THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 18, Number 0, 2013, pp. 17 Mary Ann Liebert, Inc.

. DOI: 10.1089/acm.2013.0137

Original Article

The Clinical Impact and Cost-Effectiveness of Essential Oils and Aromatherapy for the Treatment of Acne Vulgaris: A Protocol for a Randomized Controlled Trial
1 Tamara Agnew, BA (Hons), Matthew Leach, PhD,2 and Leonie Segal, PhD1

Abstract

Background: Acne is a prevalent, chronic, and sometimes severe skin disorder affecting an estimated 85% of adolescents and 50% of adults older than age 20 years. The psychosocial implications of acne can be considerable, often continuing long after physical symptoms resolve. Although effective acne medications are available, most exhibit adverse-effect proles that can leave the patient with few effective treatment options. Emerging evidence indicates that plant-derived essential oils may be a biologically plausible treatment for acne, although high-quality evidence of effectiveness and safety is lacking. Objective: To examine the clinical effectiveness and cost-effectiveness of essential oils and aromatherapy for the treatment of acne. Design: This randomized, wait-list controlled trial will have three parallel groups; 192 participants with acne vulgaris, aged 1645 years, will be recruited primarily through eight Technical and Further Education campuses across Adelaide, South Australia. Participants will be randomly assigned to standard essential oil blend, customized aromatherapy treatment, or wait-list control. Changes in the physical and psychosocial symptoms of acne will be assessed at baseline and 6 and 12 weeks by using the Leeds Acne Grading System, Assessment of Quality of Life8 Dimension instrument, and Acne-Specic Quality of Life instrument. Costs of treatment will be measured on the basis of resource inputs and unit costs and will be limited to acne treatment. The clinical effectiveness and cost-effectiveness will be compared between each intervention and against usual care, using standard health economic techniques. Conclusions: The provision of high-quality evidence of the effectiveness of essential oils and aromatherapy in the treatment of acne may help consumers make better-informed choices about acne management. Insights gained from this research will also contribute to the academic eld of complementary medicine, specically aromatherapy, for which the evidence base is extremely limited.

Introduction

cne vulgaris (acne) is a chronic, nonlife-threatening skin condition characterized by comedones (noninammatory lesions), papulopustular (inammatory) lesions, nodules, and/or cysts. Although acne lesions appear most frequently on the face, they can occur anywhere pilosebaceous glands are concentrated.1 Acne can also result in longterm physical scarring and contribute to debilitating psychosocial effects.24 Most people experience the physical symptoms of acne at some point during adolescence,5 although symptoms can continue through to adulthood.6 Incidence has been reported at 30%90%, with peak severity at around 1417 years for
1 2

males and 1619 years for females.6 The prevalence of acne has been reported at 83%5 in the 13- to 18-year-old Australian school children and 12.8%62% in adults, internationally.710 The sometimes debilitating psychosocial effects of acne do not always correlate with clinical severity,11,12 although there is often a correlation with self-perceived severity.13 These psychosocial symptoms may include aggression; embarrassment; interference with daily functioning, friendships, or relationships; and avoidance of social events. In an Australian study of 267 children with acne, most respondents reported having experienced mild disability due to acne (as measured by the Acne Disability Index); 14% reported moderate disability and 3%, severe disability.5 In the context

Health Economics and Social Policy Group, School of Nursing and Midwifery, University of South Australia, Australia. School of Nursing and Midwifery, University of South Australia, Australia.

