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Eur J PediatrDOI 10.1007/s00431-009-0978-0 Clinical trial showing superiority of a coconut and anisespray over permethrin 0.43% lotion for head louseinfestation, ISRCTN96469780 Ian F. Burgess & Elizabeth R. Brunton &Nazma A. Burgess Received: 16 February 2009 / Accepted: 23 March 2009# Springer-Verlag 2009 Abstract Permethrin is the most widely used pediculicide, head louse infestation and is found in products from North but evidence of resistance from several countries and and South America, Asia, Australia, and most countries in anecdotal reports from Germany suggest that permethrin Europe. Several studies have now shown acquired resis- lotion is now less effective. We designed a randomized, tance to this insecticide in head lice, and in most cases, this controlled, parallel group trial involving 100 participants has been identified as being primarily mediated by a with active head louse infestation to investigate the activity recessive gene mutation known as “knockdown” resistance of a coconut and anise spray and to see whether permethrin (kdr) although this is not the only mechanism for lotion is still effective, using two applications of product resistance to these insecticides, which may also be degraded 9 days apart. The spray was significantly more successful metabolically [, However, the impact of resistance is (41/50, 82.0%) cures compared with permethrin (21/50, variable depending upon the intensiveness of selection 42.0%; p<0.0001, difference 40.0%, 95% confidence pressure through extensive and frequent use of pyrethroid interval of 22.5% to 57.5%). Per-protocol success was insecticides for treatment of infestation. Effectiveness of 83.3% and 44.7%, respectively. Thirty-three people treatment is also influenced by the dosage form used for reported irritant reactions following alcohol contact with different products and whether active formulation exci- excoriated skin. We concluded that, although permethrin pients are present Consequently, some preparations lotion is still effective for some people, the coconut and with permethrin as the active ingredient may be more anise spray can be a significantly more effective alternative effective than others when used in the same community. It is for this reason that 0.43% permethrin alcoholic lotion isone of the most used preparations in Germany because Keywords Head lice . Permethrin . Essential oils .
alcohol is believed to enhance the penetration of insecti- Coconut and anise spray has been shown to be effective in killing laboratory reared lice and their eggs (E. Brunton, unpublished data) and has been evaluated in two previousclinical investigations with good success rates The insecticide permethrin is probably the most widely However, the first study used a treatment regimen different used active ingredient for treatments designed to eliminate from the one currently used for the product in Europe andexperienced approximately 10% drop-out rate []. Theother evaluated only 12 subjects []. Overall, these studiesindicated that the product is likely to have a treatment I. F. Burgess (*) : E. R. Brunton : N. A. BurgessMedical Entomology Centre, success rate of around 90%, which would make it an Insect Research & Development Limited, acceptable alternative in areas where resistance is an issue 6 Quy Court, Colliers Lane, Stow-cum-Quy, with conventional insecticides like permethrin.
We have conducted a randomized, assessor-blinded e-mail: ian@insectresearch.comURL: www.insectresearch.com (single-blinded) clinical trial to evaluate the efficacy of coconut and anise spray in comparison with that of pediculicide use, and success of previous treatments.
permethrin lotion and to compare the products for safety Appointments were made for subsequent visits to the participants in their homes for treatment and assessments.
No payment was offered for participation. Anyone who hadlice but was ineligible to participate was offered treatment using 4% dimeticone lotion as a standard of care treatmentand to prevent reinfestation of study participants.
This study was designed to compare the efficacy of acoconut and anise spray with 0.43% permethrin lotion with Ethical approval for the study was granted by Leeds (West) sufficient power to detect if the activity of either product Research Ethics Committee (EudraCT 2007-006190-87). The study was conducted in conformity with the principles of theDeclaration of Helsinki and of European Union Directive 2001/20/EC. Prior to giving consent, all participants statedthat they understood the purpose and requirements of the Participants to this study were recruited by advertising in investigation after having read the participation information newspapers or parish magazines and from direct contact booklet. Parents or guardians gave written consent for with families who had participated in previous clinical children younger than 16 years. Children also provided studies and who had expressed a wish to be included in any written or verbal assent, according to age, witnessed by the future research. In each case, an information booklet was delivered to the family, and an appointment was arrangedfor an investigator to visit. Potential participants were screened for head lice using a standard detection comb usedin previous studies (“PDC”, KSL Consulting, Denmark).
