Safety of Permethrin vs Lindane
for the Treatment of Scabies
IN
THIS ISSUE of the Archives, Franz and col-
leagues1 report on the comparative percutane-
ous absorption of lindane and permethrin. They
conclude that, for the treatment of scabies, 5%
permethrin cream is at least 40 times less likely
to cause toxic effects than 1% lindane lotion.
These authors correctly state that surprisingly little
clinically relevant information has been published re-
lated to percutaneous absorption of permethrin in hu-
mans. In fact, permethrin is one of the most extensively
studied pesticides ever developed, in terms of metabo-
lism, toxic effects, and routes of administration, includ-
ing percutaneous absorption, in both animals and hu-
mans.
Much has been published on the potential toxic ef-
fects of lindane in the central nervous system, and there
is ample evidence that this pesticide is capable of pro-
ducing damage to the central nervous system in hu-
mans. This is a rare occurrence when used as directed,
but the potential for abuse or accidental ingestion is cause
for concern. In view of the available literature on the toxic
effects of lindane, we focus instead on permethrin, real¬
izing that we can cover only a portion of the studies con¬
ducted by industry on its safety and levels of tolerance.
PERMETHRIN TOXICOLOGY RESEARCH
Permethrin, (±)-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-
2,2-dimethylcyclopropanecarboxylate, is soluble in 95%
ethanol, acetone, ether, petroleum distillate, other hy¬
drocarbons, and most other organic solvents. It is some¬
what soluble in polyethylene glycol but practically in¬
soluble in water.
Permethrin manufactured for animal and human use
is mixture of eis and trans isomers. The eis isomer is
a mental work by the pharmaceutical industry that led to
somewhat more toxic than the trans isomer and is ex¬
creted at a lower rate. Therefore, preparations with a lower
percentage of eis isomer were selected for human use. Both
Nix creme rinse for lice (Warner Wellcome Consumer
Healthcare, Morris Plains, NJ) and Elimite cream for sca¬
bies (Allergan-Herbert Inc, Irvine, Calif) contain perme¬
thrin at a 25:75 cis-trans ratio.
See also page 901
Developed the Rothamstead Experimental Sta¬
at
tion in the United Kingdom in the early 1970s, perme¬
thrin was first marketed in 1977 and was the first pho¬
tostable pyrethroid, with exceptional insecticidal activity
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and very low mammalian toxicity. We have previously
published reviews on the history and development of natu¬
ral pyrethrins and synthetic pyrethroids.2,3
The use of permethrin for the treatment of infesta¬
tions by head, crab, and body lice and the scabies mite
represents a very small portion of its applications. Be¬
tween 1979 and 1984, more than 4000 tons of perme¬
thrin was produced worldwide, mostly for use in agri¬
culture, livestock, and protection of foods and grain in
storage. In the last 5 years, permethrin has become widely
available in the United States for pest control around
homes and gardens. This extensive experience over a pe¬
riod of 20 years enabled the Committee on Toxicology
of the US National Research Council to state in 1994, "Al¬
though permethrin is highly toxic to insects and other
arthropods, it is one of the least toxic insecticides to mam¬
mals."4
In 1990, the World Health Organization published
a review based on the collective views of an interna¬
tional group of experts and concluded, "No adverse ef¬
fects have been reported following human exposure to
permethrin during the many years of its use. Neverthe¬
less, it would be wise to maintain observations of hu¬
man exposure."5 This statement was based primarily on
occupational exposure of workers engaged in the bag¬
ging, mixing, or spraying of industrial grades of perme¬
thrin for agriculture, forestry, or animal husbandry. The
review did not evaluate the experience gained from the
therapeutic use of products for lice and scabies during
the last decade.