2 of acne, disability may have related to impaired relationships and self-image, and discrimination, derision, or dismissal by potential employers and peers.14 Over-the-counter (OTC) formulations, such as benzoyl peroxide and salicylic acid, are among the most commonly used treatments for acne. If OTC products fail to produce desired results and acne is severe, patients may be prescribed medication.15 Clinical research suggests cure rates for OTC and prescription medication for acne of 36%80%.16,17 However, acne continues to represent an ongoing problem for many,18 with overall adherence to acne treatments ranging between 50%19 and 65%.20 Reported adverse effects of conventional acne treatments are diverse and sometimes severe. Effects can include local skin irritation, dermatitis, photo-aging, bacterial resistance,21 and psychiatric comorbid conditions.22,23 The drug isotretinoin, which is often prescribed for severe acne symptoms, can contribute to suicidal ideation and suicide attempts, estimated at 2.52 cases per 1000 person-years of treatment.2427 The above-mentioned concerns highlight the need for safer and effective treatments of acne. Aromatherapy (the controlled application of essential oils) shows promise in this area. In vitro studies provide supportive evidence of the biological plausibility of aromatherapy/essential oils, including in vitro antimicrobial activity against bacteria including Propionibacterium acnes implicated in the pathogenesis of acne,2830 however, limited clinical evidence is available to espouse this research.31,32 In fact, an extensive literature search of the subject area failed to locate any high-quality clinical studies investigating the effectiveness of essential oils for the treatment of acne vulgaris; other authors have also noted this.30,33 Further, there have been no published economic evaluations of the use of aromatherapy for any clinical outcome. In terms of safety, clinical evidence is sparse, although it does suggest that aromatherapy/essential oils are generally well tolerated. The most commonly reported adverse events associated with the topical application of essential oils are skin irritation and contact dermatitis.34 Although more serious outcomes have been reported, they are extremely rare and are predominantly associated with incorrect use. There is a clear need for robust evidence of the clinical effectiveness and cost-effectiveness of aromatherapy and essential oils in acne treatment. The landmark study described in this paper proposes to address this need. Design and Methods Study design The CLinical Essential oil Acne Effectiveness (CLEANsE) study is a prospective, multicenter, randomized, wait-list controlled trial with three parallel groups and a 1-week washout period (Fig. 1). This design will reduce the possible inuence of confounders, as well as major sources of bias, notably selection bias. Research objectives The objectives of the proposed study are to: 1. Compare the clinical effectiveness of a standardized essential oil blend (treatment arm 1) with individual-

AGNEW ET AL. ized aromatherapy treatment (treatment arm 2) and wait-list control (usual care) on the physical symptoms of acne; 2. Compare the effect of treatment arm 1, treatment arm 2, and usual care on the health-related quality of life of patients with acne; and 3. Calculate the incremental cost-effectiveness (cost per change in physical symptoms) and cost per qualityadjusted life-year (QALY) between treatment arm 1 and treatment arm 2 and between the two treatments and usual care, if a differential effect is found. Recruitment Participants will be recruited across Adelaide, South Australia via radio and television; this will be complimented by a series of posters, yers and emails at various vocational training institutions and metropolitan campus of University South Australia. These recruitment media will direct persons with acne to the CLEANsE study website. The website will provide additional information about the trial and direct potential participants to a short questionnaire to assess trial eligibility as well as current use of acne treatments. Eligible participants will then be invited to register their interest to participate in the trial. Upon receiving an electronic notication of interest, an investigator will telephone the potential participant to check his or her eligibility, obtain verbal consent, and make an appointment for the initial meeting. Potential participants may also contact the investigator by telephone in the rst instance for further clarication about the trial. Participants will be asked to read the participant information documents that describe the trial, randomization process, and potential risks before the rst meeting. This document also denes the participant expectations in terms of attendance for assessments and consultations and guidelines for the use of the product. At the rst face-to-face meeting, participants will complete the written consent form, after which they will receive their randomization allocation. Randomization Participants will be randomly assigned to one of the three study groups using a block randomization method and block lengths of six.35 A random-number generator will create the sequence of numbers. In accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement, the random-number sequence will be generated before trial commencement. Treatment allocation will be placed in consecutively numbered, sealed, opaque envelopes, which will be opened by the investigator after verbal consent. Participants will be advised of their allocation after baseline data collection. Blinding The nature of the two interventions and the usual care control means that it is not possible for study participants or the therapist delivering treatments 1 and 2 to be blinded. The potential risk of assessment/investigator bias will be minimized by using objective outcome measures that are capable of independent audit. Further, the primary outcome will be assessed by independent investigators blinded to treatment assignment.

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FIG. 1. CLinical Essential oil Acne Effectiveness study owchart.

