Interventions for treating head lice

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

1. to compare the effectiveness of interventions for the treatment of pediculosis capitis;

2. to compare the effectiveness of different formulations (of lotion, shampoo, creme rinse, mousse or systemic treatments) of the same insecticide against pediculosis capitis;

3. to determine the safety and tolerability of topical chemical or herbal applications, physical methods or oral treatment agents used for treating pediculosis capitis; and

4. to determine the relative effectiveness of topical pediculicides, physical methods and oral treatments.

Background

Description of the condition

Infestation with head lice (Pediculus humanus capitis) is widespread and is common in children, but also affects adults, in all countries of the world, including high‐, middle‐ and low‐income countries. Head lice infestations can be unpleasant as they become intensely irritating and, if they are left untreated and the bites are scratched, skin infections may occur. In the long term, anaemia may occur. Attitudes to head lice infestation vary greatly between societies and even within different segments of a community. In many western societies, parents are often ashamed if their children have lice, because of the common misconception that the infestation is associated with a lack of hygiene. In some other societies, infestation with lice is more accepted.

The societal cost of treating head lice infestations is high. It has been estimated that in the USA the annual cost is $120 to $240 million for permethrin alone, based on an estimate of six to 12 million infestations every year. However, this is most likely an underestimation (Hansen 2004). Based on research by Gur, annual costs for the USA may be at least $500 million for permethrin alone (Gur 2009). In developed countries, over the counter (OTC) pediculicides (agents that kill lice) are expensive, which may cause difficulties for those on low incomes, especially if several members of the family need to be treated at the same time. In low‐ and middle‐ income countries commercial products are often not available, and when they are, they are often prohibitively expensive. In these circumstances, people may use cheaper or traditional treatments instead; in some cases, people have used low grade agricultural insecticides, which can be fatal (Wohlfahrt 1982).

The human head louse is an ectoparasite (that is, a parasite that lives outside the body of the host) of humans. The adult louse is a small insect 1‐3 mm in length. It has six legs and its colour varies from tan to greyish white. The lice do not have wings and they are not able to jump or fly. They have an obligatory blood‐feeding habit, which requires them to feed on their host's blood several times each day. They are normally found on the scalp, but have also been known to occur on the eyebrows. Infestation is spread from one person to another by head to head contact. Burgess (Burgess 1996) estimates that it takes at least 30 seconds for lice to move from one head to another, therefore fleeting contact will be insufficient for transferring lice between heads. Other ways of transmitting head lice have been investigated: fomite transmission (for example, hats and headbands) remains controversial (Takano‐Lee 2005) and there may be a potential for re‐infestation via pillowcases (Speare 2003).

Head lice infestation is diagnosed by the presence of live lice on the scalp (Teale 2008). Simply finding eggs is insufficient for a diagnosis as these may not be viable. In addition, the nits (hatched and empty eggshells) may be mistakenly identified by the untrained eye as viable embryonated eggs.

Once a person has contracted head lice, the infestation develops steadily if left unchecked. The female louse mates within a couple of days of moulting to an adult and begins laying eggs soon after. The eggs are deposited on a hair, and attached close to the scalp by a glue‐like glandular discharge secreted by the female louse. The eggs hatch in 6 to 9 days and the nymphs (juvenile lice that look like the adults, only smaller) feed soon after emergence. There are three nymphal instars, each of which is completed in 3 to 5 days, so within 9 to 15 days of hatching adult lice appear and begin laying eggs. It is only the third instar nymphs and the adult lice that are capable of spreading from one person to another; the first and second instar nymphs and the eggs are not.

Prevalence and manifestation

There are substantial differences in reported prevalence rates between countries. Most articles assess the number of infested schoolchildren. A prevalence of 1.6% (Williams 2001), 8.9% (Willems 2005) and 8.3% (Thomas 2006) has been found in the USA, Belgium, and Wales, respectively. In Turkey there was a prevalence of 6.8% (presence of either eggs or nits or lice) (Kokturk 2003), in Argentina of 14% (Catalá 2005) and in India a prevalence of 16.6% was found, although finding eggs only was considered to be sufficient for the diagnosis (Khokhar 2002). A South African article reports the prevalence in two schools: in one school, with only black children, none of the pupils appeared to be infested; in another, multiracial school, 8.6% were affected. However, finding viable eggs was enough to be considered as infested (Govere 2003).

The highest prevalence of head lice infestation occurs in children between the ages of 3 and 11 (Jones 2003, Meinking 1999). Girls show a higher prevalence than boys (Willems 2005, Williams 2001). Several suggestions have been made for this difference: girls' close contact with each other, their preference for longer hair and their interchange of fomites, like tiaras (Burkhart 2007, Willems 2005). Prevalence does not vary significantly with season, and any variation seen is probably due to an alteration in social behaviour rather than climate conditions (Wickenden 1985).