Coconut and anise spray (Paranix spray/Lyclear Spray- The level of infestation was graded on an analog scale Away, Omega Pharma NV, Nazareth, Belgium; fractionated (heavy infestation is equal to more than one louse found coconut oil (caprylic capric triglyceride), propan-1-ol, anise with a single stroke of the comb, medium infestation is oil (from star anise), and ylang-ylang flower oil, the equal to one louse found with the first stroke of the comb, proportions of which are proprietary information) was and light infestation is equal to one louse found after supplied in 60-ml plastic bottles with a finger pump spray several strokes of the comb). In practice, most people with head. The permethrin lotion was supplied as 100-ml glass heavy infestation had at least 25 lice of all stages, and some bottles with a sprinkler opening containing an alcohol were estimated to have in excess of 500 mobile lice of all solution with 430 mg per 100 ml (0.43% w/v) permethrin development stages present, as well as viable eggs.
(permethrin, ethanol, propan-2-ol, water, propylene glycol, Those people with lice who conformed to the study and sodium dihydrogen phosphate; InfectoPedicul lotion, eligibility requirements were conducted through a standard InfectoPharm GmbH, Heppenheim, Germany).
informed consent and assent procedure. All family mem- In order to ensure a correct treatment, each of the bers over the age of 2 years who had lice and were products was applied in exact conformity with the otherwise eligible could be enrolled.
instructions for use supplied in the package. The coconut All participants agreed to be available for the 14-day and anise spray was applied to dry hair over its full length duration of the study prior to enrolment. Anyone who had a until wetted. When the permethrin lotion was applied, the known sensitivity to any component of the products; had hair was first shampoo-washed and then towel-dried, after used hair bleach, permanent colorants, permanent waves, or which, the lotion was applied drop by drop until all the hair undergone treatment with trimethoprim or co-trimoxazole was soaked with the fluid to the point of running off. In within the past 4 weeks; or who had used a pediculicide each case, the investigators spread the fluid through the hair within the previous 2 weeks was excluded. Also excluded using their fingers to ensure thorough coverage.
was anyone with a secondary scalp infection (impetigo), The coconut and anise spray was left in place for 15 min with a chronic scalp condition (e.g., psoriasis), was before washing out using shampoo and water. The pregnant or nursing, had participated in a clinical trial permethrin lotion was left for 45 min, after that period, it within the previous 4 weeks, or had previously participated was removed by rinsing with water alone. The washing process was performed by carers who were advised of the After consent was taken, baseline demographic data time to remove the product, which in many cases, while the were collected on gender, age, hair characteristics, previous investigator was still present. They were also advised not to divulge the identity of the treatment to investigators to investigators in batches of ten. A duplicate set was conducting assessments in order to maintain blinding.
prepared in case an emergency code break was required. As Those participants, treated using the permethrin lotion, each participant was enrolled, the investigators selected the were also asked not to shampoo their hair for 3 days.
next available numbered envelope available to them from the For both products, a second treatment was applied 9 days allocation. Randomization was by individual, so, when more later. Participants were advised not to use nit combs or other than one member of a family was enrolled, it was possible for pediculicide preparations during the course of the study.
them to receive different treatments.
Application of treatment could not be blinded due to the different physical and chemical natures of the study treatments.
This study was therefore single-blinded with post-treatment The primary outcome measure for the study was elimina- assessments performed by different investigators unaware of tion of infestation, i.e., no lice present, using two which treatment products had been used (assessor blinded).
applications of the product. Previous studies have shownthat it is possible to effect a cure using this treatment regimen but, because the background prevalence of lice inthe population is currently high , ], it is possible for Statistical analyses were performed by an independent participants to be reinfested after the second treatment. To statistical consultant. Fisher exact tests were used for address this problem, an algorithm used in past studies able presence/absence variables. Differences in success rates to distinguish moderate levels of reinfestation from cases of were measured by the 95% confidence interval (CI) treatment failure , was applied to this study also.
calculated using a normal approximation to the binomial Post-treatment assessments were conducted by dry distribution. Quantitative variables were compared by using detection combing using the “PDC” comb on days 2, 7, an unpaired t test or the Mann–Whitney U test.
