcome.[19] [18] [22] [20] [21]

Psychological distress

No data from the following reference on this outcome.[19] [18] [22] [20] [21]

Quality of life

No data from the following reference on this outcome.[19] [18] [22] [20] [21]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Skin irritation
[19]
RCT
4-armed trial 		196 people with moderate acne
In review [16] 		Adverse effects 4 weeks
with benzoyl peroxide 5.5% 4 times daily
with vehicle
[18]
RCT
4-armed trial 		393 people with moderate acne
In review [16] [17] 		Peeling 11 weeks
21% with benzoyl peroxide 5%
15% with vehicle
Significance not assessed
[22]
RCT
3-armed trial 		150 people with mild to moderate acne
In review [16] 		Adverse effects 12 weeks
22/75 (29%) with benzoyl peroxide 5%
5/75 (7%) with vehicle
P = 0.05 		Effect size not calculated Vehicle
[20]
RCT
3-armed trial 		77 people with mild to moderate
In review [16] 		Adverse effects 12 weeks
with benzoyl peroxide 5%
with vehicle
[21]
RCT		 59 people with mild to moderate acne
In review [16] 		Redness and peeling 12 weeks
21/29 (72%) with benzoyl peroxide 20%
17/30 (57%) with vehicle
Significance not assessed
Open in a new tab

Further information on studies

None.

Comment

Clinical guide:

Benzoyl peroxide is indicated as an effective first-line treatment for mild acne. It has antimicrobial and anticomedonal properties, in addition to 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

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Clindamycin (topical)

Summary

Topical antibiotics such as clindamycin reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions.

Antimicrobial resistance can develop with use of topical or oral antibiotics, and their efficacy may decrease over time.

Benefits and harms

Topical clindamycin versus placebo:

We found two systematic reviews.[16] [17] The first review (search date 1999, 7 RCTs,[18] [23] [24] [25] [26] [27] [28] 1502 people with mild to severe acne) compared topical clindamycin 1% (phosphate or hydrochloride) 1 to 4 times daily versus placebo or vehicle for 8 to 12 weeks.[16] 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,[18] [27] both of which were identified by the earlier review.

Acne severity

Topical clindamycin compared with placebo/vehicle Topical clindamycin may be more effective at reducing the number of inflammatory lesions at 8 to 12 weeks in people with mild to severe acne, but we don't know whether it is more effective at reducing total lesion count or non-inflammatory lesions (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Total lesion count
[28]
RCT		 46 people with moderate to severe acne
In review [16] [17] 		Mean lesion count 12 weeks
0.2 with clindamycin phosphate 1% twice daily
0.6 with placebo
P = 0.34 		Not significant
Non-inflammatory lesions
[18]
RCT
4-armed trial 		393 people with moderate acne
In review [16] [17] 		Mean percentage change in non-inflammatory lesions from baseline 11 weeks
–9% with clindamycin 1% 4 times daily
+11% with vehicle 4 times daily
P = 0.04 for clindamycin v vehicle 		Effect size not calculated Clindamycin
[25]
RCT		 40 people with mild to moderate acne
In review [16] 		Percentage reduction in open comedones 12 weeks
38% with clindamycin phosphate 1% twice daily
32% with placebo
Reported as not significant
P value not reported 		Not significant
[28]
RCT		 46 people with moderate to severe acne
In review [16] [17] 		Mean number of open comedones per person 12 weeks
3.3 with clindamycin phosphate 1% twice daily
5.2 with placebo
P = 0.49 		Not significant
[28]
RCT		 46 people with moderate to severe acne
In review [16] [17] 		Mean number of closed comedones per person 12 weeks
3.4 with clindamycin phosphate 1% twice daily
5.1 with placebo
P = 0.47 		Not significant
Inflammatory lesions
[18]
RCT
4-armed trial 		393 people with moderate acne
In review [16] [17] 		Mean percentage reduction in inflammatory lesions from baseline 11 weeks
35% with clindamycin 1% 4 times daily
5% with vehicle 4 times daily
P <0.001 for clindamycin v vehicle 		Effect size not calculated Clindamycin
[23]
RCT
3-armed trial 		108 people with mild to moderate acne
In review [16] 		Mean reduction in inflammatory lesion count (change from baseline) 8 weeks
From 8.52 to 2.38 with clindamycin
From 7.10 to 6.24 with placebo
No direct comparison of topical clindamycin v placebo
RCT designed to compare topical clindamycin v oral tetracycline
[25]
RCT		 40 people with mild to moderate acne
In review [16] 		Percentage reduction in papules 12 weeks
22% with clindamycin phosphate 1% twice daily
19% with placebo
Reported as not significant
P value not reported 		Not significant
[25]
RCT		 40 people with mild to moderate acne
In review [16] 		Percentage reduction in pustules 12 weeks
12% with clindamycin phosphate 1% twice daily
22% with placebo
Reported as not significant
P value not reported 		Not significant
[26]
RCT
3-armed trial 		367 people with moderate to severe acne
In review [16] 		Mean number of papules per person 8 weeks
8.3 with clindamycin
11.7 with placebo
P <0.05 for clindamycin v placebo 		Effect size not calculated Clindamycin
[26]
RCT
3-armed trial 		367 people with moderate to severe acne
In review [16] 		Mean number of pustules per person 8 weeks
1.1 with clindamycin
2.7 with placebo
P <0.05 for clindamycin v placebo 		Effect size not calculated Clindamycin
[27]
RCT
3-armed trial 		413 people with moderate acne
In review [16] [17] 		Percentage reduction in papules 8 weeks
56% with clindamycin phosphate 1% twice daily
42% with vehicle
P = 0.05 or less for clindamycin phosphate v vehicle 		Effect size not calculated Clindamycin
[27]
RCT
3-armed trial 		413 people with moderate acne
In review [16] [17] 		Percentage reduction in papules 8 weeks
64% with clindamycin hydrochloride 1% twice daily
42% with vehicle
P = 0.05 or less for clindamycin hydrochloride v vehicle 		Effect size not calculated Clindamycin
[27]
RCT
3-armed trial 		413 people with moderate acne
In review [16] [17] 		Percentage reduction in pustules 8 weeks
72% with clindamycin phosphate 1% twice daily
43% with vehicle
P = 0.05 or less for clindamycin phosphate v vehicle 		Effect size not calculated Clindamycin
[27]
RCT
3-armed trial 		413 people with moderate acne
In review [16] [17] 		Percentage reduction in pustules 8 weeks
62% with clindamycin hydrochloride 1% twice daily
43% with vehicle
Significance not assessed
[28]
RCT		 46 people with moderate to severe acne
In review [16] [17] 		Mean number of pustules per person 12 weeks
1.5 with clindamycin phosphate 1% twice daily
3.1 with placebo
P = 0.02 		Effect size not calculated Clindamycin
[28]
RCT		 46 people with moderate to severe acne
In review [16] [17] 		Mean number of papules per person 12 weeks
6.8 with clindamycin phosphate 1% twice daily
10.6 with placebo
P = 0.16 		Not significant
Open in a new tab

Patient perception of improvement

Topical clindamycin 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[23]
RCT
3-armed trial 		108 people with mild to moderate acne
In review [16] 		Proportion of people whose acne had "markedly improved" or "improved" from baseline 8 weeks
72% with clindamycin
3% with placebo
No direct comparison of topical clindamycin v placebo
RCT designed to compare topical clindamycin v oral clindamycin
[26]
RCT
3-armed trial 		367 people with moderate to severe acne
In review [16] 		Proportion of people who thought their acne was "markedly improved" or "improved" 8 weeks
88% with clindamycin
57% with placebo
P <0.05 for clindamycin v placebo 		Effect size not calculated Clindamycin
[27]
RCT
3-armed trial 		413 people with moderate acne, 8 weeks
In review [16] [17] 		Proportion of people who rated acne "markedly improved" or "improved" compared with vehicle 8 weeks
77% with clindamycin phosphate 1% twice daily
56% with vehicle
Difference for clindamycin phosphate versus placebo reported as significant
P value not reported 		Effect size not calculated Clindamycin
[27]
RCT
3-armed trial 		413 people with moderate acne, 8 weeks
In review [16] [17] 		Proportion of people who rated acne "markedly improved" or "improved" compared with vehicle 8 weeks
77% with clindamycin hydrochloride 1% twice daily
56% with vehicle
Difference for clindamycin hydrochloride versus placebo reported as significant
P value not reported 		Effect size not calculated Clindamycin
Open in a new tab

No data from the following reference on this outcome.[18] [25] [28]

Psychological distress

No data from the following reference on this outcome.[18] [23] [25] [26] [27] [28]

Quality of life

No data from the following reference on this outcome.[18] [23] [25] [26] [27] [28]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[18]
RCT
4-armed trial 		393 people with moderate acne
In review [16] [17] 		Adverse effects (erythema, dryness, peeling, burning, or pruritus) 11 weeks
with clindamycin 1% 4 times daily
with vehicle 4 times daily
Reported as not significant
P value not reported 		Not significant
[23]
RCT
3-armed trial 		108 people with mild to moderate acne
In review [16] 		Adverse effects 8 weeks
with clindamycin
with placebo
[26]
RCT
3-armed trial 		367 people with moderate to severe acne
In review [16] 		Adverse effects 8 weeks
with clindamycin
with placebo
[27]
RCT
3-armed trial 		413 people with moderate acne
In review [16] [17] 		Adverse effects 8 weeks
with clindamycin phosphate 1% twice daily
with clindamycin hydrochloride 1% twice daily
with vehicle
[28]
RCT		 46 people with moderate to severe acne
In review [16] [17] 		Adverse effects 12 weeks
with clindamycin phosphate 1% twice daily
with placebo
Open in a new tab

No data from the following reference on this outcome.[25]

Further information on studies

None.

Comment

The review[16] identified one open-label RCT, which did not meet Clinical Evidence inclusion criteria (135 people with moderate acne),[24]which found that clindamycin significantly reduced papules and pustules at 12 weeks compared with placebo. It found that clindamycin was associated with burning.

Studies of development of bacterial resistance to antibiotics suggest that topical application of antibiotics in acne may result in antibiotic resistance to Propionibacterium acnes.[7] [29] 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.[30] It found no significant change in the efficacy of 12 weeks' treatment with topical clindamycin 1.0% to 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).[30]

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.[31]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Erythromycin (topical)

Summary

Topical antibiotics, such as erythromycin, reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions.

Antimicrobial resistance can develop with use of topical or oral antibiotics, and their efficacy may decrease over time.