Participants The inclusion and exclusion criteria for study participants are listed in Table 1. Justication for several criteria is provided below: Has facial acne of at least mild severity: There is no universally accepted denition of acne, or acne severity, with inconsistent denitions used in the literature.3639 For the purposes of this study, mild acne is dened as the presence of any noninammatory comedones (blackheads and whiteheads). Age 1645 years: The minimum age of 16 years represents the point at which acne severity peaks, while the maximum Table 1. Participant Selection Criteria Inclusion criteria
 Has acne of at least

Exclusion criteria
 Is pregnant  Has a history of kidney

mild severity3335  Age 16 45 y  Is mentally capable of providing written and verbal consent36

or liver disease
 Is currently receiving,

age of 45 years represents the age by which symptoms typically subside in adults.5,6,9,40 Excluding children younger than 16 years also simplies the consent process. Is pregnant: Low-molecular-weight ( < 1000) and negatively charged molecules are able to cross the placenta, and all essential oils have a molecular weight < 500.41 Because of the lack of knowledge surrounding the potential harm of essential oils to the developing fetus,41 pregnant women will not be permitted to enter the trial. Has a history of kidney or liver disease: Essential oils are lipophilic compounds, which can be absorbed through the skin to be metabolized via the liver and kidney.42 This exclusion criterion is cautionary.43 Has ever had an epileptic seizure: Odor can activate sections of the limbic system. The most common form of partial epilepsy, mesial temporal lobe epilepsy, is often triggered by stimuli in the hippocampus, which is thought to have anatomic ties to olfaction, and therefore, may be affected by odor.44 Interventions Treatment arms Nineteen essential oils have been selected for use in this trial. These oils, which are listed in Table 2, were selected according to their chemical constituents and associated therapeutic actions. Knowledge of the properties of essential oils was based on in vitro evidence, case reports, and recorded traditional use. Participants assigned to treatment arm 1 will receive a standardized blend of essential oils (specically formulated for this trial), diluted to 5% concentration in a base

or has completed within the past 8 wk, systemic acne treatment, including oral antibiotics (tetracycline, minocycline, lymecycline, and erythromycin) and isotretinoin (Roaccutane, F. Hoffmann-La Roche).  Has ever had an epileptic seizure  Is unable to communicate in English

4 Table 2. Essential Oils and Base/Carrier Oils Selected for the CLinical Essential Oil Acne Effectiveness Trial Common name Essential oils Bergamot Cardamom Cedarwood Clary sage Cypress Frankincense Geranium German chamomile Grapefruit Juniper berry Lavender Australian oil Niaouli Patchouli Peppermint Petitgrain Sandalwood Sweet orange Tea tree Ylang ylang Base/carrier oils Grapeseed Jojoba wax Sunower Botanical name Citrus bergamia Elattaria cardamomum Cedrus atlantica Salvia sclarea Cupressus semipervirens FOL. STROB Boswellia carteri Pelargonium graveolens Chamomilla recrutita Citrus paradisi Juniperus communis Lavandula angustifolia Melaleuca quinquenervia Pogostemon cablin Menthapiperita L. Citrus aurantium var. Amara Santalum album Citrus sinensis Melaleuca alternifolia Cananga odorata Vitis vinifera Simmond siasinesis Helianthus annus L

