Ryan Mitchell Associates LLC, Westfield, New Jersey
Address correspondence to William G. Ryan, B.V.Sc., Ryan Mitchell Associates LLC, 16 Stoneleigh Park, Westfield, NJ 07090, or e-mail: email@example.com. Ellen Koch, M.D., is currently at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
Head lice are a source of scalp irritation, social disruption, and loss of school time. Health care providers need authoritative information to help avoid the costs and risks of ineffective treatment. A review was completed to provide relevant information on infestation treatments available in the United States. Three major biomedical databases were searched from 1985, when current products were first available, to 2014, focusing on U.S. reports. A total of 579 references remained after duplicates were removed. A search of the U.S. Food and Drug Administration website and labels of approved products were reviewed. A marked decline in the effectiveness of permethrin and synergized pyrethrins was found, probably because of resistance arising from widespread and indiscriminate use, and the emergence of knockdown resistance mutations. The potential toxicity of lindane in the setting of readily available, safer, and more effective alternatives, should limit its use. Prescription products shown to be safe and effective with a single application, without nit combing, are topical ivermectin, malathion, and spinosad, whereas benzyl alcohol requires two applications. Home remedies such as mayonnaise, and essential oils, have not been demonstrated to be safe or effective, and may carry potential for severe adverse events. The high risk of failure of over-the-counter treatments in eliminating head louse infestations drives a need for health care provider recognition of the limitations of current treatments and for judicious use of treatments that remain effective.
Head lice (Pediculus humanus capitis) cause scalp irritation, social disruption, poor sleep, excoriations that risk bacterial superinfection, and loss of school and caregiver work days [1, 2]. To ensure appropriate management of infestations, health care providers need objective information to avoid the costs and risks of ineffective treatments and to set realistic outcome expectations. To address that need, a group of experts with detailed knowledge of the subject, including completion of original research or significant experience in the day-to-day management of infestations, collaborated on a detailed review of the most commonly used treatments in the United States.
The head louse life cycle is completed entirely on the host, with transmission largely the result of head-to-head contact. Eggs are laid close to the scalp (up to 6 inches down the hair shaft in warmer temperatures), attached to hair by a proteinaceous cement that the female louse secretes. No evidence has demonstrated the effect of any treatment in dissolving this cement or facilitating the removal of eggs. Eggs hatch in 7 to 10 days and the immature louse, a nymph or instar, begins feeding within 1 minute after hatching (Fig. 1), undergoing three molts before reaching the adult stage and achieving reproductive capability within 24 hours after the final molt .
In the United States, filling of prescriptions for the treatment of infestations had a seasonal peak in July to September for 2012 to 2014, coinciding with the back-to-school period1 (Fig. 2). There has been an increase of approximately 4% in prescriptions over each prior year, possibly because of more infestations or more infestations failing nonprescription over-the-counter (OTC) or home remedy approaches.
This review focused on pharmaceutical therapies available in the United States. Compounds registered with the U.S. Food and Drug Administration (FDA) are presented chronologically according to time of initial use to treat head louse infestations, followed by a brief review of compounds that are promoted without FDA approval for use in cases of head louse infestations.
Materials and Methods
Three major biomedical databases were searched: Embase (term: Pediculosis; Medical Subject Heading term: louse infestations), Medline via the Embase.com database platform, and Chemical Abstracts via STN. Additional searches of PubMed were completed through October 2015. The main keywords and headings searched were Pediculus capitis, pediculosis, head lice, therapy, drug therapy, and known pediculosis therapy names (natural pyrethrins, permethrin, lindane, malathion, 5% benzyl alcohol, spinosad, ivermectin). The results were limited to English. The search strategy for two Cochrane Systematic Reviews (one withdrawn since publication) on head lice provided additional terms [3, 4]. All references were downloaded into a Reference Manager (RefMan) database and duplicates were removed, yielding a total of 579 references. Compounds not registered with the FDA but discussed in U.S.-based peer-reviewed journals and on the Centers for Disease Control and Prevention (CDC) website were searched, as were publications relevant to head louse resistance. Additional references were included from the bibliography of selected articles if justified. The FDA website was searched using product and active ingredient names, and all label information was reviewed. References were listed in an Excel spreadsheet, which all authors reviewed.