Benefits and harms

Topical erythromycin versus placebo:

We found two systematic reviews.[16] [17] The first review (search date 1999, 8 RCTs,[32] [33] [34] [35] [36] [37] [38] [39] 347 people with mild to moderate acne, 555 people with moderate to severe acne) compared topical erythromycin 1% to 2% versus vehicle for 4 to 12 weeks.[16] The review did not perform a meta-analysis owing to heterogeneity among the trials in outcomes assessed. The second systematic review (search date 2004),[17] which had more stringent inclusion criteria, included 3 RCTs, all of which were identified by the earlier review.[33] [35] [36]

Acne severity

Topical erythromycin compared with placebo Topical erythromycin may be more effective at reducing inflammatory lesions at 8 to 12 weeks in people with mild to severe acne (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[32]
RCT
4-armed trial 		160 people with mild to moderate acne
In review [16] 		Mean percentage change in total lesion count from baseline 12 weeks
–25% (95% CI –39.04% to –11.44%) with erythromycin 2%
–11% (95% CI –24.29% to +2.65%) with placebo
No direct comparison between erythromycin alone and placebo
[33]
RCT		 225 people with mild to moderate acne
In review [16] [17] 		Reduction in Cook's severity score 12 weeks
–40 with erythromycin 2% twice daily
–22 with vehicle
Reported as not significant
P value not reported 		Not significant
[35]
RCT		 175 people with moderate to severe acne unresponsive to oral tetracycline, topical benzoyl peroxide, or topical tretinoin
In review [16] [17] 		Proportion of people rated by physician as having "excellent" or "good" response 12 weeks
62% with erythromycin 2%
27% with vehicle
P <0.001 		Effect size not calculated Erythromycin
[36]
RCT		 253 people with moderate to severe acne
In review [16] [17] 		Total lesion count 12 weeks
with erythromycin 1.5% twice daily
with vehicle
Absolute results reported graphically
P = 0.01 		Effect size not calculated Erythromycin
[37]
RCT		 26 people with moderate to severe acne
In review [16] 		Proportion of people rated by physician as having "excellent" or "good" response 12 weeks
92% with erythromycin 1.5% twice daily
20% with vehicle
P = 0.005 		Effect size not calculated Erythromycin
Non-inflammatory lesions
[32]
RCT
4-armed trial 		160 people with mild to moderate acne
In review [16] 		Mean percentage change in non-inflammatory lesions from baseline 12 weeks
–17% (95% CI –38.07% to +4.63%) with erythromycin 2%
–7% (95% CI –28.31% to +14.16%) with placebo
No direct comparison between erythromycin alone and placebo
[37]
RCT		 26 people with moderate to severe acne
In review [16] 		Comedones 12 weeks
with erythromycin
with vehicle
Absolute results not reported
[34]
RCT		 187 people with mild to moderate acne
In review [16] 		Mean reduction in open comedones per person 8 weeks
–7.5 with erythromycin 2% twice daily
–4.6 with vehicle
P <0.01 		Effect size not calculated Erythromycin
[34]
RCT		 187 people with mild to moderate acne
In review [16] 		Mean reduction in closed comedones per person 8 weeks
–1.7 with erythromycin 2% twice daily
–2.3 with vehicle
Reported as not significant
P value not reported 		Not significant
[36]
RCT		 253 people with moderate to severe acne
In review [16] [17] 		Open or closed comedones 12 weeks
with erythromycin 1.5% twice daily
with vehicle
Absolute results reported graphically
Reported as not significant
P value not reported 		Not significant
Inflammatory lesions
[32]
RCT
4-armed trial 		160 people with mild to moderate acne
In review [16] 		Mean percentage change in inflammatory lesions from baseline 12 weeks
–28% (95% CI –41.29% to –14.14%) with erythromycin 2%
–10% (95% CI –24.51% to +5.36%) with placebo
No direct comparison between erythromycin alone and placebo
[33]
RCT		 225 people with mild to moderate acne
In review [16] [17] 		Percentage reduction in inflammatory lesions 12 weeks
46% with erythromycin 2% twice daily
19% with vehicle
P = 0.01 		Effect size not calculated Erythromycin
[34]
RCT		 187 people with mild to moderate acne
In review [16] 		Mean reduction in papules per person 8 weeks
–6.2 with erythromycin 2% twice daily
–4.3 with vehicle
P <0.01 		Effect size not calculated Erythromycin
[34]
RCT		 187 people with mild to moderate acne
In review [16] 		Mean reduction in pustules per person 8 weeks
–1.7 with erythromycin 2% twice daily
–1.2 with vehicle
Reported as not significant
P value not reported 		Not significant
[35]
RCT		 175 people with moderate to severe acne unresponsive to oral tetracycline, topical benzoyl peroxide, or topical tretinoin
In review [16] [17] 		Total inflammatory lesion count 12 weeks
856 with erythromycin 2%
1338 with vehicle
P <0.01 		Effect size not calculated Erythromycin
[36]
RCT		 253 people with moderate to severe acne
In review [16] [17] 		Papules and pustules 12 weeks
with erythromycin 1.5% twice daily
with vehicle
Absolute results reported graphically
P <0.025 		Effect size not calculated Erythromycin
[37]
RCT		 26 people with moderate to severe acne
In review [16] 		Proportion of people who had more than 50% reduction in papules 12 weeks
11/12 (92%) with erythromycin
4/10 (40%) with vehicle
P = 0.01 		Effect size not calculated Erythromycin
[27]
RCT		 28 people with moderate to severe acne
In review [16] 		Reduction in inflammatory lesions 4 to 8 weeks
with erythromycin 1% twice daily
with vehicle
Significance not assessed
[39]
RCT		 73 people with moderate to severe acne
In review [16] 		Proportion of people who had more than 50% reduction in inflammatory lesions 12 weeks
30% with erythromycin 2% twice daily
20% with vehicle
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Patient perception of improvement

Topical erythromycin 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[32]
RCT
4-armed trial 		160 people with mild to moderate acne
In review [16] 		Proportion of people who perceived that their acne had improved from baseline 12 weeks
58% with erythromycin 2%
53% with placebo
Significance not assessed
Open in a new tab

Psychological distress

No data from the following reference on this outcome.[32] [33] [34] [35] [36] [37] [38] [39]

Quality of life

No data from the following reference on this outcome.[32] [33] [34] [35] [36] [37] [38] [39]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[35]
RCT		 175 people with moderate to severe acne unresponsive to oral tetracycline, topical benzoyl peroxide, or topical tretinoin
In review [16] [17] 		Proportion of people with one or more adverse effects, including redness, scaling, dryness, and pruritus 12 weeks
17/90 (19%) with erythromycin 2% twice daily
21/85 (25%) with vehicle
Significance not assessed
[33]
RCT		 225 people with mild to moderate acne
In review [16] [17] 		Erythema 12 weeks
with erythromycin 2% twice daily
with vehicle
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[33]
RCT		 225 people with mild to moderate acne
In review [16] [17] 		Peeling 12 weeks
with erythromycin 2% twice daily
with vehicle
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[34]
RCT		 187 people with mild to moderate acne
In review [16] 		Adverse effects 8 weeks
with erythromycin 2% twice daily
with vehicle
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[36]
RCT		 253 people with moderate to severe acne
In review [16] [17] 		Number of people with one or more adverse effect 12 weeks
26 with erythromycin 1.5% twice daily
26 with vehicle
Absolute results reported graphically
[37]
RCT		 26 people with moderate to severe acne
In review [16] 		Adverse effects 12 weeks
with erythromycin
with vehicle
Open in a new tab

No data from the following reference on this outcome.[32] [27] [39]

Further information on studies

None.

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.[7] [29] One systematic review (search date 2003) analysed the efficacy of topical antibiotics in clinical trials (randomised and non-randomised) conducted between 1966 to 2003 using linear regression.[30] It found that the efficacy of 12 weeks' treatment with topical erythromycin 1.5% to 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

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Tretinoin (topical)

Summary

Topical preparations of tretinoin may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.

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 and harms

Topical tretinoin versus placebo:

We found one systematic review[16] (search date 1999, 5 RCTs,[40] [41] [42] [43] [44] 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 to 12 weeks. The review did not perform a meta-analysis because of heterogeneity among the RCTs in methods of outcome assessment.[16]

Acne severity

Topical tretinoin compared with placebo Topical tretinoin may be more effective at 8 to 12 weeks at reducing the number of inflammatory and non-inflammatory lesions in people with mild to severe acne (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Total lesion count
[43]
RCT
3-armed trial 		215 people with mild to moderate acne
In review [16] 		Percentage reduction in total lesion count 12 weeks
40% with tretinoin 0.025%
24% with vehicle
P <0.05 		Effect size not calculated Tretinoin
[44]
RCT
3-armed trial 		271 people with mild to moderate acne
In review [16] 		Percentage reduction in total lesion count 12 weeks
39% with tretinoin 0.025%
28% with vehicle
P <0.05 		Effect size not calculated Tretinoin
Non-inflammatory lesions
[40]
RCT
3-armed trial 		256 people with mild to moderate acne
In review [16] 		Comedones (measured by total score) 7 to 8 weeks
89 with tretinoin 0.05%
131 with vehicle
P <0.01 for tretinoin 0.05% v vehicle
The RCT had weak methods for assessing outcomes 		Effect size not calculated Tretinoin
[40]
RCT
3-armed trial 		256 people with mild to moderate acne
In review [16] 		Comedones (measured by total score) 7 to 8 weeks
94 with tretinoin 0.02%
131 with vehicle
P <0.01 for tretinoin 0.02% v vehicle
The RCT had weak methods for assessing outcomes 		Effect size not calculated Tretinoin
[41]
RCT
3-armed trial 		257 people with moderate to severe acne
In review [16] 		Number of non-inflammatory lesions 8 weeks
89 with tretinoin 0.05% twice daily
131 with vehicle twice daily
P = 0.01 		Effect size not calculated Tretinoin
[43]
RCT
3-armed trial 		215 people with mild to moderate acne
In review [16] 		Percentage reduction in non-inflammatory lesions 12 weeks
39% with tretinoin 0.025%
19% with vehicle
P <0.05 		Effect size not calculated Tretinoin
[44]
RCT
3-armed trial 		271 people with mild to moderate acne
In review [16] 		Percentage reduction in non-inflammatory lesions 12 weeks
49% with tretinoin 0.025%
31% with vehicle
P <0.05 		Effect size not calculated Tretinoin
Inflammatory lesions
[40]
RCT
3-armed trial 		256 people with mild to moderate acne
In review [16] 		Number of papules (measured by total score) 7 to 8 weeks
61 with tretinoin 0.05%
83 with vehicle
P <0.05 for tretinoin 0.05% v vehicle
The RCT had weak methods for assessing outcomes 		Effect size not calculated Tretinoin 0.05%
[40]
RCT
3-armed trial 		256 people with mild to moderate acne
In review [16] 		Number of papules (measured by total score) 7 to 8 weeks
76 with tretinoin 0.02%
83 with vehicle
Reported as not significant for tretinoin 0.02% v vehicle
P value not reported
The RCT had weak methods for assessing outcomes 		Not significant
[41]
RCT
3-armed trial 		257 people with moderate to severe acne
In review [16] 		Number of papules 8 weeks
61 with tretinoin 0.05% twice daily
83 with vehicle twice daily
P = 0.05 		Effect size not calculated Tretinoin
[43]
RCT
3-armed trial 		215 people with mild to moderate acne
In review [16] 		Percentage reduction in papules 12 weeks
42% with tretinoin 0.025%
19% with vehicle
P <0.05 		Effect size not calculated Tretinoin
[44]
RCT
3-armed trial 		271 people with mild to moderate acne
In review [16] 		Percentage reduction in papules 12 weeks
49% with tretinoin 0.025%
28% with vehicle
P <0.05 		Effect size not calculated Tretinoin
Open in a new tab