11, and 14 after the day of first treatment. The aim of theseassessments was to determine whether any lice were stillpresent, and if any were found, they were collected in the case record and examined by microscope to determine thedevelopment stage and, if appropriate, the gender. Day 14 assessment was considered the most important, so, a morethorough combing examination was made on this day. A This study was performed between March and July 2008 in successful treatment was achieved if no lice were found on the counties of Cambridgeshire and Suffolk, UK. During days 11 and 14, following the second application of this time, 139 people from 49 households were screened for treatment. Outcomes of treatment were therefore catego- head louse infestation, and a further 117 household rized as cure, reinfestation following cure, or treatment members either declined screening or were unavailable.
Our aim was to eliminate lice from each household tominimize the risk of reinfestation, so, any person who had head lice but was ineligible to join the study was offered astandard of care treatment (Hedrin® 4% lotion) for self- A total sample size of 100 participants (50 in each of the administration. The most common household sizes were six treatment groups) was considered sufficient to detect a (23 participants) or four (20 participants). From those found difference of 35% between groups in the success rate at infested, consent to participate was obtained for 85 children 14 days, with 90% power and 95% confidence. This 35% and 15 adults between the ages of two and 49, median difference represented the difference between a 35% success 10 years. Most participants (78) lived in households with rate in one product group and a 70% rate in the other group.
more than one family member participating in the study, ten The actual sample size required was 47 per group, so, families having two participants in the study, 12 families recruitment of 50 per group made allowance for dropout.
three participants, two families four, and one family eachhaving five and seven participants.
The study group was divided equally between the two treatments (50 per group), and 96 participants completed Treatment allocation was in balanced blocks of ten derived the study (Fig. ). Two dropped out from the permethrin lotion group, requesting a rescue treatment following day 6 , seed 2348, 19 March 2008). Allocation at the point of assessment on ground of lack of efficacy. One participant delivery was made from instruction sheets enclosed in from the same family was lost to follow-up from the opaque, sealed, sequentially numbered envelopes distributed coconut and anise spray group, and one child from the spray group was excluded from per-protocol analysis was achieved by 21/50 (42.0%) of the participants in the because the wrong second treatment was applied. Data permethrin lotion group and by 41/50 (82.0%) of the from these participants were included in the intention to participants in the coconut and anise spray group. In both treat analyses. All other participants had complete data sets groups, all outcomes were counted as cures (no lice with two treatments 9 days apart and follow-up checks on following the second treatment), with only one case of reinfestation in each. The difference in rate of successbetween the two treatments was estimated as 40.0% (95% CI of 22.5% to 57.5%) which meant that the coconut andanise spray was highly significantly (p<0.001) more Table shows that there were no differences between the effective than permethrin lotion in the population tested.
groups in respect of age; gender (in both groups, the Elimination of protocol violators from the analysis gave majority were female); hair length, thickness, dryness/ per-protocol success rates of 44.7% for the permethrin oiliness, or degree of curl; intensity of infestation; or lotion group and 83.3% for the coconut and anise spray previous experience using head louse products. There was group, a difference of 39.6%, which was also highly also no difference with regard to medical history.
