Comparing the efficacy of three methods of permethrin application in pediculosis capitis: A randomized clinical trial

Pediculosis capitis, also known as head lice, is a common problem that affects individuals of different socio‐economic backgrounds. Permethrin is generally considered the first‐line treatment option for head lice.


| INTRODUC TI ON
Pediculosis capitis, commonly known as head lice, poses a significant health concern for individuals of all ages and socio-economic backgrounds, particularly school-age populations. 1 Head lice feed on blood by piercing the scalp multiple times per day, thereby exposing the host to diseases and causing various problems such as itching, scratches, swelling, and secondary bacterial infections. 2 In addition to serious implications for personal hygiene, infestations can lead to social isolation, school and work absenteeism, learning disabilities, lack of self-confidence, and even psychiatric disorders. 35][6] Effective control of pediculosis requires the treatment of infected individuals. 7o main methods for treating pediculosis are the mechanical removal of lice from the hair and the use of topical pediculicides.
][10] Various pharmaceutical formulations are available, but permethrin shampoo 1% is the first-line treatment and is available without a prescription in Iran.However, other treatments such as organochlorines (lindane), organophosphates (malathion), and carbamates (carbaryl) are not widely used due to their side effects. 11udies have reported different prevalence rates for head lice infestations.In the United States, 6 to 12 million people become infected every year, costing about $367 million. 12In Iran, the prevalence of head lice among students in Hamedan was 6.85%, in Qeshm 23.9%, and in Kerman 1.8%. 13A study on permethrin found that licefree rates were 83% on Day 2, decreasing to 46% on Day 8 before a second treatment, and then increasing to 78% on Day 9 after the second treatment, remaining at 78% on day 15. 14Another study by Soleimani-Ahmadi et al. 15 found that adding another dose on Day 14 after the first dose increased the response rate from 68.9% to 90.3% among infested students in the southeast region of Iran.In this study, the effects of expanding the time of exposure in each session were also studied, as opposed to using a booster dose.
It has been demonstrated that following the manufacturer's instructions for permethrin shampoo, which involves leaving the shampoo on infested hair for 10 min and repeating the treatment in 7 days if lice are still present, does not yield satisfactory results. 16r own field studies confirm that using shampoo, while convenient, is not an effective method of treatment.It should be noted that the FDA-approved monograph for the treatment of head lice specifies the use of a "crème rinse," which is distinct from shampoo. 17eatment failure often occurs due to a lack of treatment adherence and continued contact with infested, individuals. 18Although the epidemiology and methods for controlling pediculosis have been studied, further research is necessary to evaluate drug effectiveness, given the increase in drug resistance. 19,20ven the high rate of treatment failure, we conducted various treatment regimens to assess their effectiveness.It is desirable to eradicate the disease as soon as possible to prevent its spread.
Therefore, the purpose of this study was to evaluate and compare the therapeutic effects of three different treatment methods for head lice.

| MATERIAL S AND ME THODS
The study was a double-blind, parallel, randomized, and controlled

| Objectives & interventions
The objective of this study was to compare the clinical efficacy of three different methods of permethrin application in treating pediculosis capitis.The first group was treated with the approved protocol of 1% permethrin cream (Gilaranko Company), while the second group received the manufacturer's recommended protocol of 1% permethrin shampoo (Gilaranko Company).In contrast, the third group applied the 1% permethrin shampoo for an hour.All intervention groups received education on fine-toothed combing as a supplementary treatment method.

| Sample size
According to a study conducted by Musa Soleimani Ahmad et al., 15 the prevalence of head lice in Bashagard city, located in the Hormozgan province of southeastern Iran, was found to be 67%.The study also reported the effectiveness of 1% permethrin shampoo in the first and second weeks to be 29.2% and 68.9%, respectively.The Odd ratio and Effect Size were calculated using G*Power software, which revealed a response rate (P1) of 69% in the first group and an optimal response rate (P2) of 80%, resulting in an effect size of 0.13.To detect a significant difference in eradication rates between the groups at 3 weeks, with a power of 80% and a two-tailed p-value of 0.05, a sample size of 30 participants was required in each group.If an enrolled subject had any first degree relative diagnosed with dry-combing and, if infested, was enrolled into the same treatment arm as the subject.