No data from the following reference on this outcome.[42]

Patient perception of improvement

Topical tretinoin 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[42]
RCT
3-armed trial 		60 people with mild to moderate acne
In review [16] 		Patient perception of severity on a visual analogue scale (VAS) 12 weeks
18 with tretinoin 0.05% or 0.025%
39 with vehicle
Significance not assessed
The RCT had weak methods for assessing outcomes
Open in a new tab

Psychological distress

No data from the following reference on this outcome.[40] [41] [42] [43] [44]

Quality of life

No data from the following reference on this outcome.[40] [41] [42] [43] [44]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Erythema
[40]
RCT
3-armed trial 		256 people with mild to moderate acne
In review [16] 		Erythema, peeling, or both 1 to 3 weeks
86% with tretinoin 0.05%
40% with vehicle
P <0.01 for tretinoin 0.05% v vehicle 		Effect size not calculated Vehicle
[40]
RCT
3-armed trial 		256 people with mild to moderate acne
In review [16] 		Erythema, peeling, or both 1 to 3 weeks
81% with tretinoin 0.02%
40% with vehicle
P <0.01 for tretinoin 0.02% v vehicle 		Effect size not calculated Vehicle
[41]
RCT
3-armed trial 		257 people with moderate to severe acne
In review [16] 		Erythema and desquamation 8 weeks
76/84 (90%) with tretinoin 0.05% twice daily
16/84 (19%) with vehicle twice daily
P <0.005 		Effect size not calculated Vehicle
[43]
RCT
3-armed trial 		215 people with mild to moderate acne
In review [16] 		Proportion of people with erythema 12 weeks
20% with tretinoin 0.025%
9% with vehicle
P <0.005 		Effect size not calculated Vehicle
[44]
RCT
3-armed trial 		271 people with mild to moderate acne
In review [16] 		Proportion of people with erythema 12 weeks
8% with tretinoin 0.025%
3% with vehicle
P <0.005 		Effect size not calculated Vehicle
Burning
[41]
RCT
3-armed trial 		257 people with moderate to severe acne
In review [16] 		Burning 8 weeks
69/84 (82%) with tretinoin 0.05% twice daily
23/84 (27%) with vehicle twice daily
P <0.005 		Effect size not calculated Vehicle
[44]
RCT
3-armed trial 		271 people with mild to moderate acne
In review [16] 		Proportion of people with burning 12 weeks
8% with tretinoin 0.025%
3% with vehicle
P <0.005 		Effect size not calculated Vehicle
Itching
[41]
RCT
3-armed trial 		257 people with moderate to severe acne
In review [16] 		Pruritus 8 weeks
62/84 (74%) with tretinoin 0.05% twice daily
26/84 (31%) with vehicle twice daily
P <0.005 		Effect size not calculated Vehicle
[44]
RCT
3-armed trial 		271 people with mild to moderate acne
In review [16] 		Proportion of people with itching 12 weeks
15% with tretinoin 0.025%
6% with vehicle
P <0.005 		Effect size not calculated Vehicle
Peeling
[43]
RCT
3-armed trial 		215 people with mild to moderate acne
In review [16] 		Proportion of people with peeling 12 weeks
21% with tretinoin 0.025%
3% with vehicle
P <0.005 		Effect size not calculated Vehicle
Dryness
[43]
RCT
3-armed trial 		215 people with mild to moderate acne
In review [16] 		Proportion of people with dryness 12 weeks
21% with tretinoin 0.025%
8% with vehicle
P <0.005 		Effect size not calculated Vehicle
Skin tightness
[44]
RCT
3-armed trial 		271 people with mild to moderate acne
In review [16] 		Proportion of people with skin tightness 12 weeks
22% with tretinoin 0.025%
15% with vehicle
P <0.005 		Effect size not calculated Vehicle
Open in a new tab

Further information on studies

None.

Comment

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.[45] 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.[7]

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.[7]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Adapalene (topical)

Summary

Topical adapalene may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.

Topical retinoids are not recommended in women of childbearing age not taking adequate contraceptive precautions, or during pregnancy.

Benefits and harms

Topical adapalene versus placebo:

We found one systematic review (search date 2004; 1 RCT)[17] and 3 subsequent RCTs.[46] [47] [48]

Acne severity

Topical adapalene compared with placebo Topical adapalene seems more effective at reducing the number of total lesions and 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Total lesion count
[49]
RCT		 237 people with moderate acne
In review [17] 		Mean reduction in total lesion count 12 weeks
40% with adapalene 0.1% daily
20% with vehicle
P <0.01 		Effect size not calculated Adapalene
[46]
RCT		 253 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) Total lesion count 16 weeks
with adapalene gel 0.1% daily
with placebo daily
Absolute results reported graphically
P = 0.005 		Effect size not calculated Adapalene
[46]
RCT		 253 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) Maintenance of at least 50% of the improvement in total lesion count 16 weeks
75% with adapalene gel 0.1% daily
54% with placebo daily
Absolute numbers not reported
P <0.001 		Effect size not calculated Adapalene
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Mean reduction in total lesion count 12 weeks
48% with adapalene gel 0.1% daily
36% with vehicle daily
Absolute numbers not reported
P <0.001 for adapalene 0.1% v vehicle 		Effect size not calculated Adapalene
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Success rate 12 weeks
17% with adapalene gel 0.1% daily
10% with vehicle daily
Absolute numbers not reported
P = 0.02 for adapalene 0.1% v vehicle 		Effect size not calculated Adapalene
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Mean reduction in total lesion count 12 weeks
56% with adapalene gel 0.3% daily
36% with vehicle daily
Absolute numbers not reported
P value not reported for adapalene 0.3% v vehicle
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Success rate 12 weeks
23% with adapalene gel 0.3% daily
10% with vehicle daily
Absolute numbers not reported
P value not reported for adapalene 0.3% v vehicle
[48]
RCT		 200 Japanese people with at least 30 acne lesions Median reduction in total lesion count from baseline 12 weeks
63.2% with adapalene gel 0.1% daily
36.9% with placebo (vehicle gel) daily
Absolute numbers not reported
P <0.0001 		Effect size not calculated Adapalene
Non-inflammatory lesions
[49]
RCT		 237 people with moderate acne
In review [17] 		Mean reduction in non-inflammatory lesion count
38% with adapalene 0.1% daily
20% with vehicle
P <0.01 		Effect size not calculated Adapalene
[46]
RCT		 253 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) Non-inflammatory lesion count 16 weeks
with adapalene gel 0.1% daily
with placebo daily
Absolute results reported graphically
P = 0.02 		Effect size not calculated Adapalene
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Mean reduction in non-inflammatory lesions 12 weeks
43% with adapalene gel 0.1% daily
29% with vehicle daily
Absolute numbers not reported
P <0.001 for adapalene 0.1% v vehicle 		Effect size not calculated Adapalene
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Mean reduction in non-inflammatory lesion count 12 weeks
52% with adapalene gel 0.3% daily
29% with vehicle daily
Absolute numbers not reported
P value not reported for adapalene 0.3% v vehicle
[48]
RCT		 200 Japanese people with at least 30 acne lesions Median reduction in number of non-inflammatory lesions from baseline 12 weeks
64.6% with adapalene gel 0.1% daily
38.1% with placebo (vehicle gel) daily
Absolute numbers not reported
P <0.0001 		Effect size not calculated Adapalene
Inflammatory lesions
[49]
RCT		 237 people with moderate acne
In review [17] 		Mean reduction in inflammatory lesion count
35% with adapalene 0.1% daily
19% with vehicle
P <0.01 		Effect size not calculated Adapalene
[46]
RCT		 253 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) Inflammatory lesion count 16 weeks
with adapalene gel 0.1% daily
with placebo daily
Absolute results reported graphically
P = 0.01 		Effect size not calculated Adapalene
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Mean reduction in inflammatory lesions 12 weeks
58% with adapalene gel 0.1% daily
47% with vehicle daily
Absolute numbers not reported
P <0.001 for adapalene 0.1% v vehicle 		Effect size not calculated Adapalene
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Mean reduction in inflammatory lesions 12 weeks
63% with adapalene gel 0.3% daily
47% with vehicle daily
Absolute numbers not reported
P value not reported for adapalene 0.1% v vehicle
[48]
RCT		 200 Japanese people with at least 30 acne lesions Median reduction in number of inflammatory lesions from baseline 12 weeks
63.7% with adapalene gel 0.1% daily
45.8% with placebo (vehicle gel) daily
Absolute numbers not reported
P = 0.001 		Effect size not calculated Adapalene
Open in a new tab

Patient perception of improvement

Topical adapalene compared with placebo We don't know whether topical adapalene is more effective at improving patient satisfaction in people with acne (at least 30 lesions) at 12 weeks, but topical adapalene may be more effective at increasing patient satisfaction with maintenance treatment at 12 weeks in people with severe acne who have responded to previous treatment with oral doxycycline with or without adapalene gel (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[46]
RCT		 253 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) Proportion reporting being "satisfied" or "very satisfied" with maintenance treatment 12 weeks
76% with adapalene gel 0.1% daily
65% with placebo daily
Absolute numbers not reported
P = 0.01 		Effect size not calculated Adapalene
[48]
RCT		 200 Japanese people with at least 30 acne lesions Proportion of people with greater than 75% satisfaction with treatment effect on a visual analogue scale (VAS) 12 weeks
60% with adapalene gel 0.1% daily
42% with placebo (vehicle gel) daily
Absolute numbers not reported
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Quality of life