The main outcome analysis was the comparison of rates of In both treatment groups, some lice were found after the cure or reinfestation after cure in the total population of 100 first application of treatment. However, the numbers of lice participants analyzed. According to these criteria, success on each day and the range of developmental stages recovered at each of the assessments were generally greater lotion (p<0.05), which indicates that it was more effective in the permethrin lotion treated group compared with the to prevent louse eggs from hatching than the permethrin coconut and anise spray treated group (Table Examina- lotion. This means that for both treatments, the second tion for the presence of live lice on days 2 and 7, which is application is generally necessary for elimination of related to immediate activity of the treatments and to the infestation because some louse eggs may not be adequately ability of the treatments to inhibit louse eggs from hatching, coated with product during the treatment process. However, found that 35 (70%) of the participants in the permethrin 16 (32%) of those treated using permethrin lotion showed lotion group and 26 (52%) of the participants in the coconut all developmental stages of lice on one or both assessment and anise group had lice at one or more developmental days following the first treatment, compared with just two stages on either of these two days. In most cases, these lice (4%) of those treated with the spray, indicating that the were newly emerged nymphs. In the group treated using the efficacy of the permethrin product was significantly lower coconut and anise spray, the number of people with lice (p<0.01) and possibly affected by resistance to the approximately doubled between days 2 and 7 due to hatching of eggs, although the actual number of young All participants treated using permethrin lotion reported nymphs found on participants treated using the spray was not shampooing hair until at least 3 days after treatment. Of significantly lower than on those treated using permethrin these, 27/50 (54%) had not shampooed their hair by day 6 Table 2 Presence of lice on days 2, 7, 11, and 14 Number of participants with lice (number of participants [mean number of lice, range]) Lice at any stage 1st stage nymphs 2nd stage nymphs 3rd stage nymphs Adult males examination. In the per-protocol group, a non-significant trend was found in which those who delayed shampoo useuntil day 6 (9/25=36%) were less likely to be cured than There were 55 adverse events reported, and 37 participants those who shampooed between days 3 and 6 (12/23=52%).
reported one or more adverse events, 20 in the permethrin The quantity of treatment applied varied with the thickness lotion group, and 17 in the coconut and anise spray group.
(density) and length of the hair on each participant, longer Of these, 44 adverse events were recorded in 33 partic- and/or thicker hair requiring more product than shorter and/or ipants in relationship to study treatment. The remainder finer hair. If required, a second bottle of product was available (11 events) were related to concomitant illness or minor for use on long or thick hair in order to ensure adequate accidents. In the permethrin lotion group, 12 of the 50 coverage, but in practice, this was found to be unnecessary.
participants analyzed had a single adverse event, six had Weighing of the bottles before and after treatment two adverse events, one had three adverse events, and one allowed an estimation of the quantity of product applied had four events (20 participants experiencing an adverse at each treatment. Generally, approximately twice as much event and 31 adverse events in total). In the coconut and permethrin lotion was used as coconut and anise spray.
anise spray group, 12 of the 50 participants had one adverse Mean estimates of permethrin lotion used were 46 g (range event, three had two adverse events, and two had three from 13.8 to 85.1) for the first application and 44 g (range adverse events (17 participants with an adverse event and from 6.7 to 84.2) for the second application. Quantities of coconut and anise spray used were 30.6 g (range from 8.9 Adverse events related to treatment were mostly to 49.5) for the first application and 25.7 g (range from 6.8 stinging or burning sensations on the scalp or neck or to 49.7) for the second application.
both during and after treatment. Most of these events were The two products were comparable in their ease of apparently related to intensity of infestation and the application and of spreading the preparations through the number of bite reactions on the scalp. However, it was hair. However, there were some significant differences clear that the cause of the adverse events in each case was between the products with regard to the feeling of the the level of alcohol in the products, with a possible effect product on the hair and scalp. The coconut and anise spray from essential oil in the spray, these components being was more likely to feel itchy or warm rather than cool (p< likely irritants to broken or excoriated skin. Such events 0.01). The odor of the spray was considered strong were more or less evenly distributed between the two compared with that of the lotion (p<0.001) but was acceptable for both products, and the spray was considered No subject had a serious adverse event, and there was no more difficult to wash out, mainly because the hair was evidence of any difference between groups in respect of greasier after use (p<0.001). Nevertheless, a majority of frequency, outcome, action taken, relationship to study participants said they would prefer to use the spray again treatment, relationship to concomitant illness or drug, or compared with the lotion (86% vs 58%, p<0.004).