Many patients do not have symptoms (Mumcuoglu 1991). Any itching caused by the insect bites is an allergic reaction to the saliva of the lice, which is injected during feeding. In a first infestation, this pruritus itching) may take 2 to 6 weeks to develop (Burkhart 2006). This means that most people may not know that they have lice up until this point. If the child is infested for a second time, itching usually starts earlier, that is, in 1 to 2 days (Burkhart 2006).

As well as itching, other symptoms can be associated with head lice infestation. Head lice are one of the commonest causes of impetigo of the scalp in high‐income countries (Burgess 1995a). In exceptional circumstances, if the infection is caused by a nephritogenic strain of streptococci it may cause glomerulonephritis (kidney inflammation) (Mumcuoglu 1991). Pyoderma can occur when bite lesions are excoriated (destroyed by scratching). Bites may also become infected by the bacteria carried on the bodies or limbs of the lice or in their faeces. In some cases, infected bites have led to lymphadenopathy (lymph node enlargement) (Chung 1991, Mumcuoglu 1991). Some authors suggest there could be a relation between head lice infestation and some other infections, like trench fever and louse‐borne epidemic typhus. These infections are caused by the bacteria Bartonella quintana and Rickettsia prowazekii, respectively (Robinson 2003, Sasaki 2006).

Social impact

In Western societies, parents generally react with shock and revulsion when they discover that their children have head lice. This entomophobic reaction is common in most people and sometimes also occurs in the professionals dealing with the problem. The association of having head lice and being dirty is common although unfounded, as lice are equally likely to be found on clean or dirty hair. These reactions lead to difficulties when tracing contacts because parents often do not want to admit to their friends and other members of their family that their children have lice because of the embarrassment and social stigma attached. However, in other parts of the world, contracting head lice does not provoke such extreme reactions, so in theory contact tracing may be performed.

Description of the intervention

Interventions

An almost inexhaustible list could be made of interventions that have been tried to treat head lice. There are different categories of head lice treatments; topical (meaning that they are applied directly to the hair) and oral agents, physical methods and other measures. The most common interventions are discussed below and are shown in Table 1.

Table 1.

Overview of known treatments for head lice

Topical, presumed neurotoxic	Oral agents	Topical, presumed non‐neurotoxic	Physical
Benzyl alcohol	Albendazole (Akisu 2006)	Anise, ylang‐ylang and coconut oils (Mumcuoglu 2002)	Bald shaving of the head
Benzyl benzoate (Rajan 1975)	Co‐trimoxazole (Hipolito 2001)	Coconut and anise spray (Burgess 2010)	Bug busting (Bingham 2000)
Bioallethrin (Fan 1992)	Diethylcarbamazine (DEC) (Munirathinam 2009)	Coconut‐derived emulsion (Connolly 2009)	Electronic louse comb (O'Brien 1998)
Bioresmethrin (Maunder 1981)	Ivermectin (Nofal 2010)	Eucalyptus oil (Greive 2007)	Fine‐toothed comb (De Souza Bueno 2001)
Carbaryl (Maunder 1981)	Levamisole (Namazi 2001)	Grapefruit extract (Abdel‐Ghaffar 2010)	Hot air (Goates 2006)
Chlorphenamidine (Maunder 1981)	Thiabendazole (Namazi 2003)	Herbal oil	Metal comb combined with formic acid (DeFelice 1989)
Clophenothane (Jensen 1978)		Mayonnaise
Crotamiton (Karacic 1982)		Melaleuca oil (tea tree oil) and lavender oil (Barker 2010)
Dichlorodiphenyltrichloroethane DDT (Nelson 1957)		Melted butter
Deltamethrin or decamethrin (Camasmie Curiati 1984)		Natural plant extract (El‐Basheir 2002)
Deltamethrin and piperonyl butoxide (De Souza Bueno 2001)
Dimeticone (Heukelbach 2008)		Neem seed extract (azadirachtin) (Abdel‐Ghaffar 2007)
D‐phenothrin, phenotrin or sumithrin (Chosidow 1994)		Olive oil	Other measures
Isopropyl alcohol		Paw paw tree extract (twigs), thymol, and tea tree oil (McCage 2002)	Cleaning fomites (such as teddy bears)
Isopropyl myristate (Kaul 2007)		Petroleum jelly	Education (Norsa'adah 2006)
Ivermectin (Youssef 1995)		Quassia tincture (Jensen 1978)
Lindane (Brandenburg 1986)		Tub margarine
Malathion (Chosidow 1994)		Vinegar
Permethrin (Brandenburg 1986)
Piperonyl butoxide
Pirimiphos‐methyl (Sinniah 1983)
Pyrethrin (Clore 1993)
Spinosad (Stough 2009)
Stearyl alcohol

Historically louse control was achieved by physical means such as combing, picking out lice by hand or by shaving the hair. These physical means were also sometimes coupled with the use of naturally occurring medicines, which are still used extensively in poorer parts of the world, as modern alternatives are often too expensive or not available. In the UK, a combing method known as bug busting is also used to control head lice. This method requires the hair to be wet combed for 30 minutes every third or fourth day using a special comb. This comb makes it easier to remove lice as well as eggs, because it is finer toothed than a regular detection comb. Similar methods have been used elsewhere. A systematic database search led to the conclusion that "there is some evidence that wet combing is an effective treatment" (Tebruegge 2007). Although it is a time‐consuming intervention, Belgian parents were offered the choice and preferred it over the use of insecticides (Vander Stichele 2002).