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[49]
RCT		 237 people with moderate acne
In review [17] 		Quality of life 12 weeks
with adapalene 0.1% daily
with vehicle
Absolute results not reported
Open in a new tab

No data from the following reference on this outcome.[46] [47]

Psychological distress

No data from the following reference on this outcome.[46] [47] [49]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Skin adverse effects
[49]
RCT		 237 people with moderate acne
In review [17] 		Adverse effects (erythema, dryness, scaling, stinging/burning, and pruritus) 2 weeks
with adapalene 0.1% daily
with vehicle
P <0.01 		Effect size not calculated Vehicle
[49]
RCT		 237 people with moderate acne
In review [17] 		Adverse effects (erythema, dryness, scaling, stinging/burning) 12 weeks
with adapalene 0.1% daily
with vehicle
Reported as not significant
P value not reported 		Not significant
[46]
RCT		 253 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) Adverse effects (erythema, scaling, dryness, stinging, burning)
25% with adapalene gel 0.1% daily
23% with placebo daily
Absolute numbers not reported
Significance not assessed
[47]
RCT
3-armed trial 		653 people with mild to moderate acne vulgaris Adverse effects (dry skin and skin discomfort) 12 weeks
22% with adapalene gel 0.3% daily
12% with adapalene gel 0.1% daily
5% with vehicle daily
Absolute numbers not reported
Significance not assessed
[48]
RCT		 200 Japanese people with at least 30 acne lesions Adverse events related to study drugs 12 weeks
56/100 (56%) with adapalene gel 0.1% daily
8/99 (8%) with placebo (vehicle gel) daily
Open in a new tab

Further information on studies

None.

Comment

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.[45] 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.[7]

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.[7] Adapalene 0.3% is not available in the UK.

Substantive changes

Adapalene (topical) New evidence added.[48] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Azelaic acid (topical)

Summary

Topical azelaic acid reduces inflammatory and non-inflammatory lesions compared with placebo, but can cause itching, burning, stinging, and redness of the skin.

Topical azelaic acid has been associated with itching, stinging, burning, and erythema.

Benefits and harms

Azelaic acid versus placebo:

We found two systematic reviews, which compared topical azelaic acid 20% versus placebo.[16] [17] The first review (search date 1999)[16] identified two RCTs.[50] [51] The second review (search date 2004),[17] which had more stringent inclusion criteria than the earlier review, included one RCT[51] also identified by the earlier review.

Acne severity

Azelaic acid compared with placebo Topical azelaic acid may be more effective at 8 to 12 weeks at reducing the number of comedones and inflammatory lesions in people with moderate acne (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Total lesion count
[51]
RCT		 92 people with moderate acne
In review [16] [17] 		Proportion of people who had a physician rating of response to treatment of "excellent" or "good" 12 weeks
28/43 (65%) with azelaic acid
18/49 (37%) with placebo
P = 0.05 		Effect size not calculated Azelaic acid
Non-inflammatory lesions
[51]
RCT		 92 people with moderate acne
In review [16] [17] 		Percentage reduction in comedones
56% with azelaic acid
0% with placebo
P = 0.05 		Effect size not calculated Azelaic acid
[50]
RCT		 40 people, severity of acne unclear
In review [16] 		Percentage reduction in non-inflammatory lesions 8 weeks
50% with azelaic acid
25% with placebo
P = 0.027 		Effect size not calculated Azelaic acid
Inflammatory lesions
[51]
RCT		 92 people with moderate acne
In review [16] [17] 		Percentage reduction in inflammatory lesions
72% with azelaic acid
47% with vehicle
P = 0.05 		Effect size not calculated Azelaic acid
[50]
RCT		 40 people, severity of acne unclear
In review [16] 		Percentage reduction in inflammatory lesions 8 weeks
50% with azelaic acid
12% with placebo
P = 0.001 		Effect size not calculated Azelaic acid
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Patient perception of improvement

No data from the following reference on this outcome.[50] [51]

Psychological distress

No data from the following reference on this outcome.[50] [51]

Quality of life

No data from the following reference on this outcome.[50] [51]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[51]
RCT		 92 people with moderate acne
In review [16] [17] 		Proportion of people with burning
4/43 (9%) with azelaic acid
1/49 (2%) with vehicle
Significance not assessed
[51]
RCT		 92 people with moderate acne
In review [16] [17] 		Proportion of people with itching
2/43 (5%) with azelaic acid
0/49 (0%) with vehicle
Significance not assessed
[51]
RCT		 92 people with moderate acne
In review [16] [17] 		Proportion of people with erythema
2/43 (5%) with azelaic acid
1/49 (2%) with vehicle
Significance not assessed
[50]
RCT		 40 people, severity of acne unclear
In review [16] 		Itching and stinging 8 weeks
2/20 (10%) with azelaic acid
1/20 (5%) with placebo
Significance not assessed
Open in a new tab

Further information on studies

None.

Comment

One non-systematic review of RCTs and uncontrolled studies found that 0% to 5% of people taking azelaic acid had scaling, 5% to 23% had burning, and 13% to 29% had itching.[52]

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

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Erythromycin plus zinc (topical)

Summary

Topical antibiotics, such as erythromycin with zinc, reduce inflammatory lesions compared with placebo, but have not been shown to reduce non-inflammatory lesions.

Benefits and harms

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.[16] The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed.

Acne severity

Topical erythromycin plus zinc 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 to 12 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[53]
RCT
4-armed trial 		149 men, severity of acne unclear
In review [16] 		Reduction in severity measured by Cook's acne grading scale 10 weeks
46% with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
7% with topical vehicle plus oral placebo
P <0.001 for topical erythromycin plus zinc liquid plus oral placebo v topical vehicle plus oral placebo 		Effect size not calculated Erythromycin plus zinc
[53]
RCT
4-armed trial 		149 men, severity of acne unclear
In review [16] 		Reduction in severity measured by Cook's acne grading scale 10 weeks
33% with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
7% with topical vehicle plus oral placebo
P <0.01 for topical erythromycin plus zinc gel plus oral placebo v topical vehicle plus oral placebo 		Effect size not calculated Erythromycin plus zinc
Non-inflammatory lesions
[54]
RCT		 73 women with Cook's acne grade score 3 or more
In review [16] 		Reduction in non-inflammatory lesions 12 weeks
61% with topical erythromycin plus zinc acetate
48% with vehicle
P <0.01 		Effect size not calculated Erythromycin plus zinc
Inflammatory lesions
[53]
RCT
4-armed trial 		149 men, severity of acne unclear
In review [16] 		Reduction in papules measured by Cook's acne grading scale 10 weeks
58% with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
25% with topical vehicle plus oral placebo
P <0.001 for topical erythromycin plus zinc liquid plus oral placebo v topical vehicle plus oral placebo 		Effect size not calculated Erythromycin plus zinc
[53]
RCT
4-armed trial 		149 men, severity of acne unclear
In review [16] 		Reduction in papules measured by Cook's acne grading scale 10 weeks
45% with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
25% with topical vehicle plus oral placebo
P <0.05 for topical erythromycin plus zinc gel plus oral placebo v topical vehicle plus oral placebo 		Effect size not calculated Erythromycin plus zinc
[53]
RCT
4-armed trial 		149 men, severity of acne unclear
In review [16] 		Reduction in pustules measured by Cook's acne grading scale 10 weeks
with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
with topical vehicle plus oral placebo
Absolute results not reported
Reported as not significant for topical erythromycin plus zinc liquid plus oral placebo v topical vehicle plus oral placebo
P value not reported 		Not significant
[53]
RCT
4-armed trial 		149 men, severity of acne unclear
In review [16] 		Reduction in pustules measured by Cook's acne grading scale 10 weeks
with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
with topical vehicle plus oral placebo
Absolute results not reported
Reported as not significant for topical erythromycin plus zinc gel plus oral placebo v topical vehicle plus oral placebo
P value not reported 		Not significant
[54]
RCT		 73 women with Cook's acne grade score 3 or more
In review [16] 		Reduction in inflammatory lesions 12 weeks
73% with topical erythromycin (4%) plus zinc acetate (1.2%) twice daily
46% with vehicle
P <0.01 		Effect size not calculated Erythromycin plus zinc
Open in a new tab

Patient perception of improvement

No data from the following reference on this outcome.[53] [54]

Psychological distress

No data from the following reference on this outcome.[53] [54]

Quality of life

No data from the following reference on this outcome.[53] [54]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[53]
RCT
4-armed trial 		149 men, severity of acne unclear
In review [16] 		Adverse effects 10 weeks
with topical erythromycin (4%) plus zinc octoate (1.2%) liquid plus oral placebo
with topical erythromycin (4%) plus zinc acetate (1.2%) gel plus oral placebo
with topical vehicle plus oral placebo
[54]
RCT		 73 women with Cook's acne grade score 3 or more
In review [16] 		Adverse effects 12 weeks
with topical erythromycin plus zinc acetate
with vehicle
Open in a new tab

Further information on studies

None.

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.[7] [29] One systematic review (search date 2003) has found evidence that the efficacy of topical erythromycin 1.5% to 2% has decreased over the period 1966 to 2003, which may be as a result of increasing bacterial resistance (see comment on topical erythromycin).[30]

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

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Isotretinoin (topical)

Summary

Topical preparations of isotretinoin may reduce inflammatory and non-inflammatory lesions, but can also cause redness, burning, dryness, and soreness of the skin.

Topical isotretinoin has been associated with severe erythema, dryness, soreness, and burning.

Topical retinoids are not recommended in women of childbearing age who are not taking adequate contraceptive precautions, or during pregnancy.