| Randomization & blinding
For the randomization process, the block randomization method was employed.To achieve this, 10 blocks consisting of 9 people were created using the Sealed Envelope online software, with 30 patients assigned to each group.The groups were labeled as Group A, Group B, and Group C, and the software generated 10 blocks of 9 options.
Out of a total of 90 codes, 30 were allocated to Group A, 30 to Group B, and 30 to Group C.
In this trial, the assessors were blinded to the treatment allocation.Although the patients applying the treatment were able to distinguish between the different products based on their physical attributes, blinding was achieved by employing separate staff for the application and data assessment processes.The analysts who performed the final efficacy analysis for each treatment group were also blinded to the identification of each treatment group until the completion of the analysis.

| Method of the study
The study included 157 participants with head lice over the age of six, who were referred to two pharmacies located in the north and west of Tehran.Each subject underwent a comprehensive examination for head lice or nits using eye examination (objective observation by combing, involving examining a section of hair that may be infested with lice) and dry combing (combing the hair from the scalp to the tip of the hair using a fine-toothed without using water. Each section of hair should be combed up to six times) by a trained individual.Inclusion criteria consisted of being over 6 years of age, residing in Tehran, and having head lice or nit based on eye examination or dry combing.Individuals with a history of allergies to permethrin in any formulation, scalp disease, non-adherence, treatment with lice products in the last 4 weeks, and pregnant women were excluded from the study.All participants completed the consent form, and at the beginning of the study, the examiner filled out the case report form (CRF) for each individual.
All patients were treated using one of three methods, and after using the product according to the specified duration in each group, they were instructed to comb their hair with a finetoothed comb and then rinse with lukewarm water.Follow-up appointments were scheduled at the end of the first, second, and third weeks to monitor the treatment process and to check for any side effects.The products were provided for a week, and patients were required to attend an appointment at the end of each week.
At the end of the third week, a trained person examined the subjects' hair for the presence of lice, and a questionnaire was filled out.Three individuals were excluded from the study, as depicted in Figure 1.

| Evaluation criteria
To assess the efficacy of each method, the absence of lice was determined in individuals who underwent the dry combing method.A trained person inspected the presence of lice on Day 1 and at the end of the first, second, and third weeks.

| Statistical analysis
Statistical analysis was conducted using SPSS software version 25.
Initially, the collected data from the surveys were transferred to the software, and descriptive statistical methods such as frequency reporting, mean, and standard deviation were used.To compare the means of the groups, the ANOVA test was employed with a significance level of 0.05.

| RE SULTS
Out of the initial 157 patients, 154 cases (95 women and 59 men) completed the study per protocol.There were no significant differences observed in demographic and baseline characteristics among the patients.A more detailed presentation of the baseline results can be found in Table 1.
The group that received permethrin shampoo for 1 h showed the lowest average time for lice eradication (per week) with a value of 1.22 ± 0.42, which was statistically significant when compared to the other two groups (p < 0.05).Moreover, the mean itching time in the 1-h permethrin shampoo group was significantly lower than in the other groups (p < 0.05).Table 2 presents the average time of lice eradication and itching elimination in each group.
A clearer illustration of the trend of the response rate of infestation and itching can be found in Figures 2 and 3.
Post hoc analysis revealed that the group receiving 1-h permethrin shampoo exhibited the shortest time to eradicate lice compared to the other two groups.Additionally, the group receiving 1-h permethrin shampoo showed a shorter time to eliminate itching (on a weekly basis) compared to the other two groups, which was statistically significant (p = 0.001).Table 3 presents the results of this analysis.Some cases of local discomfort such as erythema and scalp skin rash were reported in the study.One person reported this symptom while using the cream method, while the number increased to 2 for shampoo users in the 10-min group and 4 in the 1-h group.
One patient in the 1-h permethrin shampoo group discontinued the treatment due to morbilliform skin eruptions, while another patient in the permethrin cream group stopped treatment due to erythema and localized edema.