Before the advent of modern insecticides, chemical treatments were either of botanical origin unique to each geographical region or based on inorganic poisons and petroleum‐based organics (Burgess 1995a). After the second world war, DDT was widely used for louse control, although the development of DDT‐resistant lice and environmental concern has led to its replacement with newer, more rapidly acting insecticides. Other pediculicides (from 'pediculicidal' meaning 'lethal to lice') that have been used previously, but whose use has been discontinued, include benzyl benzoate, crotamiton and lindane (gamma‐benzene hexachloride). Pediculicides that are still in use in Europe are malathion, permethrin, carbaryl, d‐phenothrin, bioallethrin and synergized pyrethrins. Two other pediculicides are known to be used for the treatment of head lice; deltamethrin (which is the same as decamethrin), which has been used in Brazil (Asenov 2010), and possibly in other South American countries (Sasaki 1985, Schenone 1985); and pirimiphos‐methyl in the Czech Republic (Rupes 1995) and Malaysia (Sinniah 1983). Ivermectin is being used systemically (Ameen 2010, Chosidow 2010) as well as topically (Youssef 1995), although it is not registered for use against head lice by the American Food and Drug Administration. Other antiparasitic drugs that have been used against head lice are albendazole (Akisu 2006, Munirathinam 2009), thiabendazole (Namazi 2003), levamisole (Namazi 2001) and diethylcarbamazine (Munirathinam 2009). Another systemic treatment that has been applied is the antibiotic cotrimoxazole (a combination of trimethoprim and sulfamethoxazole) (Hipolito 2001, Sim 2003).

Formulation

The way in which these insecticides are formulated into the marketed products may have a pronounced effect on their efficacy and acceptability. In some cases the vehicle for the pediculicide may also have some degree of pediculicidal effect that will enhance the performance of the insecticide. This must be taken into account when comparing products, which may have the same active ingredient (insecticide), but different formulations. Formulation can also affect the acceptability of the pediculicide to the public. The products that become the most popular and that are hence used most frequently are those that, in general, tend to be the easiest to use, with the shortest application time and the most pleasing cosmetic attributes (such as smell). This can lead to a single product domination of the market, which may result in an increased rate of resistance development.

Safety

Concerns regarding the toxicity of some of the insecticides used to treat head lice infestation have been expressed by members of the public and recorded in the popular press. Isolated incidents of toxicity have also been reported in the scientific literature (Culver 1988, Lee 1976, Lewis 1977, Scowen 1995, Shuster 1996).

Other measures

It is believed that time spent curing an individual is wasted unless infested contacts are also traced and treated. By doing this the risk of re‐infestation to the patient will be reduced, as will the degree of the transmission of lice on a wider scale. As most infestations have existed for weeks rather than days before they are discovered, contacts over the previous month are at risk. However, as tracing all contacts may not be feasible, studies may have restricted this to closer relations such as family members and classmates.

No nit policies

Something needs to be said about the so‐called 'no nit policy'. When a school has such a policy, it means that children who are identified as having nits in their hair are excluded from the school until they are free of them. Although the American National Pediculosis Association supports this policy (NPA 2011), it is widely criticised, for example, by the American Association of Pediatrics and the National Association of School Nurses (Frankowski 2010). When nits are found, it is not sure whether there are lice as well. In addition, children with nits miss school days and therefore a parent must stay away from work or a child‐minder has to be paid, which results in considerable costs (Mumcuoglu 2006).

Resistance

Resistance to permethrin is present worldwide, for example, in the USA (Yoon 2003), Denmark (Kristensen 2006), and Argentina (Vassena 2003). Downs et al. performed a study about pediculicides in England and concluded that lice showed resistance to permethrin, malathion, and phenothrin (Downs 2002); and that, furthermore, carbaryl resistance appeared to develop. Another country where malathion resistance has been demonstrated is Denmark (Kristensen 2006). A French study, conducted in elementary schools in Paris, concluded that some resistance to phenothrin had developed in head lice (Chosidow 1994). Differences in resistance patterns exist within countries, and even in schools in one city, as illustrated by an Australian study (Hunter 2003).