The clinical experience of using 1% permethrin
creme rinse for head lice (Nix) and 5% permethrin der¬
mal cream for scabies (Elimite) over 16 years has been
reassuring. This is not surprising, because the develop¬
the approval of Nix and Elimite was extensive and of high
quality. Most of the research was conducted or spon¬
sored by the Burroughs Wellcome Co (now GlaxoWell-
come) in the United States and United Kingdom. Fol¬
lowing a large number of toxicologie tests in animals, a
series of controlled trials were performed in which pure
permethrin or its isomers were applied to the skin of hu¬
man volunteers, as were the complete formulations of Nix
and Elimite. Percutaneous absorption was calculated by
measuring the excretion of 3-(2,2-dichlorovinyl)-2,2-
dimethylcyclopropanecarboxylic acid, commonly re¬
ferred to as CVA. These investigations confirmed that per¬
methrin is very poorly absorbed through mammalian skin,
is rapidly degraded to inactive metabolites, and is rap¬
idly excreted, almost entirely in the urine. In 1994, an
 exhaustive review of the toxic effects of permethrin in
animals and humans was compiled by the Department
of Pesticide Regulation of the California Environmental
Protection Agency.6 This document contains over 100 ref¬
erences to studies relating to the toxic effects and safety
of permethrin. Most of these studies have not previ¬
ously been published in the general literature.
The Burroughs Wellcome Co submission for ap¬
proval by regulatory agencies in several countries in¬
cluded the results of 11 clinical trials of Nix and Elimite
in which permethrin products were applied to the skin
of human volunteers and the percutaneous absorption
measured. Exposures ranged from single applications to
weekly treatments over 8 weeks. More than 100 volun¬
teers were included in these studies, which were con¬
ducted between 1977 and 1984. No quantifiable levels
of intact permethrin were found in plasma or urine after
treatments. The maximum percutaneous absorption from
5% permethrin cream (Elimite) calculated by measure¬
ments of CVA in urine was 2.08% of the applied dose,
and the mean percentage absorbed was less than 1%.
The most definitive work, in our opinion, was con¬
ducted by Brent G. Perry, MD, at the Johns Hopkins Hos¬
pital in Baltimore, Md, in 1986. Carbon 14-radiolabeled
permethrin was applied to the shaved backs of 6 healthy
volunteers.7 Plasma, urine, and feces were collected for 5
days after treatment, during which time the sites were not
washed. Carefully controlled measurements conducted by
a research team at the Burroughs Wellcome Co indicated
the following:
Among the 6 subjects, the amount of permethrin ab¬
sorbed ranged from less than 0.30% to 2.08%. It was rap¬
idly metabolized and excreted in the urine. These inves¬
tigations demonstrated that the principal factor limiting
absorption into the systemic circulation was slow pen¬
etration through the skin, and this was independent of
the dose applied.
These studies provided another example of the re¬
markable ability of the human skin to protect us from
external chemical agents, in spite of the fact that the per¬
methrin used was dissolved in isopropanol, in which it
is highly soluble. Indeed, the reason isopropanol was cho¬
sen rather than 5% permethrin cream was based on the
poor absorption of permethrin from this product in pre¬
vious animal and human studies, rendering subsequent
quantification difficult or impossible.
Two important factors were demonstrated in this
study that help to explain the poor penetration. First was
the observation, based on measurements of 14C-
permethrin in Scotch tape strippings of the stratum cor-
neum. Most 14C-permethrin was found in strips 1 to 5.
The concentration of radiocarbon in the 20th tape strip
was only 9% of that in the outermost layer. Thus, the bar¬
rier function of the stratum corneum played a major role
in limiting absorption.
What of the possibility of this insecticide obtaining
access to the circulation through sweat ducts or hair fol¬
licles? Such a scenario might well be applicable to the
treatment of pediculosis of the scalp or of crab lice in the
pubic and axillary areas. Here again, cutaneous de¬
fenses came to the rescue, in this case probably fortu¬
itously. There was evidence that the topically applied per-
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methrin was distributed both to the stratum corneum and
to the hair follicles and apocrine and sebaceous glands.
Twenty-four hours after application, approximately 9.5%
of the applied dose was found in the stratum corneum,
and only 1.47% in the gauze dressings covering the sites
of application. At 48 hours, 60% of the dose was found
in the dressings, but the stratum corneum now con¬
tained only 4.54%.
This indicated that the permethrin had been ab¬
sorbed into the skin appendages and excreted back to the
skin surface by sweat and sebum. The investigators be¬
lieve it is unlikely that much permethrin is liberated into
the dermis once it is bound to sebum, since permethrin
is highly lipophilic and very hydrophobic.