| DISCUSS ION
Permethrin treatment failure is a common issue, leading to the use of organophosphorus and organochlorine poisons that have more complications and limitations than permethrin. 14To address this, some treatment protocols suggest continuing permethrin treatment and repeating it for several weeks.However, studies 10,15 have shown that in some areas, the initial response to treatment is <50%, and prolonging infection duration increases the likelihood of transmission.Despite this, no studies have evaluated the effectiveness of increasing permethrin exposure time per session versus increasing the number of sessions.
This study aimed to assess and compare the effectiveness of three permethrin treatment methods for head lice.Results indicated a significant difference in the time it took to eradicate lice and eliminate itching using the 1-h permethrin shampoo regimen compared to the other two regimens (10-minute permethrin shampoo and permethrin cream).
Soleimani Ahmadi et al. conducted a study in 2017 in which 150 female students aged 7-12 years from six villages in Bashagard city of Hormozgan province were randomly assigned to intervention and control groups.In the intervention group, each student received three bottles of 60 mL of 1% permethrin shampoo.The patients were instructed to use the shampoo once every 7 days, leaving it on their hair for 10 min each time.The study showed that the effectiveness of 1% permethrin shampoo at the end of the first, second, and third weeks was 29.2%, 68.9%, and 90.3%, respectively. 15 Soleimani's study, the response rate to permethrin shampoo treatment in the first week was 29.2%, while in this study, the response rates with shampoo and cream were 50% and 49%, respectively.This difference may be due to low compliance or the pattern    The study found no significant difference in efficacy between permethrin shampoo and cream, but patients tended to prefer shampoo due to its ease of use.In the 1-h permethrin shampoo group, head lice were removed in 76% of patients in the first week, which was significantly higher than the other two groups and very close to the desired response rate of 80% in the first week.Local side effects trended higher in the 1-h shampoo group, but the difference was not statistically significant and the side effects were tolerable.
This study also assessed the presence of head itch in patients.
Results indicated a significant difference in the incidence of itching between the group that received 1-h permethrin shampoo and the other two groups in the second week.This can be explained by the fact that itching is caused by the stimulation of proteins in lice saliva and can persist for some time after lice eradication.
However, the ongoing presence of itch does not indicate treatment failure, and itching typically subsides after lice eradication. 24Our results were consistent with this finding, as the response rates were significant between groups for the first week of lice eradication and the second week of itching elimination, as demonstrated in Figures 2 and 3.
Dimeticone formulations have been used as an alternative to permethrin for lice control.Studies have compared permethrin and dimeticone, with some showing that dimeticone was more effective.
For instance, in the study by Kalari et al., 25 participants used either 1% permethrin, 0.2% parasidose (d-phenothrin), or 4% dimeticone lotion twice a week, and the dimeticone group had a full response.
Another study 26 found that applying dimeticone liquid gel was significantly more effective than twice applying permethrin cream rinse (p < 0.001).Based on these findings, a well-designed randomized controlled trial comparing 1-h permethrin with dimeticone application could determine whether increasing permethrin exposure time overcomes resistance, as dimeticone is not as widely known, used, and affordable as permethrin formulations.

| Limitations
A key constraint of the current investigation was the inability to implement blinding procedures.To mitigate this potential source of bias, the prescriber and the patient's trainer were excluded from involvement in the evaluation of treatment response and patient follow-up.

| CON CLUS ION
Prolonging the exposure time to permethrin shampoo to 1 h resulted in a higher rate of lice eradication during the initial week and improved relief from itching during the second week.While this extended exposure did lead to a slightly higher incidence of local side effects, these complications were deemed tolerable by the patients.
trial that took place between April and September 2021.The study was registered with the ethics committee of the Faculty of Pharmacy at Shahid Beheshti University of Tehran under the code IR.SBMU.PHARMACY.REC.1398.109.Additionally, the study was registered on the Iranian Registry of Clinical Trials (IRCT) website, which is a primary register set up by the World Health Organization (WHO), with registration number IRCT20170608034390N8 on November 14, 2021.

F I G U R E 1
Flow diagram for clinical trials.| 3069 GHALANDARI et al.TA B L E 1 Baseline patient characteristics.

F I G U R E 3
of lice-free participants End of first week End of second week End of third week *: p -value = 0.008 **: p -value = 0.004 * ** Rate of scalp itching alleviation (%).
of first week End of second week End of third week *: p -value = 0.042 **: p -value = 0.02 ** * Percent of lice-free participants of resistance to permethrin.Genotyping in another study 21 revealed high levels of mutation among samples from Canada and the United States, likely due to the intensive use of pyrethrins-or pyrethroidbased pediculicides.Similar studies in Thailand 22 and Europe 23 have also shown a rise in resistance.The high success rate observed in this study could suggest a way to overcome resistance due to mutations without resorting to highly toxic alternatives, by prolonging the time of exposure.

Variable Permethrin shampoo 10 min Permethrin shampoo 1 h Permethrin cream rinse 10 min p-value
Time to eradicate lice and eliminate itching by group.
F I G U R E 2 Rate of eradication (%).