To delay resistance, a policy of rotating recommended insecticides on an annual or triennial basis was implemented by most health authorities in the UK. The monopoly that school health clinics held on the supply of pediculicides ended in 1992. Since then, the increasing availability of OTC pediculicides means rotation is unenforceable (Burgess 1998), and, coupled with existing resistance, is rendered ineffective. The current recommendation (Teale 2008) is to use a mosaic model, that is, the same product is used for a course of treatment (two applications spaced 7 days apart) and, if the first insecticide fails, a different insecticide from another substance class is used for a course of treatment.

In groups where there is resistance to a specific agent, it may be misleading to compare a new treatment with an old one, for example, when the old therapy reaches a cure rate of 50%, and the new agent performs significantly better (75%). The conclusion could be reached that the new agent is a real improvement, while 75% is still a relatively low rate of cure. Therefore, it is important to ask whether there could be background resistance to the therapy under investigation. Studies in Western countries, with high exposure to OTC pediculicides, are at risk for showing such significant improvements. In addition, pharmaceutical companies could make use of this phenomenon and wrongly suggest that their new therapy is extremely effective.

Comparisons

This review will examine the existing evidence, using randomized controlled trials (RCTs) of the effectiveness and safety of the preparations and methods used in the curative treatment of head lice infestation on humans. This review will concentrate on placebo (vehicle) controlled and comparative trials as these are the most useful types of study for comparing the efficacy of different active ingredients and formulations. In vitro studies will be excluded from the review because the methods used and the results obtained from these investigations do not give an accurate representation of the effectiveness of a product when used in the field on people infested with head lice. The susceptibility of laboratory lice to insecticides may be greater than that of field‐collected lice, as they will not have been subject to (the same) treatments as lice circulating in the population. Also, in in vitro studies the insecticide is often applied directly onto the louse, which is not representative of a real‐life situation.

Another aspect of topical treatments is their ability to kill the lice eggs (that is, their ovicidal effect). Although less important than the direct pediculicide effects of a treatment, it could influence the cure rate, as surviving eggs will hatch and need to be killed by a second application. Therefore, this review will examine the ovicidal effect (the percentage of egg mortality) as well.

A previous systematic review (not a Cochrane review) was conducted in 1995 by Vander Stichele (Vander Stichele 1995a). However, this review was criticized in a number of publications (for example, Burgess 1995b and Stallbaumer 1995), which indicated that the review was weak in certain areas, including the choice of some inappropriate quality criteria, such as the time or season of study and swimming. Some trials that were deemed to be of suitable quality, were found upon closer inspection to be seriously flawed in their methodological quality. The author agreed that analysis using stricter criteria would be appropriate and should be conducted as a Cochrane Review (Vander Stichele 1995b).

In 1999 the first version of this Cochrane review, 'Interventions for treating headlice' was published, and in 2001 it was last assessed as being up to date. It was withdrawn in 2006 because it was then considered out of date.

The overall aim of this review is to assess the comparative effectiveness of treatments for head lice.

How the intervention might work

The (supposed) working mechanisms of different treatment options are discussed here.

Topical pediculicidal agents

An important group of pediculicides are the neurotoxic agents, those that affect the nervous system of the louse. This can be realized in different ways. The effect of malathion rests on inhibiting the enzyme cholinesterase, while permethrin disturbs sodium transportation in neuron membranes (DrugBank 2010). Lindane blocks the γ‐Aminobutyric acid (GABA) gated chloride channel, resulting in hyperstimulation of the nervous system (DrugBank 2010, Lebwohl 2007).

The non‐neurotoxic agents have other properties that make them effective in treating head lice infestations. In dimeticone, several modes of action have been proposed, but it seems likely that its effect relies on the disruption of water excretion by the louse (Burgess 2009). It appears that benzyl alcohol keeps the spiracles of the louse opened, so the inactive components are able to enter the respiratory system and kill the louse (Meinking 2010).

Generally the pediculicide has to be applied twice, with a period of one week between the two treatments. Eggs need 6 to 9 days to hatch (see 'Description of the condition') and if they survive after the first phase of treatment, they will be killed by the second application.

Oral treatment

Most oral medication options against head lice consist of antiparasitic and antibiotic drugs.

Ivermectin is a broad spectrum antiparasitic agent, exerting its effect by increasing the influx of chloride ions in muscle cells and neuronal membranes. This influx leads to hyperpolarization of the cell that subsequently causes the paralysis and death of the parasite (DrugBank 2010, Lebwohl 2007). For ivermectin to be pediculicidal, the louse must feed on blood containing the active substance (Lebwohl 2007). Another way in which they are assumed to act is by disrupting the GABA‐mediated neurotransmission in the central nervous system (Chosidow 2010, DrugBank 2010 ).

The antibiotic agent cotrimoxazole is thought to exert its effect on the bacteria that live in the gut of the louse, therefore killing the louse (Lebwohl 2007).