AGNEW ET AL. life stressors; and views about the role of diet, stress, and lifestyle and other factors on their acne. The consultation and essential oil selection are based on a biopsychosocial model of healing,48 which understands health as being the result of a balance between many inuences, including biological, psychological, social, and environmental,49 and how the person responds to these inuences.50 All aromatherapy consultations and initial assessments, for all participants, will be delivered by the primary investigator. Follow-up assessments will be completed by the primary investigator or a research assistant. The essential oil blends will be delivered via an airless pump bottle (0.7 mL per application). Both intervention groups will be asked to apply the product to facial acne lesions after cleansing the face, twice daily, for 12 weeks. Moisturizer, sunscreen, and/or make-up can be applied 15 minutes after the application of acne treatment. Participants in the two aromatherapy treatment arms will be required to discontinue OTC products 1 week before and throughout the trial.51 The 1-week washout period will reduce the carryover effect of other acne products. Wait-list control Participants assigned to wait-list control will be asked to continue with usual care for the duration of the trial, which will be documented in a diary. At the end of the 3-month trial period, control participants will be offered a 3-month supply of a standardized essential oil blend, as used in treatment arm 1. Participants will not be permitted to wear foundation during the clinical assessment because it will affect the accuracy of the assessment. Participants will be advised to remove facial make-up 30 minutes before each appointment to allow any associated erythema to have resolved. Data collection Data will be collected from each participant at three time points: baseline, week 6, and week 12. Data collection will commence in August 2012 and be completed by December 2013. Table 3 provides detail of the various measures that will be completed for each study arm. Outcome measures Acne severity is the primary outcome and will be assessed from a series of digital photographs using the Leeds revised acne severity scale. This scale ranges from 1 (least severe) to 12 (most severe). Severity assessment includes extent of inammation, range and size of inamed lesions and associated erythema.52,53 This tool is an update of the original Leeds technique,52 which incorporates advances in digital photography. A series of three facial photographs (left, right, and center) will be taken of each participant at baseline, week 6, and week 12 by using a standardized photographic protocol. Digital images will then be de-identied and forwarded securely to an independent clinician to complete the Leeds scale. Self-reported symptom severity will also be collected at baseline and week 12. Participants will be asked to dene their symptoms as mild, moderate, severe, or very severe and to comment on whether the symptoms are the worst they have ever been.

consisting primarily of jojoba wax. The essential oils included in this blend will be chosen on the basis of the therapeutic properties of the individual oil and the synergy of the blend. This approach to blending, known as the molecular approach, is symptom-based.45 Two standard blends will be developed for treatment arm 1 in order to accommodate a participants personal scent preference. Because of commercial-in-condence, the authors are unable to disclose the precise composition of the two standardized blends; it is possible to state only that blend 1 contains 7 essential oils and blend 2 contains 6 essential oils (selected from Table 2), in a blended base that supports the healing properties of the essential oils. Participants assigned to treatment arm 2 will participate in a comprehensive health and well-being consultation delivered by a trained aromatherapist, which will inform the composition of an individualized essential oil blend (also diluted to 5% concentration in a base consisting primarily of jojoba wax). For each participant in treatment arm 2, the individualized blend will be created from the 19 oils listed in Table 2. Oil selection will be based on the therapeutic qualities of the oils, and blending will be done according to the principles covered in aromatherapy training. The product is designed to address the participants physical symptoms, as well as act on the limbic system to help reduce stress,46 which is often cited as having a causative link with acne.47 The 60- to 75-minute consultation will examine the participants current and presenting problem; recent use of orthodox and complementary medicines for acne; other health issues and how these issues are being managed; family history of the presenting problem; environmental factors; major

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Table 3. Randomized Controlled Trial Data Collection and Activities by Timing and Treatment Allocation Data Informed consent Enrollment form/baseline data (5 min) Health questionnaire (5 min) Clinical photography (2 min) Acne-QoL (5 min) AQoL-8D (5 min) Trial exit forms (5 min) Activity Consultation (5 min) Consultation (45 min) Product Participant diary Week 1 1, 1, 1, 1, 1, 1, 2, 2, 2, 2, 2, 2, 3 3 3 3 3 3 Week 6 Week 12 Throughout

1, 2, 3 1, 2, 3 1, 2, 3

1, 1, 1, 1,

2, 2, 2, 2,

3 3 3 3

1 2 1, 2

2 1, 2 3 1, 2 3

1, treatment arm 1; 2, treatment arm 2; 3, wait-list control/usual care. Acne-QoL, Acne-Specic Quality of Life instrument; AQoL8D, Assessment of Quality of Life8 Dimension instrument.