also required all parents/carers to comb the hair with a nitcomb to remove eggs and lice daily. Therefore, the level of We have found that coconut oil and anise spray gave intervention in those studies was greater than we employed, superior efficacy for elimination of head louse infestation yet the intention to treat cure rate for the Israeli study (60/70, than 0.43% permethrin lotion, both products applied on two 85.7%) was not significantly different from our result using only two applications 9 days apart. We cannot draw a Coconut and anise spray is a class I medical device that comparison with the Italian study because the combing acts by coating lice in an oily film, obstructing the component of treatment clearly contributed much of the respiratory system in a similar way to several other medical successful outcome as nearly all participants, including those device products for control of head lice , However, treated using a relatively weak comparator product, were as the application time is relatively short, it is likely that effectively cured by removal of all lice and eggshells before triglycerides persisting on the hair and lice subsequent to washing contribute to the efficacy. As the mode of action Physiological resistance to insecticide-based products is appears to be mainly due to the physical effects of coconut now considered widespread in Europe and North America oil coating the louse surface, it is not envisaged that lice [, –and affects not only pyrethroid insecti- may develop resistance to the product unlike pharmacolog- cides like permethrin but also the organophosphate mala- ically active insecticides like permethrin. Resistance to thion , and previously used chemicals like the permethrin has been shown to cause treatment failure in the cyclodiene hexachlorocyclohexane (HCH or lindane). The UK [We would therefore expect to encounter a extent of this resistance varies not only with the country but proportion of cases in every community with lice resistant also with the region, district, town, or even street [, , , ]. Consequently, there are no clear figures indicating the In practice, we found approximately one third of our proportion of cases in a population likely to experience participants did not respond to treatment using permethrin resistance, but resistance in some form has been found in lotion, and that the alcohol in the lotion does not appear to more than 80% of lice in some populations ], or to contribute to the activity of the product to ensure its influence the outcome of treatment in between 70% and effectiveness in use. In contrast, the coconut and anise 90% of cases of infestation in affected areas. As a spray was not only effective in most households, even result, physically acting preparations like coconut and anise where other family members treated using permethrin had spray are now the treatment of choice for many consumers, experienced treatment failure; it was also more cost especially as they are not affected by resistance, and there is effective. Based on the weights of product used in our no recognized mechanism whereby lice might develop study, we estimate that for an average application of 0.43% tolerance of these materials. As a result, we believe that permethrin lotion, the cost would be approximately €10.94 coconut and anise spray should remain a viable treatment per application (€2.43 per cl). In contrast, the cost of an option for most people well into the future.
average application of coconut and anise spray would beapproximately €9.64 (€3.32 per cl).
We were unable to detect any age-related trend for Acknowledgements This study was supported financially by Omega obtaining a successful treatment using either product, which Pharma NV, Nazareth, Belgium, which played no active role in the indicates that success, or lack of it, in eliminating lice was design of the study, interpretation of the results, or the writing of themanuscript. We wish to thank Dr Marc Dams and Isabelle Dedeken for not related to a likely increased risk of reinfestation in administrative support. Thanks also to Laurence Noiroux of S-Clinica, children as they played with their peers.
Brussels, Belgium for statistical analyses. Investigation team members We found a higher incidence of “stinging at the site of who contributed to the study but were not named as authors were Ian application” adverse events to treatment in this study than Jones, Audrey Pepperman, and Christine Sullivan. Medical supervisionfor clinical queries was provided by Dr Paul Silverston.
in our previous investigations [and this can only beattributed to alcohol components of treatment. However,none of the experiences lasted more than about 20 min and ceased when the alcohol had evaporated. We did notobserve any subsequent Draize-type reactions. There are 1. Burgess IF (1999) Dermatopharmacology of antiparasitics and no reported incidents of sensitization or allergy caused by insect repellents. In: Gabard B, Elsner P, Surber C, Treffel P (eds) any of the ingredients of either product, and we found no Dermatopharmacology of topical preparations. Springer-Verlag, evidence such reactions in our study.
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