Physical methods

The effect of physical methods relies on the physical removal or destruction of the lice and eggs. Combing is the most well known example of this group of therapies. Special, fine‐toothed combs are available that can be used to comb the wet hair. A benefit of combing wet rather than dry hair may be its retardation of the movements of the louse.

Hot air treatment can be applied. Its effect is assumed to be the desiccation of the louse (Goates 2006).

The proposed working mechanism of electronic devices (such as combs) is electrocuting the louse.

Takano‐Lee et al suggested that substances like petroleum jelly possibly could suffocate the eggs. Submersion in water is another option, but it would take at least 8 hours to kill the lice (Takano‐Lee 2004). Coconut and anise spray probably exerts its effect by generating an oily coat on the louse, so the respiratory system is blocked (Burgess 2010).

Other methods

A range of interventions aiming at restricting the spread of lice and re‐infestation is available, including education and cleaning measures, like washing teddy bears.

Why it is important to do this review

This is a protocol of a new Cochrane Review that supersedes the original Cochrane Review on interventions for head lice (Dodd 2001). A new protocol was needed because the methodology in various areas of systematic reviews has developed considerably.

Given the high prevalence of head lice infestation and the extensive supply of therapies, it is essential for clinicians and public health workers to have a reliable overview of these therapies, in order to make a well‐considered choice.

In 2001 the last updated version of this Cochrane review was published. However, in the last decade a considerable number of new trials have been performed, and the growing problem of resistance to regular treatments has led to the development of some new treatment options.

Objectives

1. to compare the effectiveness of interventions for the treatment of pediculosis capitis;

2. to compare the effectiveness of different formulations (of lotion, shampoo, creme rinse, mousse or systemic treatments) of the same insecticide against pediculosis capitis;

3. to determine the safety and tolerability of topical chemical or herbal applications, physical methods or oral treatment agents used for treating pediculosis capitis; and

4. to determine the relative effectiveness of topical pediculicides, physical methods and oral treatments.

Methods

Criteria for considering studies for this review

Types of studies

All published and unpublished RCTs comparing treatments for head lice, including placebo. We will also include trials where treatment was combined with health education or contact tracing, or a combination of these. The inclusion criterion for RCTs is that participants should have live lice or lice and eggs, present on their head before enrolment on the study, not just eggs alone.

Types of participants

For this review studies will be included if the participants are children of any age or adults diagnosed as being infested with head lice, as determined by the presence of live lice, not just eggs.

In the efficacy analysis, we will take into account whether the participants were exposed to pediculicides before the start of the study or a louse detection comb was used to remove lice following treatment with pediculicide, or both.

Types of interventions

Any topical treatment, physical method or oral/systemic treatment used to attempt to cure infestation with head lice including traditional herbal treatments. Physical control methods such as bug busting (combing) will also be included, and also the (additional) value of health education, or contact tracing combined with treatment, or both. In addition, measures to prevent re‐infestation or lice spreading to other people will be included.

Types of outcome measures

Primary outcomes

Patients being completely free from lice within 48 hours after first application by day 7 and by day 14, respectively. When a study assesses efficacy on days other than day 7 or 14 we will use these data as if they were day 7 or 14 (dependent on the assessment day: thus, for example, day 10 will be considered as day 7, and day 11 as day 14).

Secondary outcomes

1. The ovicidal effect (ability to kill eggs) of the treatment determined by comparing in vitro hatching rates (defined as the difference between pre‐treatment and post‐treatment hatch rates );

2. Adverse reactions

   1. minor: defined as causing no limitation of normal activities. Examples are stinging of the scalp and eye irritation that disappear after removing the lotion.

   2. moderate: defined as causing some limitation of normal activities. Examples are scalp stinging that continues for hours or longer after washing out the lotion, and dehydration of the scalp.

   3. major:defined as causing inability to carry out usual activities. This includes: fatal, life‐threatening, disabling or incapacitating side effects, hospitalization or prolonged hospitalization, newly diagnosed cancer;

3. Acceptability of compound and formulation to patient and the patient's parents (such as its ease of use and complaints about its odour), and the percentage of dropouts from the study;

4. Development of resistance: assessed by laboratory tests.

Search methods for identification of studies

Electronic searches

We will attempt to identify all potential studies regardless of language or publication status (published, unpublished, in press, and in progress).

Databases

We will search the following electronic databases, using the search terms and strategy described in Appendix 1: Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library; MEDLINE (1949 to present); EMBASE (1980 to present); CINAHL (1981 to present); LILACS (1982 to present). We will also search the metaRegister of Controlled Trials (mRCT) using 'headlice OR head lice OR pedicul*' as search terms.

We will search the following trial registers for recently completed and ongoing trials: www.clinicaltrials.gov; www.who.int/ictrp; www.controlled‐trials.com; www.trialregister.nl.