Benefits and harms

Topical isotretinoin versus placebo:

We found one systematic review[16] (search date 1999, 3 RCTs,[20] [55] [56] 472 people with mild to moderate acne) and one subsequent RCT[32] comparing isotretinoin versus placebo (vehicle). The review did not perform a meta-analysis because of heterogeneity among the trials in methods of outcome assessment.[16]

Acne severity

Topical isotretinoin 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[55]
RCT		 313 people with moderate acne
In review [16] 		Mean reduction in severity scores
40% with isotretinoin
20% with vehicle
Reported as significant
P value not reported 		Effect size not calculated Isotretinoin
[20]
RCT
3-armed trial 		77 people with mild to moderate acne
In review [16] 		Mean change in severity scores 12 weeks
0 with isotretinoin
1 with vehicle
P <0.05 for isotretinoin v vehicle 		Effect size not calculated Isotretinoin
[32]
RCT
4-armed trial 		160 people with mild to moderate acne Mean change in total lesion count from baseline 12 weeks
–21.52% (95% CI –32.44% to –10.60%) with isotretinoin
–10.82% (95% CI –24.29% to +2.65% with vehicle
Significance of between-group difference not assessed
Non-inflammatory lesions
[55]
RCT		 313 people with moderate acne
In review [16] 		Mean reduction in non-inflammatory lesions
46% with isotretinoin
14% with vehicle
Reported as significant
P value not reported 		Effect size not calculated Isotretinoin
[20]
RCT
3-armed trial 		77 people with mild to moderate acne
In review [16] 		Mean change in number of non-inflammatory lesions 12 weeks
–47% with isotretinoin
+6% with vehicle
P = 0.01 for isotretinoin v vehicle 		Effect size not calculated Isotretinoin
[32]
RCT
4-armed trial 		160 people with mild to moderate acne Mean change in non-inflammatory lesion count from baseline 12 weeks
–18.49 (95% CI –35.5 to –1.63) with isotretinoin
–7.07 (95% CI –28.31 to +14.16) with vehicle
Significance of between-group difference not assessed
Inflammatory lesions
[55]
RCT		 313 people with moderate acne
In review [16] 		Mean reduction in inflammatory lesions
55% with isotretinoin
25% with vehicle
Reported as significant
P value not reported 		Effect size not calculated Isotretinoin
[20]
RCT
3-armed trial 		77 people with mild to moderate acne
In review [16] 		Mean change in number of inflammatory lesions 12 weeks
–33% with isotretinoin
+9% with vehicle
P = 0.01 for isotretinoin v vehicle 		Effect size not calculated Isotretinoin
[56]
RCT
3-armed trial 		82 people with mild to moderate acne
In review [16] 		Mean change in papules from baseline 12 weeks
–7.6 with isotretinoin 0.05%
–13.3 with isotretinoin 0.1%
–7.3 with placebo
Significance of differences between groups not assessed
[56]
RCT
3-armed trial 		82 people with mild to moderate acne
In review [16] 		Mean change in whiteheads from baseline 12 weeks
–9.6 with isotretinoin 0.05%
–9.4 with isotretinoin 0.1%
–2.6 with placebo
Significance of differences between groups not assessed
[32]
RCT
4-armed trial 		160 people with mild to moderate acne Mean change in inflammatory lesion count from baseline 12 weeks
–15.66 (95% CI –27.71 to –3.62) with isotretinoin
–9.58 (95% CI –24.51 to +5.36) with vehicle
Significance of differences between groups not assessed
Open in a new tab

Patient perception of improvement

Topical isotretinoin 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[32]
RCT
4-armed trial 		160 people with mild to moderate acne Proportion of people who perceived that their acne had improved from baseline 12 weeks
66% with isotretinoin
53% with vehicle
Absolute numbers not reported
Significance not assessed
Open in a new tab

Psychological distress

No data from the following reference on this outcome.[20] [55] [56] [32]

Quality of life

No data from the following reference on this outcome.[20] [55] [56] [32]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Skin adverse effects
[55]
RCT		 313 people with moderate acne
In review [16] 		Proportion of people with peeling
71% with isotretinoin
51% with vehicle
Absolute numbers not reported
Significance not assessed
[55]
RCT		 313 people with moderate acne
In review [16] 		Proportion of people with erythema
76% with isotretinoin
62% with vehicle
Absolute numbers not reported
Significance not assessed
[20]
RCT
3-armed trial 		77 people with mild to moderate acne
In review [16] 		Adverse effects 12 weeks
with isotretinoin
with vehicle
[56]
RCT
3-armed trial 		82 people with mild to moderate acne
In review [16] 		Peeling 12 weeks
with isotretinoin 0.05%
with isotretinoin 0.1%
with placebo
Absolute results not reported
P <0.01
Unclear whether P value is for separate comparisons of isotretinoin v placebo or combined analysis of both isotretinoin groups versus placebo
[32]
RCT
4-armed trial 		160 people with mild to moderate acne Overall tolerance 12 weeks
with isotretinoin
with vehicle
Reported as not significant
P value not reported
This RCT is likely to have been underpowered to detect a clinically important difference in adverse effects among treatments
Open in a new tab

Further information on studies

None.

Comment

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.[7]

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 who are not taking adequate contraceptive precautions.[7]

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Tetracycline (topical)

Summary

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.

Benefits and harms

Topical tetracycline versus placebo:

We found one systematic review (search date 1999, 4 RCTs, 355 people with moderate to severe acne).[16] The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed.

Acne severity

Topical tetracycline compared with placebo Topical tetracycline may be more effective at reducing severity of acne at 12 to 16 weeks in people with mild to moderate acne (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[57]
RCT
3-armed trial 		75 people
In review [16] 		Mean reduction in severity 12 weeks
1.43 with topical tetracycline 0.5% plus oral placebo
0.62 with topical plus oral placebo
P <0.05 		Effect size not calculated Tetracycline
[58]
RCT
3-armed trial 		60 male adolescents
In review [16] 		Proportion of people with improvement of at least 1 on a scale from 0 (least improvement) to 8 (most improvement)
14/19 (74%) with topical tetracycline plus oral placebo
6/17 (35%) with topical vehicle plus oral placebo
Significance not assessed
[59]
RCT
3-armed trial 		135 people aged 18 to 25 years with mild to moderate acne
In review [16] 		Acne severity 7, 10, and 12 weeks
with topical tetracycline 0.22% plus oral placebo
with topical vehicle plus oral placebo
Absolute results reported graphically
P <0.05 		Effect size not calculated Tetracycline
[60]
RCT		 85 people with mild to moderate acne
In review [16] 		Proportion of people who had improved acne on a scale from 0 to 8 16 weeks
29/31 (94%) with topical tetracycline 2.2%
13/23 (57%) with placebo
P = 0.035 		Effect size not calculated Tetracycline
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Patient perception of improvement

Topical tetracycline 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[60]
RCT		 85 people with mild to moderate acne
In review [16] 		Proportion of people who considered that their condition was better than before treatment
25/31 (81%) with topical tetracycline
18/24 (75%) with placebo
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[57] [58] [59]

Psychological distress

No data from the following reference on this outcome.[57] [58] [59] [60]

Quality of life

No data from the following reference on this outcome.[57] [58] [59] [60]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Skin discoloration
[57]
RCT
3-armed trial 		75 people
In review [16] 		Skin discoloration
with topical tetracycline 0.5% plus oral placebo
with topical plus oral placebo
[59]
RCT
3-armed trial 		135 people aged 18 to 25 years with mild to moderate acne
In review [16] 		Skin discoloration
with topical tetracycline 0.22% plus oral placebo
with topical vehicle plus oral placebo
Absolute results reported graphically
[60]
RCT		 85 people with mild to moderate acne
In review [16] 		Proportion of people with skin discoloration
17/43 (40%) with topical tetracycline 2.2%
4/42 (10%) with placebo
P <0.005 		Effect size not calculated Placebo
Open in a new tab

No data from the following reference on this outcome.[58]

Further information on studies

None.

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.[7] [29]

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

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Erythromycin (oral)

Summary

Oral erythromycin is considered useful for people with more severe acne, although we don't know for sure whether it is effective. Oral antibiotics can cause adverse effects such as contraceptive failure.

Benefits and harms

Oral erythromycin versus placebo:

We found two systematic reviews (search dates 2004;[17] not reported[61]), which identified no RCTs comparing oral erythromycin versus placebo. We found no subsequent RCTs.

Oral erythromycin versus oral doxycycline:

We found one RCT.[62]

Acne severity

Oral erythromycin compared with oral doxycycline We don’t know how oral erythromycin and oral doxycycline compare at reducing the number of papules and pustules at 6 weeks in people with moderate acne (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Inflammatory lesions
[62]
RCT		 56 people with moderate acne Mean number of papules and pustules 6 weeks
16 with oral doxycycline (100 mg daily for 2 weeks, then on alternate days for 4 weeks)
15 with oral erythromycin (500 mg twice daily for 2 weeks, then 250 mg twice daily for 4 weeks)
P >0.1 		Not significant
Open in a new tab

Patient perception of improvement

No data from the following reference on this outcome.[62]

Psychological distress

No data from the following reference on this outcome.[62]

Quality of life

No data from the following reference on this outcome.[62]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[62]
RCT		 56 people with moderate acne Adverse effects 6 weeks
with doxycycline (100 mg daily for 2 weeks, then on alternate days for 4 weeks)
with erythromycin (500 mg twice daily for 2 weeks, then 250 mg twice daily for 4 weeks)
Open in a new tab

Oral erythromycin versus oral tetracycline:

We found two systematic reviews.[16] [17] The first review (search date 1999)[16] identified 3 RCTs (300 people)[63] [64] [65], which compared oral erythromycin versus oral tetracycline in people with mild, moderate, or severe acne. The second review (search date 2004),[17] which had more stringent inclusion criteria, included one RCT identified by the first review.[64]

Acne severity

Oral erythromycin compared with oral tetracycline We don’t know how oral erythromycin and oral tetracycline compare 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[63]
RCT		 60 people with moderate to severe acne
In review [16] 		Proportion of people symptom-free 6 months
9/21 (43%) with erythromycin 200 to 400 mg daily
7/21 (33%) with tetracycline 250 to 400 mg daily
Reported as not significant
P value not reported 		Not significant
[65]
RCT		 40 people with mild, moderate, or severe acne
In review [16] 		Proportion with "good" or "very good" response as assessed by their physician 16 weeks
65% with erythromycin 250 mg twice daily
90% with tetracycline 250 mg twice daily
Significance not assessed
Non-inflammatory lesions
[64]
RCT		 200 people with moderate to severe acne
In review [16] [17] 		Percentage change in open comedones 12 weeks
–26% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–31% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)
Reported as not significant
P value not reported 		Not significant
[64]
RCT		 200 people with moderate to severe acne
In review [16] [17] 		Percentage change in closed comedones 12 weeks
–17% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–36% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)
Reported as not significant
P value not reported 		Not significant
Inflammatory lesions
[63]
RCT		 60 people with moderate to severe acne
In review [16] 		Inflammation score on face 6 months
1 with erythromycin 200 to 400 mg daily
1 with tetracycline 250 to 400 mg daily
Reported as not significant
P value not reported 		Not significant
[64]
RCT		 200 people with moderate to severe acne
In review [16] [17] 		Percentage change in papules 12 weeks
–60% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–62% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)
Reported as not significant
P value not reported 		Not significant
[64]
RCT		 200 people with moderate to severe acne
In review [16] [17] 		Percentage change in pustules 12 weeks
–73% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
–65% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Patient perception of improvement