PERMETHRIN METABOLISM
The principal means of metabolism of permethrin in ani¬
mals is through ester cleavage, which then allows rapid
excretion of the inactive metabolites. The presence of es¬
terases in human skin and their role in the absorption of
many substances is well documented.8,9
All of this helps to explain why it is difficult or im¬
possible to detect intact permethrin in plasma following
topical application and why less than 2% of the perme¬
thrin in the Nix or Elimite formulations is absorbed into
the circulation. This rate of absorption was confirmed in
1994 by an independent laboratory contracted by the
Block Drug Co, Jersey City, NJ. After total body appli¬
cations with 5% permethrin lotion for 12 to 14 hours,
most of the volunteers had no detectable intact perme¬
thrin in plasma samples. A few samples yielded ex¬
tremely small traces of permethrin detectable at the high¬
est level of sensitivity (10 ng/mL). The maximum level
found in any specimen was less than 0.032% of the ap¬
plied dose.
Wang et al,10 in 1981, using radioactive-labeled per¬
methrin and human skin in an in vitro model, estimated
that 0.6% of the applied dose was absorbed. Franz and
colleagues also used human skin for their in vitro stud¬
ies, and they calculated that 0.7% of the permethrin was
absorbed. The work of Franz et al is more pertinent to
the treatment of scabies, since they used Elimite perme¬
thrin cream as prescribed by physicians. The closely simi¬
lar results suggest that absorption is primarily regulated
by the innate barrier function of the skin rather than by
the dose applied or the vehicle, further reinforcing the
work of Bartelt and Hubbell.7
Franz et al also demonstrated that human skin is in¬
herently less permeable to permethrin than guinea pig
skin. This supports the findings of previous studies, which
show wide variations in absorption and dermal median
lethal dose between species of animals. When applied in
an ethanol vehicle, 60% is absorbed in the rat, 30% in
rabbits, and 12% in beagle dogs.3 Sidon et al11 in 1988
reported dermal absorption of 45% in rats.
Franz et al also measured significantly greater per¬
cutaneous transfer of lindane than permethrin, but the
story does not end there. We do not know how long es¬
terase activity in the skin is maintained after death, but
there obviously was no active transport of permethrin by
blood circulation to esterase-rich organs (eg, the liver)
 as would be the case in the in vivo situation. Unlike liv¬
ing skin, in which sebum excretion appears to play a role
in the transport of permethrin, we assume that this does
not occur inexperiments with cadaver skin. In view of
the above observations, it is likely that the difference in
safety between 5% permethrin and 1% lindane products
is even greater than that suggested by the experiments
of Franz and colleagues.
If percutaneous absorption and systemic toxic ef¬
fects were the only factors to be considered, from the point
of view of the prescribing physician, the choice would
seem clear: permethrin is safer than lindane. Other fac¬
tors that may affect prescribing practices include ad¬
verse reactions, primary irritation, allergenic effects, pho-
totoxic effects, efficacy, and cost.
ADVERSE REACTIONS TO PERMETHRIN
In preparing this editorial, we reviewed the available lit¬
erature, to which we added our own experiences during
controlled clinical trials, looking for reports of adverse
reactions to permethrin products applied to humans for
the treatment of lice and scabies. One percent perme¬
thrin creme rinse (Nix, Lyclear, GlaxoWellcome,
Greenville, NC) is the most closely studied pediculicide
ever introduced. More than 21 000 patients have been
evaluated under controlled conditions, including 18 000
monitored during postmarket surveillance.12 The over¬
all incidence of reported adverse events was 2.5 per 1000
applications, which is low for any topical medication.
Elimite (5% permethrin cream for scabies) also has
an excellent record for safety. In the United States, phar¬
maceutical companies are required to record and report
all patient complaints to the Food and Drug Adminis¬
tration. Between January 1990 and December 1995, Al-
lergan-Herbert Inc, the only distributor of permethrin
cream for scabies in the United States, received only 6
reports of adverse events per 100 000 U distributed (Al-
lergan-Herbert Inc, oral and written communications, Feb¬
ruary 29,1996). This includes spontaneous reports from
patients, some of which are unconfirmed by physicians.
The rate of central nervous system side effects re¬
ported by physicians to be at least possibly related to treat¬
ment was approximately 1 per 500 000 U distributed, but
in no case has a causal relationship been reported be¬
tween Elimite treatment and a serious central nervous
system side effect (Allergan-Herbert Inc, oral and writ¬
ten communications, February 29, 1996).