Searching other resources

Researchers, organizations, and pharmaceutical companies

We will contact researchers and pharmaceutical companies in the field (see Dodd 2001) to identify additional studies that may be eligible for inclusion.

Reference lists 

We will check the reference lists of all studies identified by the above methods.

Manual search

We will handsearch abstract books and proceedings of relevant conferences (specifically the international congresses on phthiraptera) from the date of the last search of the original review.We will reconsider the studies that were excluded in the original review, as our inclusion criteria have slightly changed since then.

Adverse effects

The Medicines Control Agency (MCA) in the UK, and the Federal Drug Administration (FDA) in the USA, will be contacted for details of any reports of adverse effects relating to the use of pediculicides. The data collected by the MCA are collated from the yellow card reporting scheme. Reports of adverse effects made to the FDA for OTC products are published in the Federal Register, but reports concerning prescription only medication are reported separately.

Data collection and analysis

Selection of studies

The titles and abstracts of all trials identified from the searched databases and other sources will be screened by two independent reviewers. These reviewers will independently select trials which meet previously defined inclusion criteria. Where agreement is not reached, a third reviewer will settle any debate.

Data extraction and management

Two authors will independently extract the data from the included studies. The data will be compared, and any disagreement will be resolved by a third author.

Assessment of risk of bias in included studies

Two authors will independently assess the risk of bias, with the following elements: generating the randomization sequence; concealment of allocation; blinding of patients, physicians and investigators; addressing incomplete outcome data; selective reporting and other bias (Higgins 2009).

Measures of treatment effect

Treatment effect will be measured using two outcomes:

1. proportion of patients without lice at day 1, day 7 and day 14.

2. ovicidal effect, calculated as pre‐treatment hatch rate (%) ‐ post‐treatment hatch rate (%) = % mortality.

All outcomes, which will presumably be dichotomous (cured or not) will be analysed as risk ratios.

Treatment effect can be analysed in different ways. The main primary outcome will be the pediculicidal effect, since the diagnosis relies on the presence of live lice. It is important to evaluate both the treatment's pediculicidal and ovicidal abilities, as killing only one of them does not end the life cycle of the louse.

The pediculicidal effect should ideally be determined by visual inspection shortly after application of the treatment, and after 7 and 14 days, respectively. The ovicidal effect should ideally be evaluated in vitro, by comparing the pre‐treatment with the post‐treatment hatch rate (%). Therefore, eggs need to be collected just before and just after applying the therapy, as well as after 7 and 14 days.

We will interpret effects in relation to changing resistance patterns, taking into account the year the study was done, the region, and failure rate in the comparator arm.

When in studies inspection took place after different follow‐up intervals we will select those that were closest to 7 and 14 days.

Some of the pediculicides available on the market kill both lice and their eggs. Therefore, the ovicidal effect of these products will be compared.

Ovicidal effect is calculated as

pre‐treatment hatch rate (%) ‐ post‐treatment hatch rate (%) = % mortality (of eggs)

We will also take into account whether the treatment strategy also included the environment, including treating other family members; treating the whole classroom and cleaning teddy bears,

Unit of analysis issues

It is not sure whether this will be an issue in this review, but it may be, for example, when groups of patients (school classes, schools or communities etc.) have been randomized or when a new treatment is used after the first one is unsuccessful. If relevant, we will follow the guidance provided in the Cochrane Handbook (Higgins 2009) to deal with these situations.

Dealing with missing data

We will describe the proportion of missing observations for our primary outcomes. We will attempt to collect missing data identified in published articles, abstracts and posters by collecting them from unpublished data, which we hope to obtain from the sponsors of clinical trials. If possible, further sensitivity analyses will be undertaken to determine the effect of the addition of these data to the final results. We will not impute data.

Assessment of heterogeneity

Our first assessment of the heterogeneity of included studies will be based on clinical judgment: patients, settings, and the part of the world where they were conducted. In case of sufficient homogeneity, we will assess statistical heterogeneity. We will pool data from different studies if I² < 70%.

Assessment of reporting biases

By searching trial registers we aim at reducing the risk of missing unpublished studies. However, this is relevant only for recent years, as trial registers are a recent phenomenon. If we have identified at least 10 studies with comparable outcomes, we will construct a funnel plot to assess whether there is a risk of publication bias.

Data synthesis

Depending on the homogeneity of the included studies, both clinically and statistically, data will be pooled. Both fixed‐ and random‐effects models will be applied in all analyses. There is no self‐evident cut‐off point for heterogeneity, especially clinical heterogeneity. By applying both models, we can show how they differ in their results.

Subgroup analysis and investigation of heterogeneity

1. For this update we plan the following subgroup analyses, if at least three studies per group are available and each group reports on at least 100 patients:

2. studies in high income countries versus low income and middle income countries;

3. studies in difficult‐to‐treat head lice versus other studies;

4. studies that assess the presence of lice at follow up comprehensively versus other studies;

5. studies that exclude patients who used treatment against head lice before entering the trial versus other studies; and

6. studies that combined pediculicidal treatment with comprehensive combing versus studies where pediculicidal treatment was not combined with combing.