Oral erythromycin 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[64]
RCT		 200 people with moderate to severe acne
In review [16] [17] 		Proportion of people who reported acne as "markedly improved" or "improved" 12 weeks
77% with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
89% with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)
Reported as not significant
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[63] [65]

Psychological distress

No data from the following reference on this outcome.[63] [64] [65]

Quality of life

No data from the following reference on this outcome.[63] [64] [65]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[63]
RCT		 60 people with moderate to severe acne
In review [16] 		Adverse effects
with erythromycin 200 to 400 mg daily
with tetracycline 250 to 400 mg daily
[64]
RCT		 200 people with moderate to severe acne
In review [16] [17] 		Number of people reporting an adverse effect
12 with erythromycin (333 mg 3 times daily for 4 weeks, then once daily for 8 weeks)
7 with tetracycline (500 mg twice daily for 4 weeks, then once daily for 8 weeks)
[65]
RCT		 40 people with mild, moderate, or severe acne
In review [16] 		Adverse effects
with erythromycin 250 mg twice daily
with tetracycline 250 mg twice daily
Open in a new tab

Further information on studies

None.

Comment

Propionibacterium acnes is 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.[66] 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

No new evidence

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Doxycycline (oral)

Summary

Oral doxycycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.

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 and harms

Oral doxycycline versus placebo:

We found 3 systematic reviews (search dates 1999,[16] 2004,[17] not reported[61]), which between them identified two RCTs comparing doxycycline versus placebo.[67] [68]

Acne severity

Oral doxycycline compared with placebo Oral doxycycline may be more effective than placebo at improving clinician's global assessment and inflammatory and non-inflammatory lesions after 6 months in people with moderate acne. However, we don’t know whether oral doxycycline is more effective at reducing the number of inflammatory lesions at 4 weeks in people with mild acne (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Total lesion count
[68]
RCT		 51 people with moderate acne
In review [17] [61] 		Clinician’s global assessment scores 6 months
4.4 with doxycycline 20 mg twice daily
5.1 with placebo
P = 0.03 		Effect size not calculated Doxycycline
Inflammatory lesions
[67]
RCT
Crossover design 		62 people with mild acne
In review [16] [61] 		Percentage change in the number of inflammatory lesions from baseline 4 weeks
–36% with oral doxycycline 100 mg daily
+12% with placebo
Significance of between-group difference not assessed
The RCT had large loss to follow-up (no further data reported)
[68]
RCT		 51 people with moderate acne
In review [17] [61] 		Reduction in inflammatory lesions 6 months
50% with doxycycline 20 mg twice daily
30% with placebo
P = 0.04 		Effect size not calculated Doxycycline
Non-inflammatory lesions
[68]
RCT		 51 people with moderate acne
In review [17] [61] 		Reduction in comedones 6 months
54% with doxycycline 20 mg twice daily
11% with placebo
P <0.01 		Effect size not calculated Doxycycline
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Patient perception of improvement

Oral doxycycline compared with placebo We don’t know whether oral doxycycline is more effective at improving patient perception of acne at 6 months in people with moderate acne (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[68]
RCT		 51 people with moderate acne
In review [17] [61] 		Patient perception of improvement 6 months
4.8 with doxycycline 20 mg twice daily
5.3 with placebo
Reported as not significant
P value and CI not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.[67]

Psychological distress

No data from the following reference on this outcome.[67] [68]

Quality of life

No data from the following reference on this outcome.[67] [68]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[67]
RCT
Crossover design 		62 people with mild acne
In review [16] [61] 		Adverse effects
with oral doxycycline 100 mg daily
with placebo
The RCT had large loss to follow-up (no further data reported)
The RCT may have been underpowered to detect a difference in adverse effects
Open in a new tab

No data from the following reference on this outcome.[68]

Oral doxycycline versus oral erythromycin:

See option on oral erythromycin.

Oral doxycycline versus oral minocycline:

See option on oral minocycline.

Oral doxycycline versus oral oxytetracycline:

We found one double-blind RCT.[69]

Acne severity

Oral doxycycline compared with oral oxytetracycline We don’t know how oral doxycycline and oral oxytetracycline compare at reducing the number of lesions at 8 weeks in people with moderate to severe acne (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[69]
RCT
Crossover design 		28 people with moderate to severe acne Mean number of lesions per person 8 weeks
62 with oral doxycycline (100 mg daily for 8 weeks)
32 with oral oxytetracycline (250 mg 3 times daily for 4 weeks then once daily for 4 weeks)
Reported as not significant
P value not reported 		Not significant
Open in a new tab

Patient perception of improvement

No data from the following reference on this outcome.[69]

Psychological distress

No data from the following reference on this outcome.[69]

Quality of life

No data from the following reference on this outcome.[69]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[69]
RCT
Crossover design 		28 people with moderate to severe acne Adverse effects
with oral doxycycline (100 mg daily for 8 weeks)
with oral oxytetracycline (250 mg 3 times daily for 4 weeks then once daily for 4 weeks)
Open in a new tab

Further information on studies

None.

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.[70] [71] Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

Doxycycline (oral) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Lymecycline (oral)

Summary

Oral lymecycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.

Oral antibiotics can cause adverse effects such as contraceptive failure.

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 and harms

Oral lymecycline versus placebo:

We found one systematic review (search date 1999), which identified no RCTs comparing oral lymecycline versus placebo.[16] We found no subsequent RCTs.

Oral lymecycline versus oral minocycline:

See option on oral minocycline.

Further information on studies

None.

Comment

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.[70] [71] Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

Lymecycline (oral) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Minocycline (oral)

Summary

Oral minocycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.

Oral antibiotics can cause adverse effects such as contraceptive failure.

Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.

Minocycline has been associated with an increased risk of systemic lupus erythematosus, and of liver disorders.

Benefits and harms

Oral minocycline versus placebo:

We found one systematic review (search date 2002),[73] which identified one crossover RCT. We also found a pooled analysis of 3 RCTs comparing minocycline (extended-release formulation) versus placebo, reported in one publication.[74] One of the RCTs was a 4-armed phase 2 trial comparing minocycline at 3 different doses (1, 2, or 3 mg/kg/day) versus placebo; however, only the data on minocycline 1 mg/kg/day versus placebo (114 people) were included in the pooled analysis. The other two RCTs (924 people) were phase 3 trials comparing minocycline 1 mg/kg/day versus placebo. For additional information on harms of minocycline, in particular systemic lupus erythematosus and liver toxicity from observational studies, see comments.

Acne severity

Oral minocycline compared with placebo Oral minocycline may be more effective at reducing the number of inflammatory lesions and total number of lesions at 12 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[75]
RCT
Crossover design 		50 people, 43 completed
In review [73] 		Total lesion score (compared with baseline score of 100%) 5 weeks
60% with oral minocycline (200 mg daily for first 7 days, then 100 mg daily)
84% with placebo
Absolute results not reported
No direct comparison between groups
The RCT was of insufficient duration to adequately assess the effects of minocycline
[74] 1038 people with moderate or severe facial acne Reduction from baseline in total number of lesions 12 weeks
33% with extended-release minocycline (1 mg/kg daily)
22% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated Minocycline
Inflammatory lesions
[74] 1038 people with moderate or severe facial acne Reduction in number of inflammatory lesions from baseline 12 weeks
46% with extended-release minocycline (1 mg/kg daily)
32% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated Minocycline
Open in a new tab

Patient perception of improvement

No data from the following reference on this outcome.[75] [74]

Psychological distress

No data from the following reference on this outcome.[75] [74]

Quality of life

No data from the following reference on this outcome.[75] [74]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall adverse effects
[74] 1038 people with moderate or severe facial acne Adverse effects 12 weeks
56% with minocycline
54% with placebo
Significance not assessed
Open in a new tab

No data from the following reference on this outcome.[75]

Oral minocycline versus oral doxycycline:

We found two systematic reviews (search dates 2002, 5 RCTs;[73] 2006, 1 RCT [also identified by the first review][72]) comparing oral minocycline versus oral doxycycline. The first review did not perform a meta-analysis because of heterogeneity among the trials in methods, outcomes assessed, and drug doses. It found problems with the methods used in all of the RCTs: 3 were open label, and the two double-blind RCTs reported insufficient information to allow calculation of effect sizes.[73] Similarly, the second systematic review did not perform a meta-analysis.[72] Only one RCT (identified by both reviews) fulfilled Clinical Evidence inclusion criteria.[76]

Acne severity

Oral minocycline compared with oral doxycycline We don't know how oral minocycline and oral doxycycline compare at decreasing the total number of lesions or the number of papules or pustules, or open or closed comedones on the face, back, and chest after 12 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[76]
RCT		 79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72] 		Number of all lesions on the face, back, and chest 12 weeks
with oral minocycline
with oral doxycycline
Absolute results reported graphically
Reported as no significant difference 		Not significant
Inflammatory lesions
[76]
RCT		 79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72] 		Number of papules and pustules on the face, back, and chest 12 weeks
with oral minocycline
with oral doxycycline
Absolute results reported graphically
Reported as no significant difference 		Not significant
Non-inflammatory lesions
[76]
RCT		 79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72] 		Number of all open comedones and closed comedones on the face, back, and chest 12 weeks
with oral minocycline
with oral doxycycline (mean dosage 66 mg)
Absolute results reported graphically
Reported as no significant difference 		Not significant
Open in a new tab

Patient perception of improvement

Oral minocycline compared with oral doxycycline We don't know how oral minocycline and oral doxycycline compare at increasing patient perception of improvement (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[76]
RCT		 79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72] 		Proportion of patients who evaluated treatment as effective or very effective 12 weeks
90% with oral minocycline
85% with oral tetracycline
Absolute results reported graphically
Statistical assessment not reported
Open in a new tab

Psychological distress

No data from the following reference on this outcome.[76]

Quality of life

No data from the following reference on this outcome.[76]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[76]
RCT		 79 people with mild to moderate inflammatory acne randomised, 64 people completed
In review [73] [72] 		Adverse effects 12 weeks
with oral minocycline
with oral doxycycline
Absolute results reported graphically
Open in a new tab

Oral minocycline versus oral lymecycline:

We found two systematic reviews (search dates 2002, 2 RCTs [1 RCT also identified by the second review];[73] 2006, 3 RCTs[72]) comparing oral minocycline versus oral lymecycline. Neither of the reviews pooled the data, and so we have reported those RCTs that agreed with Clinical Evidence inclusion criteria.