Results: Head Louse Infestations—Therapy
Lindane, a prescription medication first registered in the 1950s, inhibits the γ-aminobutyric acid (GABA) receptor–chloride channel complex, leading to insect neuronal hyperstimulation, followed by paralysis and death . A 1995 systematic review concluded that lindane was insufficiently effective to justify use for head louse infestations . Banned in California, lindane carries a box label warning of serious adverse events, including death, at the recommended dose rate [5, 7, 8]. Lindane is indicated for patients who cannot tolerate or have failed other approved therapies and should be used with caution in infants, children, elderly adults, immunosuppressed individuals, individuals weighing less than 110 pounds, and patients taking seizure medications . The potential toxicity, the corresponding label limitations, and the availability of approved safer and more effective alternatives limit lindane's use.
Pyrethrins and Permethrin (pyrethroids)
The pyrethrins and permethrin have been available for treatment of head louse infestations since the early 1980s and are registered by the FDA as OTC products. Extracted from chrysanthemums, pyrethrins are unstable and easily inactivated, and are often combined with a synergist, piperonyl butoxide (PBO), to enhance effectiveness. Modification of their molecular structure produces “synthetic” pyrethroids, which are more environmentally stable than “natural” pyrethrins. Permethrin, a pyrethroid, is the most widely used head louse treatment in the United States. These compounds target voltage-sensitive sodium channels (VSSCs) in the insect nervous system, causing nerve depolarization and hyperexcitation followed by muscle paralysis and death [9, 10].
Long-term use has confirmed the safety of these compounds, but a shared site of action with dichlorodiphenyltrichloroethane (DDT), and widespread use linked to easy OTC availability may have contributed to a progressive and substantial decline in their effectiveness. Published data involving clinical evidence of product failure, ex vivo studies, and genotypic evidence from head lice collected from across the United States support that the emergence of resistance has caused this decline.
Clinical Evidence of Pyrethroid Resistance
In the United States, randomized controlled trials (RCTs) investigating the effectiveness of pyrethroids in the control of infestations have been reported over four decades (Table 1) [11-19]. In the early studies, effectiveness was 96% to 100%. Recent clinical studies from across the United States have found that permethrin effectiveness has declined to 25%, even with nit combing, a level described as being no better than placebo [18-20].
Table 1. Clinical Effectiveness Studies of Permethrin and Pyrethrins Reported from the United States
Year of publication (reference)
Nit combing used
Single-treatment effectiveness, %
Efficacy based on a single treatment or a second contingent treatment applied to treatment failures.
Anecdotal reports of inefficacy emerging in the 1990s prompted ex vivo investigations. One investigation compared head louse populations taken from children in Idaho and Massachusetts with a history of likely permethrin exposure with populations from children in Sabah, Borneo, with no such history . Whereas the lice from Borneo were susceptible to increasing permethrin concentrations, those from the United States were not, indicating that greater frequency of use or greater concentrations of permethrin would not improve effectiveness. In another investigation, head lice from children in Ohio survived a 15-minute immersion in marketed formulations of PBO-synergized pyrethrins or permethrin .
Genotypic Evidence of Resistance
Genotyping investigations have demonstrated a strong link between heritable recessive genetic point mutations and head lice survival after exposure to pyrethroids . These knockdown resistance (kdr) mutations in the VSSC α-subunit gene cause insensitivity to pyrethroids at their targeted binding site and align with mutations linked to nerve insensitivity to DDT and resistance to pyrethroids in other insects [24, 25]. Widespread applications of DDT in the mid-20th century may have facilitated the emergence of kdr mutations in head lice, which has been accelerated by the widespread use and easy availability of pyrethroid compounds as head louse treatments since the 1980s .
Genetic testing has demonstrated an almost uniform distribution of kdr mutations in head louse populations throughout the United States. In populations collected between 1999 and 2008, kdr mutation frequency was 84.4%; the frequency has since increased to 99.6% .