In case of heterogeneity we will describe the study characteristics that are related to this heterogeneity.

Sensitivity analysis

We will perform sensitivity analyses by excluding studies of low quality; and comparing fixed‐ and random‐effects models.

Appendices

Appendix 1. Search strategies

Search set		CIDG SRa	CENTRAL	LILACSb	CINAHL	TOXLINE	SCIENCE CITATION INDEX and BIOSIS previews
	1	Headlice	Lice infestations/ Therapy [Mesh]	Headlice	Headlice ti, ab	Headlice	Headlice
	2	Head lice	Pediculus [Mesh]	Head lice	Head lice ti, ab	Head lice	Head lice
	3	Head louse	head louse ti, ab, kw	Head louse	Head louse ti, ab	Head louse	Head louse
	4	Pediculus	Head lice OR headlice ti, ab, kw	Pediculus	Pediculus ti, ab	Pediculus	Pediculus
	5	Pediculosis	Pediculus ti, ab, kw	Pediculosis	Pediculosis ti, ab	Pediculosis	Pediculosis
	6	1 OR 2 OR 3 OR 4 OR 5	Pediculosis ti, ab, kw	1 OR 2 OR 3 OR 4 OR 5	1 OR 2 OR 3 OR 4 OR 5	1 OR 2 OR 3 OR 4 OR 5	1 OR 2 OR 3 OR 4 OR 5
	7		Lice Infestations [Mesh]	Treatment$	Treatment* ti, ab	Treatment*	Treatment*
	8		1 OR 2 OR 3 Or 4 OR 5 OR 6 OR 7	Therap$	Therap* ti, ab	Therap*	Therap*
	9		Treatment* ti, ab, kw	Intervention$	Intervention* ti, ab	Intervention*	Intervention*
	10		Therap* ti, ab, kw	Shampoo$	Shampoo* ti, ab	Shampoo*	Shampoo*
	11		Intervention* ti, ab, kw	Crème rinse	Crème rinse ti, ab	Crème rinse	Crème rinse
	12		Shampoo* ti, ab, kw	Lotion$	Lotion* ti, ab	Lotion*	Lotion*
	13		Crème rinse ti, ab, kw	Mousse$	Mousse* ti, ab	Mousse*	Mousse*
	14		Lotion* ti, ab, kw	Comb$	Comb* ti, ab	Comb*	Comb*
	15		Mousse* ti, ab, kw	7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14	7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14	7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14	7 OR 8 OR 9 OR 10 OR 11 OR 12 OR 13 OR 14
	16		Comb* ti, ab	6 AND 15	6 AND 15	6 AND 15	6 AND 15
	17		Therapeutics [Mesh]		Randomized ti, ab		Randomized
	18		9 OR 10 OR 11 OR 12 OR 13 OR 14 OR 15 OR 16 OR 17		Randomised  ti, ab		Randomised
	19		8 AND 18		Randomly ti, ab		Randomly
	20				Group* ti, ab		Group*
	21				Placebo ti, ab		Placebo
	22				17 OR 18 OR 19 Or 20 OR 21		17 OR 18 OR 19 Or 20 OR 21
	23				16 AND 22		16 AND 22

 ^aCochrane Infectious Diseases Group Specialized Register

  ^bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2011) 