Acne severity

Oral minocycline compared with oral lymecycline Oral minocycline and oral lymecycline 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Total count
[77]
RCT		 144 people with at least 20 inflammatory lesions on the face
In review [73] [72] 		Overall reduction in total lesion count 12 weeks
43% with minocycline
45% with lymecycline
Reported as no significant difference between groups
Intention-to-treat analysis 		Not significant
[78]
RCT		 136 people randomised
In review [72] 		Mean reduction in total lesion count from baseline 12 weeks
–55% with minocycline (100 mg daily)
–56% with lymecycline (300 mg daily)
Absolute numbers not reported
Difference –0.29
95% CI –10.53 to +9.95
Intention-to-treat analysis 		Not significant
Non-inflammatory lesions
[77]
RCT		 144 people with at least 20 inflammatory lesions on the face
In review [73] [72] 		Overall reduction in non-inflammatory lesion count 12 weeks
32% with minocycline
41% with lymecycline
P = 0.093
Intention-to-treat analysis 		Not significant
[78]
RCT		 136 people randomised
In review [72] 		Mean reduction in non-inflammatory lesion count from baseline 12 weeks
–47% with minocycline (100 mg daily)
– 54% with lymecycline (300 mg daily)
Absolute numbers not reported
95% CI –23.8 to +8.1
Intention-to-treat analysis 		Not significant
[79]
RCT
3-armed trial 		86 people, 68 completed
In review [72] 		Total lesion count 12 weeks
with minocycline (100 mg daily for 4 weeks followed by 50 mg daily for 8 weeks)
with lymecycline (300 mg daily for 12 weeks)
Absolute results reported graphically
P (minocycline 100 mg/50 mg v lymecycline) <0.05 		Effect size not calculated Minocycline 100 mg/50 mg
[79]
RCT
3-armed trial 		86 people, 68 completed (week 12)
In review [72] 		Total lesion count 12 weeks
with minocycline (50 mg daily for 12 weeks)
with lymecycline (300 mg daily for 12 weeks)
Absolute results reported graphically
Reported as no clinically relevant difference between minocycline 50 mg v lymecycline
Inflammatory lesions
[77]
RCT		 144 people with at least 20 inflammatory lesions on the face
In review [73] [72] 		Overall reduction in inflammatory lesion count 12 weeks
52.2% with minocycline
50.6% with lymecycline
Reported as no significant difference between groups
Intention-to-treat analysis 		Not significant
[78]
RCT		 136 people randomised
In review [72] 		Mean reduction in inflammatory count from baseline 12 weeks
–64.5% with minocycline (100 mg daily)
–58.7% with lymecycline (300 mg daily)
Absolute numbers not reported
Difference +2.32
95% CI –9.59 to +14.22
Intention-to-treat analysis 		Not significant
Open in a new tab

Patient perception of improvement

Oral minocycline 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[77]
RCT		 144 people with at least 20 inflammatory lesions on the face
In review [73] [72] 		Proportion of patients who considered their condition to have improved, much improved, or cleared 12 weeks
83% with minocycline
85% with lymecycline
Absolute numbers not reported
Reported no significant difference between groups 		Not significant
[78]
RCT		 136 people randomised
In review [72] 		Proportion of patients who considered their condition to have improved, much improved, or cleared 12 weeks
44/68 (65%) with minocycline (100 mg daily)
57/66 (86%) with lymecycline (300 mg daily)
Open in a new tab

Psychological distress

No data from the following reference on this outcome.[73]

Quality of life

No data from the following reference on this outcome.[73]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[78]
RCT		 136 people randomised
In review [72] 		Proportion of people with at least 1 adverse effect 12 weeks
20/68 (29%) with minocycline (100 mg daily)
18/66 (27%) with lymecycline (300 mg daily)
Open in a new tab

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 that did not meet Clinical Evidence inclusion criteria.[73]We found one subsequent RCT.[80]

Acne severity

No data from the following reference on this outcome.[80]

Patient perception of improvement

Oral minocycline compared with oral oxytetracycline Oral minocycline seems no more effective at increasing the proportion of people who report moderate improvement at 18 weeks (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[80]
RCT
5-armed trial 		649 people with mild to moderate acne (Leeds acne grade 3 or less) Proportion of people reporting at least moderate improvement in facial acne 18 weeks
70/130 (54%) with oral minocycline 100 mg once daily plus topical placebo
72/131 (55%) with oral oxytetracycline 500 mg twice daily plus topical placebo
OR 0.95
95% CI 0.58 to 1.55 		Not significant
Open in a new tab

Psychological distress

No data from the following reference on this outcome.[80]

Quality of life

No data from the following reference on this outcome.[80]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Skin adverse effects
[80]
RCT
5-armed trial 		649 people with mild to moderate acne (Leeds acne grade 3 or less) Skin adverse effects 18 weeks
4% with oral minocycline 100 mg once daily plus topical placebo
4% with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported
Significance not assessed
Gastrointestinal adverse effects
[80]
RCT
5-armed trial 		649 people with mild to moderate acne (Leeds acne grade 3 or less) Gastrointestinal adverse effects 18 weeks
9% with oral minocycline 100 mg once daily plus topical placebo
8% with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported
Significance not assessed
Central nervous system adverse events
[80]
RCT
5-armed trial 		649 people with mild to moderate acne (Leeds acne grade 3 or less) Central nervous system adverse events 18 weeks
11% with oral minocycline 100 mg once daily plus topical placebo
17% with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported
Significance not assessed
Musculoskeletal symptoms
[80]
RCT
5-armed trial 		649 people with mild to moderate acne (Leeds acne grade 3 or less) Proportion of people with musculoskeletal symptoms week 12
2% with oral minocycline 100 mg once daily plus topical placebo
with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported
[80]
RCT
5-armed trial 		649 people with mild to moderate acne (Leeds acne grade 3 or less) Proportion of people with musculoskeletal symptoms week 18
4% with oral minocycline 100 mg once daily plus topical placebo
with oral oxytetracycline 500 mg twice daily plus topical placebo
Absolute numbers not reported
Open in a new tab

Oral minocycline versus oral tetracycline:

We found two systematic reviews (search dates 2002, 6 RCTs;[73] 2006, 5 RCTs [all of which were also identified by the first review][72]) comparing oral minocycline versus oral tetracycline. The reviews did not perform meta-analyses because of heterogeneity among the trials in outcomes assessed. We have reported those RCTs that satisfy Clinical Evidence inclusion criteria.

Acne severity

Oral minocycline compared with oral tetracycline Oral minocycline and oral tetracycline seem equally effective at improving overall acne severity assessed on a variety of scales (including the Samuelson Lesion Scale) (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[73]
Systematic review		 100 people randomised, 82 people completed
Data from 1 RCT		 Investigator assessed improvement 12 weeks
32/50 (64%) with minocycline (100 mg daily)
36/50 (72%) with tetracycline (500 mg daily)
OR 0.69
95% CI 0.30 to 1.61
(Absolute numbers and statistics from systematic review as we were unable to access the original text of this RCT) 		Not significant
[81]
RCT		 62 college students with moderate to severe inflammatory acne
In review [73] [72] 		Investigator assessed severity scores (change from baseline) 12 weeks
from 5.50 to 2.88 with minocycline (50 mg twice daily)
from 5.04 to 2.85 with tetracycline (250 mg twice daily)
Reported as no significant difference between groups 		Not significant
Open in a new tab

Patient perception of improvement

Oral minocycline compared with oral tetracycline We don't know how oral minocycline and oral tetracycline compare at increasing the proportion of people with moderate to severe acne who report an overall improvement or rate response as satisfactory (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[81]
RCT		 62 college students with moderate to severe inflammatory acne
In review [73] [72] 		Patient assessed severity scores (change from baseline) 12 weeks
from 5.32 to 3.27 with minocycline (50 mg twice daily)
from 4.89 to 3.48 with tetracycline (250 mg twice daily)
Reported as no significant difference between groups 		Not significant
[73]
Systematic review		 100 people randomised, 82 people completed
Data from 1 RCT		 Patient perception of improvement 20 weeks
with minocycline (100 mg daily)
with tetracycline (500 mg daily)		 Not significant
Open in a new tab

Psychological distress

No data from the following reference on this outcome.[73]

Quality of life

No data from the following reference on this outcome.[73]

Adverse effects

No data from the following reference on this outcome.[73]

Further information on studies

None.

Comment

See comment on oral erythromycin regarding antibiotic resistance.

Adverse effects:

We found 3 systematic reviews assessing the adverse effects of minocycline.[73] [82] [83] The first review (search date 2002) pooled data on adverse effects of minocycline from 21 RCTs examining minocycline versus control (placebo or other oral or topical treatments).[73] 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.[73] One prospective cohort study identified by the review (700 people) assessed adverse effects in people taking minocycline 100 to 200 mg daily for a mean 10.5 months.[84] 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.

Systemic lupus erythematosus (SLE):

We found two systematic reviews.[73] [82] The first review[73] identified one case control study[85] (27,688 people aged 15–19 years with acne) assessing the risk of 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.[82] 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.[86]

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.[83] 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).

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.[87] Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.[70] [71] They may cause contraceptive failure during the initial weeks of treatment.

Substantive changes

Minocycline (oral) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Oxytetracycline (oral)

Summary

Oral oxytetracycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective.

Oral antibiotics can cause adverse effects such as contraceptive failure.

Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.

Benefits and harms

Oral oxytetracycline versus placebo:

We found one systematic review (search date not reported),[61] which identified no RCTs comparing oral oxytetracycline versus placebo. We found no subsequent RCTs.

Oral oxytetracycline versus oral minocycline:

See option on oral minocycline.

Oral oxytetracycline versus oral doxycycline:

See option on oral doxycycline.

Further information on studies

None.

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.[70] [71] Oral antibiotics may cause failure of oral contraceptives during the initial weeks of treatment.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Tetracycline (oral)

Summary

Oral tetracycline is considered useful for people with more severe acne, although we don't know for sure whether it is effective. Oral antibiotics can cause adverse effects such as contraceptive failure.