Quality of life will be assessed by using two instruments: the Acne-Specic Quality of Life questionnaire (Acne QoL), a 19-item scale covering four domains (self-perception, roleemotional, role-social, and symptoms), and the Assessment of Quality of Life-8 dimension (AQoL-8D; adolescent version) instrument.54 The AQoL-8D covers eight domains: independent living, senses, pain, mental health, happiness, self-worth, coping, and relationships. The AQoL-8D is a preference-based utility instrument that can be used in health economic evaluations to estimate QALYs. Both instruments will be self-administered by participants at baseline, week 6, and week 12 during appointments with the investigator. For acne product use and cost (usual care group only), usual care participants will be requested at the start of the trial to complete a participant diary to capture acne product use. Participants will be asked to record the name, quantity, and cost of any products used to treat acne during the trial. Participants will also be asked to estimate how frequently (i.e., times per year) they would typically purchase the product. Analysis of costs will be limited to the cost of acne treatment (i.e., treatment group only). The cost of aromatherapy treatment will be calculated in Australian dollars for each individual participant. The cost of the essential oils (treatment arms 1 and 2) and the aromatherapy consultation (treatment arm 2) will be based on the wholesale price of essential oils and dispensing bottles, plus retail mark-up, and the consultation time multiplied by the recommended hourly rate. Acne treatment compliance is a major barrier to successful treatment outcomes for patients with acne.19 Hence, all participants will complete the Elaboration dun outil devaluation de lobservance des traitements medicamenteux questionnaire55 at baseline to ascertain their risk for nonadherence to a medicine regimen. At weeks 6 and 12, participants will complete the Medical Outcomes Study General Adherence tool56 to evaluate participant recall of acne product use within the previous 7 days. These tools will be used to generate hypotheses on the effect of the consultation on clinical outcomes. Data Analysis Sample size calculation By using the primary outcome severity of acne and an expected effect size of 0.5, a sample size of 64 per group will

have 80% power to detect a 2-point reduction on the Leeds acne severity scale with the a level set at 0.05. To accommodate for an expected dropout rate of 8%,57 this study will recruit a minimum of 207 participants (69 in each arm). Analysis All data will be entered into SPSS software, version 21 (SPSS Inc., Chicago, Illinois), for data cleaning and analysis. Means and standard deviations will be used to describe continuous data (e.g., age) with normal distributions. Medians and interquartile ranges will be used for continuous variables whose distributions are sufciently skewed. Frequency distributions and percentages will be used for categorical variables. All data will be analyzed by intention-to-treat. Chisquared tests and paired t-tests will be used to describe differences between groups at baseline if data are normally distributed; the Wilcoxon rank test will be used if data are sufciently skewed. For the primary outcome, the three groups will be compared by using mean scores, but also by the percentage of participants who shift between different severity levels, including total resolution of acne symptoms. Economic evaluation: cost-effectiveness The economic evaluation will estimate the cost differences between the two treatment arms and between each treatment arm and the usual care group. Cost data will be combined with primary outcomes to estimate the cost per case of acne resolved and the cost per change in acne score (if a difference in outcome is observed). Similarly, if a difference in the quality-of-life utility score is observed, a cost utility analysis will be conducted to assess the incremental cost per QALY for each intervention, following standard methods, as described in Figure 2. To develop QALYs, this will be modeled by incorporating various assumed values for the time period over which treatment differences would be maintained. Conclusions This is the rst known randomized controlled trial to evaluate the clinical effectiveness of an essential oil blend and aromatherapy consultation, as practiced by clinical