It was reported that permethrin treatment eliminated head lice carrying kdr mutations . This report is yet to be confirmed in peer-reviewed literature but nonetheless points to the possibility of factors other than kdr mutations contributing to pyrethroid treatment failures, including improper application, other resistance mechanisms such as cuticular modifications that result in reduced insecticide penetration, and metabolic changes that allow the insect to inactivate or expel the chemical before it exerts its fatal effects . Overall, the almost uniform distribution and homozygosity of kdr mutations in head lice in the United States indicate that the most likely outcome of applications of pyrethrins or permethrin for head louse infestations is treatment failure.
Malathion (formulated with isopropyl alcohol [78%] and terpineol [12%])
Malathion, an organophosphate insecticide, irreversibly inhibits acetylcholinesterase, leading to accumulation of acetylcholine in the cholinergic synapse, neuronal hyperexcitability, and insect death . Initially approved by the FDA in the 1980s, malathion (0.5%) head louse shampoo was subsequently withdrawn. By 1998, concern about resistance to then-available products led the CDC to request its reinstatement .
The formulation is applied to the hair, which is allowed to dry naturally and then shampooed 8 to 12 hours later . One RCT showed elimination of infestations in 29 of 30 patients 14 days after a single treatment or 7 days after a contingent treatment applied 7 days after the first. In another RCT, an 80% cure rate (35 of 44 patients) after a single 20-minute exposure indicates that a shorter application period may be appropriate but requires validation in a multicenter study . The absence from the United States of reported head lice resistance to malathion, which is widespread in many countries, has been attributed to the activity of formulation excipients that are complementary to the toxic action of malathion [9, 17, 28, 30].
Although generally regarded as safe, the malathion formulation is malodorous, flammable, and irritating; labeling indicates that second-degree burns have been associated with treatment . Safety in children younger than 6 years old has not been demonstrated, although exposed children as young as 2 years old showed no signs of adverse events other than a mild or moderate burning sensation of the scalp . The absence of reports of treatment-related systemic adverse events suggests that there is minimal risk of systemic toxicity when the product is applied carefully and according to label instructions.
A 5% benzyl alcohol formulation was approved in 2007 for people 6 months of age and older as a prescription treatment of head lice infestations, but with no activity against ova. Treatment consists of two applications separated by a 1-week interval. This regimen eliminated head lice in 76.2% and 75.0% of subjects enrolled in two RCTs conducted across the United States .
Adverse reactions were limited to minor, transient application site irritation, with minimal absorption after topical application . Although intravenous administration of benzyl alcohol–containing products has been associated with neonatal gasping syndrome, the age cohort likely to be infested with head lice and the low level of absorption after topical application suggest that this syndrome is not a risk when the product is used according to label instructions .
Spinosad exerts its insecticidal activity primarily through binding to nicotinic acetylcholine receptors, mimicking the agonistic effects of acetylcholine, and by antagonizing GABA receptors, causing insect motor excitation, paralysis, and death [27, 33]. A benzyl alcohol–containing formulation of spinosad (0.9%) was approved in 2011 for prescription use in people 6 months of age and older to treat head lice infestations.
In two parallel RCTs conducted across the United States, 68.1% of patients in one study and 75.9% in the other were free of lice 14 days after a single spinosad application [18, 19]. Patients who were found to be infested 7 days after one treatment received a second application and were assessed 14 days later. When data from single-application patients were combined with those receiving a second treatment, 84.6% and 86.7% were lice free [18, 34]. Efficacies after a single application without nit combing are strongly suggestive of effectiveness against head lice eggs.
Applied to dry hair and rinsed out 10 minutes later, spinosad has good mammalian safety, with no detected absorption. Data indicate minor, transient application site effects as the only concern .
Topical Ivermectin 0.5%
Ivermectin kills insects by binding to glutamate- and GABA-gated chloride ion channels, causing insect nerve paralysis and subsequent death . The FDA approved a 0.5% ivermectin lotion containing olive oil and Shea butter in 2012 for treatment of head lice infestations in patients 6 months of age and older . In two RCTs conducted across the United States, the effectiveness of 0.5% ivermectin 14 days after a single application, without nit combing, was found to be 76.1% and 71.4% . These results align with a dose determination study in which a single application cured 73.7% of subjects . Ivermectin does not have direct ovicidal activity, but in an ex vivo study, all nymphs died after hatching from ova exposed to the 0.5% lotion for 10 minutes. This posteclosion effect was attributed to an ivermectin-induced mouthpart paralysis that resulted in an inability to feed .