This reflects our own experiences in personally su¬
pervising the treatment of some 2500 cases of scabies and
their contacts from 1982 to 1995. Most were patients liv¬
ing in humid tropical climates, where irritation or in¬
creased absorption might be expected, and where sec¬
ondary infections and open sores on the skin are common.
In the United States, the most common complaints as¬
sociated with Elimite treatment are localized burning, ir¬
ritation, or tingling sensations, usually of short dura¬
tion. These reports should be considered in light of the
fact that the cream is applied to skin already sensitive,
pruritic, and often excoriated as a result of the scabies
infestation. This phenomenon is well known to derma¬
tologists and may be likened to the effects that occur in
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skin inflamed by dermatophytosis or candidiasis when
topical antifungal medications are applied, although no
effects occur on normal, uninvolved skin. It should also
be noted that Elimite cream is preserved with formalde¬
hyde, which might be expected to produce some cases
of allergic contact dermatitis. In practice, only 9 reports
of allergic reactions have been received by Allergan-
Herbert Inc. Three of these were unconfirmed by the phy¬
sicians. This translates to a rate of about 0.12 patients
per 100 000 U distributed (Allergan-Herbert Inc, oral and
written communications, February 29, 1996).
This clinical experience is backed up by well-
controlled investigations. In 1986, Snodgrass13 applied
technical-grade 40% permethrin in 95% ethanol to the
arms or backs of 184 subjects of both sexes, ranging in
age from 18 to 80 years. The solution was applied 3 times
per week for 3 weeks under occlusive patches, which were
left on between applications. Two weeks later, a chal¬
lenge patch was applied to previously untreated sites.
None of the subjects showed evidence of allergic con¬
tact dermatitis. Several subjects reported transient burn¬
ing, stinging, or itching, which is not surprising consid¬
ering the high concentration used and considering that
the permethrin was dissolved in 95% ethanol.
Primary irritation occurring at the time of treat¬
ment or soon afterward appears to be more common than
allergic contact dermatitis and is highly individualized.
In 10 years we have encountered only 5 patients in Mi¬
ami, Fla, who experienced intolerable burning and/or itch¬
ing within minutes of Elimite application. Four of these
patients had scabies and acquired immunodeficiency syn¬
drome (AIDS). Tim Berger, MD, at the University of Cali¬
fornia in San Francisco has noted this adverse reaction
of burning from Elimite in approximately 3% of the pa¬
tients he sees who have scabies and AIDS (oral and writ¬
ten communications, March 11 and 12, 1996). He has
not found that Elimite causes this reaction in immuno-
competent patients. It is generally recognized that pa¬
tients with AIDS may exhibit reduced tolerance for topi¬
cal medications. We have no explanation of the
mechanisms involved in this type of reaction.
In addition to safety factors, permethrin appears to
have advantages over lindane products in terms of effi¬
cacy in some areas of the world and perhaps in some parts
of the United States. Reports comparing 5% permethrin
with 1% lindane indicate that the permethrin product is
more efficacious.14 16 We are aware of 15 locations of lin¬
dane treatment failures in the United States. Physicians
and health care workers in some other areas of the world
(Egypt, Peru, Panama, Mexico, New Zealand, El Salva¬
dor) have also seen poor results from lindane treat¬
ment.
Although safety and efficacy should be the princi¬
pal determinants in the choice of therapy, in many situ¬
ations, such as large-scale community control projects,
or in countries where public health funding is severely
limited, cost may be an important factor. In the United
States, the average wholesale price of a 60-g tube of Eli¬
mite cream is $17 to $18. The average wholesale price
of a 60-mL bottle of 1% lindane lotion is about $6. The
cost to the patient may be as high as $28 for Elimite cream
and $9 for lindane lotion.
 In our opinion, the eventual cost to the family, to tection Agency; 1994.
7. Bartelt N, Hubbell JP. Percutaneous Absorption of Topically Applied 14C\x=req-\
institutions such as nursing homes and schools, and to Permethrin in Volunteers: Final Medical Report. Research Triangle Park, NC:
entire communities should be given serious consider¬ Burroughs Wellcome Co/Fairfield American Corp; 1989:378-410. Publication
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cides. In communities with a high prevalence of sca¬ taneous therapeutics. Pharm Res. 1984;4:148.
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resources and has little effect on prevalence.19 Failure to first-pass metabolism in human skin. J Pharm Sci. 1984;73:1499.
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