AGNEW ET AL.
7. Khunger N, Kumar C. A clinico-epidemiological study of adult acne: is it different from adolescent acne? Ind J Dermatol Venereol Leprol 2012;78:335341. 8. Plunkett A, Merlin K, Gill D, et al. The frequency of common nonmalignant skin conditions in adults in central Victoria, Australia. Int J Dermatol 1999;38:901908. 9. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:577580. 10. Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br J Dermatol 1997;136:6670. 11. Bowe WP, Leyden JJ, Crerand CE, et al. Body dysmorphic disorder symptoms among patients with acne vulgaris. J Am Acad Dermatol 2007;57:222230. 12. Kilkenny M, Stathakis V, Hibbert ME, et al. Acne in Victorian adolescents: associations with age, gender, puberty and psychiatric symptoms. J Paediatr Child Health. 1997;33:430433. 13. Mulder MMS, Sigurdsson V, van Zuuren EJ, et al. Psycholosical impact of acne vulgaris: evaluation of the relation between a change in clinical acne severity and psychosocial state. Dermatology. 2001;203:124130. 14. Fried RG, Webster GF, Eicheneld LF, et al. Medical and psychosocial impact of acne. Semin Cutan Med Surg 2010;29(2 Suppl):912. 15. Stoll S, Shalita AR, Webster GF, et al. The effect of the menstrual cycle on acne. J Am Acad Dermatol 2001;45:957960. 16. Burkhart CG, Burkhart CN. Treatment of acne vulgaris without antibiotics: tertiary amine-benzoyl peroxide combination vs benzoyl peroxide alone (Proactive SolutionTM). Int J Dermatol 2007;46:8993. 17. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004;292:726735. 18. Armstrong AW, Cheeney S, Wu J, et al. Harnessing the power of crowds: crowdsourcing as a novel research method for evaluation of acne treatments. Am J Clin Dermatol 2012;13:405416. no B, Thiboutot D, Gollnick H, et al. Large-scale world19. Dre wide observational study of adherence with acne therapy. Int J Dermatol 2010;49:448456. 20. Zaghloul SS, Cunliffe WJ, Goodeld MJD. Objective assessment of compliance with treatments in acne. Br J Dermatol 2005;152:10151021. 21. Yen T, Yuan C-Y, Huang C-M. Current status of acne vaccines. Exp Rev Dermatol 2010;5:561566. 22. Fabbrocini G, Padova M, Cacciapuoti S, et al. Acne. In: Tosti A, Grimes PE, De Padova MP, eds. Color Atlas of Chemical Peels. Berlin: Springer; 2012:95105. 23. Thiboutot DM. Acne: an overview of clinical research ndings. Dermatol Clin 1997;15:97109. 24. Bremner JD, Shearer K, McCaffery P. Retinoic acid and affective disorders: the evidence for an association. J Clin Psychiatry 2012;73:3750. m A, Alfredsson L, Sjo lin-Forsberg G, et al. Asso25. Sundstro ciation of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ. 2010;341: c5812. 26. Goodeld MJD, Cox NH, Bowser A, et al. Advice on the safe introduction and continued use of isotretinoin in acne in the U.K. Br J Dermatol 2010;162:11721179. 27. Kontaxakis VP, Skourides D, Ferentinos P, et al. Isotretinoin and psychopathology: a review. Ann Gen Psychiatry. 2009; 8:29. 28. Hammer KA, Carson CF, Riley TV. Antimicrobial activity of essential oils and other plant extracts. J Appl Microbiol 1999; 86:985990.

FIG. 2. Example of quality of life, cost-utility analysis formula comparing treatment arm 2 to treatment arm 1.

aromatherapists, for the treatment of acne vulgaris. The provision of high-quality evidence of the effectiveness of essential oils and aromatherapy in the treatment of acne will help consumers make more informed choices about acne treatment. Insights gained from this research will also contribute to the academic eld of complementary medicine, specically aromatherapy, for which the evidence base is extremely limited. Ethics Approval The study has been approved by the University of South Australia Human Research Ethics Committee and will be conducted in accordance with the National Health and Medical Research Council Code for the Responsible Conduct of Research. The trial is also registered with the Australian New Zealand Clinical Trials Registry (ANZCTR). The standardized product will be registered under the notication of intent to supply unapproved therapeutic goods under the clinical trial notication scheme of the Australian Therapeutic Goods Administration. The trial is registered in the Australian New Zealand Clinical Trials Registry: ACTRN12612000193875. Acknowledgments The authors would like to thank Sydney Essential Oil Company for providing the essential oils and base product for all interventions, and TAFE SA North and South Institutes for allowing the team to conduct the research on their campuses. Author Disclosure Statement The authors state that no competing nancial interests exist. References
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Address correspondence to: Tamara Agnew, BA (Hons) Health Economics and Social Policy Group School Nursing and Midwifery University South Australia P4-26, City East Campus North Terrace Adelaide, South Australia 5000 Australia E-mail: tamara.agnew@mymail.unisa.edu.au