Tetracyclines may harm bones and teeth, and should not be taken by pregnant or breastfeeding women.

Benefits and harms

Oral tetracycline versus placebo:

We found 3 systematic reviews.[16] [17] [61] 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.[16] The review did not perform a meta-analysis because of heterogeneity among the trials in outcomes assessed. The second review (search date 2004),[17] which had more stringent inclusion criteria, identified one RCT included in the earlier review.[23] The third review (search date not reported) did not include any further RCTs.[61]

Acne severity

Oral tetracycline compared with placebo Oral tetracycline may be more effective at reducing severity of acne at 6 to 13 weeks in people with acne (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Overall severity
[26]
RCT
3-armed trial 		367 people with moderate to severe acne
In review [16] 		Proportion for whom physician assessment of treatment was "excellent" or "good"
64% with oral tetracycline
46% with placebo
P <0.05 		Effect size not calculated Tetracycline
[57]
RCT
3-armed trial 		75 people with moderate acne
In review [16] 		Mean reduction in acne severity grade measured on a scale from 0 (least severe) to 8 (most severe) 6 weeks
1.14 with oral tetracycline 250 mg twice daily plus topical placebo
0.43 with topical plus oral placebo
P <0.05 		Effect size not calculated Tetracycline
[57]
RCT
3-armed trial 		75 people with moderate acne
In review [16] 		Mean reduction in acne severity grade measured on a scale from 0 (least severe) to 8 (most severe) 13 weeks
1.91 with oral tetracycline 250 mg twice daily plus topical placebo
0.62 with topical plus oral placebo
P <0.05 		Effect size not calculated Tetracycline
[58]
RCT
3-armed trial 		60 male adolescents with mild to moderate acne
In review [16] 		Improvement from baseline of 1 or more on a scale from 0 to 8 8 weeks
12/18 (67%) with oral tetracycline plus topical vehicle
6/17 (35%) with oral placebo plus topical vehicle
Significance not assessed
[59]
RCT
3-armed trial 		135 people aged 18 to 25 years with mild to moderate acne, Cook's grades 0 to 8
In review [16] 		Acne severity 7 weeks
with oral tetracycline plus topical vehicle
with topical vehicle plus oral placebo
Absolute results reported graphically
P <0.05 		Effect size not calculated Tetracycline
[59]
RCT
3-armed trial 		135 people aged 18 to 25 years with mild to moderate acne, Cook's grades 0 to 8
In review [16] 		Acne severity 10 weeks
with oral tetracycline plus topical vehicle
with topical vehicle plus oral placebo
Absolute results reported graphically
P <0.05 		Effect size not calculated Tetracycline
[59]
RCT
3-armed trial 		135 people aged 18 to 25 years with mild to moderate acne, Cook's grades 0 to 8
In review [16] 		Acne severity 12 weeks
with oral tetracycline plus topical vehicle
with topical vehicle plus oral placebo
Absolute results reported graphically
P <0.05 		Effect size not calculated Tetracycline
[88]
RCT		 51 people (severity of acne unclear)
In review [16] 		Change in Pillsbury modified score 12 weeks
–2 with tetracycline 250 mg twice daily
0 with placebo
P = 0.001 		Effect size not calculated Tetracycline
[88]
RCT		 51 people (severity of acne unclear)
In review [16] 		Proportion of people assessed as "improved" 12 weeks
23/24 (96%) with tetracycline 250 mg twice daily
15/27 (56%) with placebo
P = 0.01 		Effect size not calculated Tetracycline
Inflammatory lesions
[23]
RCT
3-armed trial 		108 people with mild to moderate acne
In review [16] [17] 		Mean inflammatory lesion count (change from baseline) 8 weeks
2.66 with oral tetracycline 500 mg twice daily
6.24 with placebo
Significance of between-group difference not assessed
RCT designed to compare oral tetracycline v topical clindamycin
[89]
RCT
4-armed trial 		68 people with mild to moderate acne
In review [16] 		Percentage reduction in inflammatory lesions 8 weeks
26% with tetracycline plus placebo
16% with placebo
Reported as not significant
P value not reported
RCT may have lacked power to detect a clinically important difference among groups 		Not significant
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Patient perception of improvement

Oral tetracycline compared with placebo Oral tetracycline seems 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Patient perception of improvement
[23]
RCT
3-armed trial 		108 people with mild to moderate acne
In review [16] [17] 		"Markedly improved" or "improved" from baseline
72% with oral tetracycline 500 mg twice daily
3% with placebo
Significance of between-group difference not assessed
RCT designed to compare oral tetracycline v topical clindamycin
[26]
RCT
3-armed trial 		367 people with moderate to severe acne
In review [16] 		Proportion of people who thought their acne was "markedly improved" or "improved"
84% with oral tetracycline
57% with placebo
P <0.05 		Effect size not calculated Tetracycline
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No data from the following reference on this outcome.[57] [58] [59] [88] [89]

Psychological distress

No data from the following reference on this outcome.[23] [26] [57] [58] [59] [88] [89]

Quality of life

No data from the following reference on this outcome.[23] [26] [57] [58] [59] [88] [89]

Adverse effects

No data from the following reference on this outcome.[23] [26] [57] [58] [59] [88] [89]

Oral tetracycline versus oral erythromycin:

See option on oral erythromycin.

Oral tetracycline versus oral minocycline:

See option on oral minocycline.

Oral tetracycline versus oral isotretinoin:

See option on oral retinoids

Further information on studies

The RCT reported in the discussion section of the article that patient perception of improvement was "close" to clinical assessment; no further data provided.

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) New evidence added.[72] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Jan 5;2011:1714.

Isotretinoin (oral)

Summary

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 and harms

Oral isotretinoin versus placebo:

We found one RCT.[90] For additional information from observational studies on harms of isotretinoin, see comment.

Acne severity

Oral isotretinoin 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).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Nodules
[90]
RCT		 33 people with treatment-resistant cystic and conglobate acne Mean change in nodules 1 month
–32% with oral isotretinoin (0.5 mg/kg/day)
+33% with placebo group
Absolute numbers not reported
P <0.008 		Effect size not calculated Isotretinoin
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Patient perception of improvement

No data from the following reference on this outcome.[90]

Psychological distress

No data from the following reference on this outcome.[90]

Quality of life

No data from the following reference on this outcome.[90]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[90]
RCT		 33 people with treatment-resistant cystic and conglobate acne Adverse effects
with oral isotretinoin (0.5 mg/kg/day)
with placebo group
Absolute results not reported
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Oral isotretinoin versus oral tetracycline:

We found one small RCT.[91] For additional information from observational studies on harms of isotretinoin, see comment.

Acne severity

Oral isotretinoin compared with oral tetracycline Oral isotretinoin is more effective at reducing acne cysts, pustules, and comedones at 24 weeks in people with severe nodulocystic acne (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Inflammatory lesions
[91]
RCT		 29 people with severe nodulocystic acne Reduction in acne cysts 24 weeks
82% with oral isotretinoin (1–2 mg/kg/day)
52% with oral tetracycline (0.5–1 mg/day)
Absolute numbers not reported
P <0.01 		Effect size not calculated Isotretinoin
[91]
RCT		 29 people with severe nodulocystic acne Reduction in pustules and comedones 24 weeks
85% with oral isotretinoin (1–2 mg/kg/day)
58% with oral tetracycline (0.5–1 mg/day)
Absolute numbers not reported
P <0.01 		Effect size not calculated Isotretinoin
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Patient perception of improvement

No data from the following reference on this outcome.[91]

Psychological distress

No data from the following reference on this outcome.[91]

Quality of life

No data from the following reference on this outcome.[91]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[91]
RCT		 29 people with severe nodulocystic acne Xerosis
15/15 (100%) with isotretinoin
2/15 (13%) with oral tetracycline
Significance not assessed
[91]
RCT		 29 people with severe nodulocystic acne Cheilitis/dry lips
15/15 (100%) with isotretinoin
3/15 (20%) with oral tetracycline
Significance not assessed
[91]
RCT		 29 people with severe nodulocystic acne Dry nose
10/15 (67%) with isotretinoin
1/15 (7%) with oral tetracycline
Significance not assessed
[91]
RCT		 29 people with severe nodulocystic acne Dry mouth
3/15 (20%) with isotretinoin
1/15 (7%) with oral tetracycline
Significance not assessed
[91]
RCT		 29 people with severe nodulocystic acne Adverse effects (other)
with isotretinoin
with oral tetracycline
Absolute results not reported
Significance not assessed
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Further information on studies

An open phase extension to this RCT for a further 2 to 4 months showed further improvement in the treatment group as dose increased to a mean of 0.9 mg/kg/day.

Comment

Skin:

Dry skin and mucosal surfaces are a well-known adverse effect of isotretinoin treatment. We found one open study (80 people with a range of acne types failing to respond to oral antibiotics) of intermittent dosing with isotretinoin 0.5 mg/kg/daily (1 week in 4 for 6 months), to determine the relative efficacy versus adverse effects.[92] Although there was no control group, the authors reported modest cheilitis at the lower end of the spectrum for isotretinoin adverse effects.[92]

Liver function:

Isotretinoin 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.[93]

Pregnancy (teratogenesis):

Isotretinoin 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.[94] In the second study (8609 women), 90 women became pregnant, with 9 women progressing to live birth. One of the 9 infants had a congenital anomaly of the neck and face.[95] 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 two systematic reviews (search dates 2004;[96] not reported[97]). The first review included one prospective survey[98] and one case control study[99] that was also included in the second review, on 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 records 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.[98] The second systematic review included 6 prospective studies (of which 2 were RCTs [158 people], 3 were cohort studies [272 people], and 1 was a descriptive study [189 people]) and 3 retrospective studies (of which 2 were cohort studies [32,092 people], and 1 was a descriptive study [877 people]). A total of 9 studies examined the association between isotretinoin and depression, whereas only two studies examined the association between isotretinoin and suicidal behaviour. The review concluded that overall no association could be demonstrated between risk of depression or suicidal behaviour and use of isotretinoin. However, it was acknowledged that all included studies fell short of providing a definitive answer, mainly through small size and difficulties in randomisation and blinding. The review authors commented that more than 100,000 people and long-term follow-up would be needed in an RCT to provide conclusive evidence about an association between isotretinoin and suicide.[97] We found one subsequent cohort study indicating 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.

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 are not as clear for this group as they are 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.[100] 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. One systematic review from primary care suggested that, although the general practitioner (GP) 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.[100]

Substantive changes

No new evidence

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