An assay after a 10-minute application on louse-infested children detected absorption at levels substantially lower than those found to be safe after administration of ivermectin tablets (indicated for treatment of onchocerciasis and strongyloidosis) [40, 41]. The 0.5% lotion was found to be nonsensitizing and a nonirritant and had a favorable irritation profile . A significant reduction in pruritus was recorded the day after treatment, suggesting some emollient effect .
No data have been published to verify the effectiveness and safety of more than one application of 0.5% ivermectin lotion, but the absence of reported dermatologic effects of this formulation, de minimus postapplication absorption of ivermectin, and the known safety of repeated treatments with an oral formulation suggest that additional treatments would not be problematic .
Ivermectin Tablets for Oral Administration
The use of oral ivermectin as a treatment for head lice infestations has been reported in a single structured assessment. Subjects 2 years of age and older in Israel, France, and Ireland, all weighing more than 15 kg, received two treatments with ivermectin tablets (400 μg/kg) 1 week apart . Final assessments 1 week after the second treatment found that lice had been eliminated from 95.2% of subjects. Although this outcome is promising, further data are needed to verify these results and to confirm the safety of this above-label dose, particularly in the age cohort most likely to be infested with head lice.
In repeated studies outside the United States, dimethicone has shown activity against head lice, although its mechanism of action has not been established [44, 45]. No data are available to support the effectiveness or safety of the formulation available in the United States.
Home remedies such as petroleum jelly, olive oil, and mayonnaise have been found to be ineffective ex vivo [2, 46]. These therapies may transiently suppress louse metabolic activity, giving the false impression of death, only to have them awaken shortly thereafter—the so-called “resurrection effect” . Essential oils (such as melaleuca [tea tree] oil), often described as “natural” therapies, have no clinical data to support their use in the United States. Moreover, there are no studies evaluating the safety of any of these remedies, including their potential for contact sensitization and other potentially severe adverse events [47, 48].
Head lice assessment protocols for FDA approval require that effectiveness assessments be completed at least 14 days after the final treatment. A limitation of this protocol is the risk of reinfestation from external sources in that 14-day period. Successfully treated subjects who become reinfested would therefore introduce a bias against the tested treatment. Thus today's protocols can be expected to provide a conservative estimate of product effectiveness and probably account in part for the failure of the registered topical formulations of malathion, benzyl alcohol, spinosad, and ivermectin to achieve study effectiveness of 90% or more.
Two recently approved products (spinosad and topical ivermectin) have been found to be effective without nit combing. Although combing is appropriate to remove dead lice and eggs that can be dislodged, our experience suggests that rigorous removal of eggs is unnecessary other than for cosmetic purposes. Along with the American Academy of Pediatrics, we find no justification for “no nit” school policies that result in a loss of school days and caregiver time off work or for routine screening of children for infestations, which have not been shown to reduce the risk of transmission of head lice .
Widespread use of pyrethroids has precipitated their current ineffectiveness in the treatment of infestations. Lessons from the control of agricultural pests show that the emergence of resistance is an inevitable consequence of repeated exposure of populations to any single insecticide or group of commonly acting insecticides. Exposure to sublethal doses can place a strong resistance selection pressure on that population. Similarly, incorrect application of a treatment may create resistance pressure. After apparent product failure, re-treatment with the same product (or one with the same mechanism of action) may reinforce that selection and accelerate the emergence of resistance. Re-treatment of persistent lice infestations should be completed with a product different from any already used. Although recently introduced treatments have been found to be safe and effective, if used indiscriminately or excessively, the fate of these agents will be similar to that of the pyrethroids.
The availability of proven and safe prescription remedies offers the opportunity to manage head louse infestations strategically and effectively. Given the current situation of resistance and apparent inefficacy of OTC treatments, primary health care providers should understand how to manage head lice infestations, take an active role in the diagnosis of infections, and guide appropriate use of well-tested, proven, FDA-reviewed products.
IMS Health, National Prescription Audit: Sampling of approximately 57,000 pharmacies, which dispense nearly 80% of the retail prescriptions in the United States. Prescriptions, including refills, dispensed at retail pharmacies and paid for by commercial insurance, Medicaid, Medicare, or cash were included.