Search set	MEDLINEb	EMBASEb
1	Lice infestations/Therapy [Mesh]	Pediculosis [Emtree]
2	Pediculus [Mesh]	Pediculus [Emtree]
3	head louse ti, ab	head louse ti, ab
4	Head lice OR Headlice ti, ab	Head lice OR Headlice ti, ab
5	Pediculus ti, ab	Pediculus ti, ab
6	Pediculosis ti, ab	Pediculosis ti, ab
7	Lice Infestations [Mesh]
8	1 OR 2 OR 3 Or 4 OR 5 OR 6 OR 7	1 OR 2 OR 3 Or 4 OR 5 OR 6
9	Treatment* ti, ab	Therapy [Emtree]
10	Therap* ti, ab	Therap* ti, ab
11	Intervention* ti, ab	Intervention* ti, ab
12	Shampoo* ti, ab	Shampoo* ti, ab
13	Crème rinse ti, ab	Crème rinse ti, ab
14	Lotion* ti, ab	Lotion* ti, ab
15	Mousse* ti, ab	Mousse* ti, ab
16	Comb* ti, ab	Comb* ti, ab
17	Therapeutics [Mesh]
18	Pediculicid* ti, ab	Pediculicid* ti, ab
19	chlorphenamidine ti, ab	chlorphenamidine ti, ab
20	bioresmethrin ti, ab	bioresmethrin ti, ab
21	ivermectin ti, ab	ivermectin ti, ab
22	malathion ti, ab	malathion ti, ab
23	permethrin ti, ab	permethrin ti, ab
24	dimeticone ti, ab	dimeticone ti, ab
25	Lindane ti, ab	Lindane ti, ab
26	crotamiton ti, ab	crotamiton ti, ab
27	spinosad ti, ab	spinosad ti, ab
28	bioallethrin ti, ab	bioallethrin ti, ab
29	phenothrin ti, ab	phenothrin ti, ab
30	Piperonyl butoxide ti, ab	Piperonyl butoxide ti, ab
31	sumithrin ti, ab	sumithrin ti, ab
32	d‐phenothrin ti, ab	d‐phenothrin ti, ab
33	deltamethrin ti, ab	deltamethrin ti, ab
34	decamethrin ti, ab	decamethrin ti, ab
35	carbaryl ti, ab	carbaryl ti, ab
36	Pyrethrin ti, ab	Pyrethrin ti, ab
37	Pirimiphos‐methyl ti, ab	Pirimiphos‐methyl ti, ab
38	DDT ti, ab	DDT ti, ab
39	Benzyl alcohol ti, ab	Benzyl alcohol ti, ab
40	Benzyl benzoate ti, ab	Benzyl benzoate ti, ab
41	Isopropyl myristate ti, ab	Isopropyl myristate ti, ab
42	clophenothane ti, ab	clophenothane ti, ab
43	Isopropyl alcohol ti, ab	Isopropyl alcohol ti, ab
44	Stearyl alcohol ti, ab	Stearyl alcohol ti, ab
45	albendazole ti, ab	albendazole ti, ab
46	thiabendazole ti, ab	thiabendazole ti, ab
47	levamisole ti, ab	levamisole ti, ab
48	diethylcarbamazine ti, ab	diethylcarbamazine ti, ab
49	cotrimoxazole ti, ab	cotrimoxazole ti, ab
50	Co‐trimoxazole ti, ab	Co‐trimoxazole ti, ab
51	coconut ti, ab	coconut ti, ab
52	anise ti, ab	anise ti, ab
53	Ylang‐ylang ti, ab	Ylang‐ylang ti, ab
54	mayonnaise ti, ab	mayonnaise ti, ab
55	Petroleum jelly ti, ab	Petroleum jelly ti, ab
56	Tub margarine ti, ab	Tub margarine ti, ab
57	Herbal oil ti, ab	Herbal oil ti, ab
58	Olive oil ti, ab	Olive oil ti, ab
59	vinegar ti, ab	vinegar ti, ab
60	Melted butter ti, ab	Melted butter ti, ab
61	Neem seed ti, ab	Neem seed ti, ab
62	azadirachtin ti, ab	azadirachtin ti, ab
63	grapefruit ti, ab	grapefruit ti, ab
64	melaleuca ti, ab	melaleuca ti, ab
65	Tea tree ti, ab	Tea tree ti, ab
66	lavender ti, ab	lavender ti, ab
67	Natural plant ti, ab	Natural plant ti, ab
68	eucalyptus ti, ab	eucalyptus ti, ab
69	quassia ti, ab	quassia ti, ab
70	paw ti, ab	paw ti, ab
71	thymol ti, ab	thymol ti, ab
72	Electr* ti, ab	Electr* ti, ab
73	bug ti, ab	bug ti, ab
74	Bust* ti, ab	Bust* ti, ab
75	Formic acid ti, ab	Formic acid ti, ab
76	air ti, ab	air ti, ab
77	Hot air ti, ab	Hot air ti, ab
78	shaving ti, ab	shaving ti, ab
79	bald ti, ab	bald ti, ab
80	9 OR 10 OR 11 … OR 77 OR 78 OR 79	9 OR 10 OR 11 … OR 77 OR 78 OR 79
81	8 AND 80	8 AND 80

 ^bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2011)

What's new

Date	Event	Description
22 May 2018	Amended	This protocol was published in 2011 on the Cochrane Library. It has been withdrawn due to lack of progress by the review author team.

Contributions of authors

Johannes C van der Wouden and Tim Klootwijk drafted the revision of the protocol. Arie Knuistingh Neven, Just Eekhof, Robert Vander Stichele, Laurence Le Cleach and Giao Do commented on the drafts.

Sources of support

Internal sources

• Department of General Practice, Erasmus MC, Rotterdam, Netherlands.

  In kind support

• Department of General Practice, University Medical Center, Leiden, Netherlands.

  In kind support

External sources

• No sources of support supplied

Declarations of interest

The authors declare they have no conflict of interest.

Notes

This protocol was published in 2011 on the Cochrane Library. It has been withdrawn due to lack of progress by the review author team.

Withdrawn from publication for reasons stated in the review