194 Research Letters
JANUARY 2018
improvements, others reporting no effect, and some
reporting worsening of pruritus.
With the limited number of studies, there is still
insufficient evidence to make a conclusion about the
effectiveness of BoNT/A in the treatment of localized
chronic pruritus. Other limitations include the lack of
randomized controlled trials, the small sample size in
each study, the wide variety of outcome measures,
and the role of placebo effect. Given these limita-
tions, it is too early to recommend the regular use of
BoNT/A in the treatment of chronic localized pruri-
tus; however, it remains an option for the clinician in
cases of recalcitrant localized pruritus. Of note, there
are 3 ongoing, large-scale trials evaluating the
efficacy of BoNT/A in relieving localized chronic
itch caused by notalgia paresthetica, hypertrophic
scars, and histamine prickeinduced itch.3-5
Emily Boozalis, BA, Mary Sheu, MD, Jacqueline
Selph, MD, and Shawn G. Kwatra, MD
Department of Dermatology, Johns Hopkins Uni-
versity School of Medicine, Baltimore, Maryland
Funding sources: None.
Conflicts of interest: None declared.
Correspondence to: Shawn G. Kwatra, MD, Cancer
Research Building II, Johns Hopkins University
School of Medicine, 1550 Orleans St, Baltimore,
MD 21231
E-mail: skwatra1@jhmi.edu
REFERENCES
1. Wanitphakdeedecha R, Ungaksornpairote C, Kaewkes A,
Rojanavanich V, Phothong W, Manuskiatti W. The comparison
between intradermal injection of abobotulinumtoxinA and
normal saline for face-lifting: a split-face randomized
controlled trial. J Cosmet Dermatol. 2016;15:452-457.
2. Gazerani P, Pedersen NS, Drewes AM, Arendt-Nielsen L. Botuli-
num toxin type A reduces histamine-induced itch and vasomotor
responses in human skin. Br J Dermatol. 2009;161:737-745.
3. Innovaderm Research Inc. Treatment of notalgia paresthetica with
xeomin. ClinicalTrials.gov; 2012. Available at: https://clinicaltrials.
gov/ct2/show/NCT01098019?term¼notalgia1paresthetica1
with1xeomin&rank¼1. Accessed November 14, 2016.
4. Kaohsiung Veterans General Hospital. The use of botulinum
toxin in the treatment of itching from hypertrophic scar—a
randomised controlled trial. ClinicalTrials.gov; 2015. Available
at: https://clinicaltrials.gov/ct2/show/NCT02168634?term¼
botulinum1hypertrophic1scar1itching&rank¼1. Accessed
November 14, 2016.
5. Aalborg University. To study the peripheral effect of botulinum
toxin-A (botox-A) on experimentally induced cutaneous pain
in healthy subjects. ClinicalTrials.gov; 2008. Available at:
https://clinicaltrials.gov/ct2/show/NCT00435682?term¼botu
linum1experimentally1induced1cutaneous1pain&rank¼1.
Accessed November 14, 2016.
http://dx.doi.org/10.1016/j.jaad.2017.08.001
J AM ACAD DERMATOL
Ivermectin versus permethrin in the
treatment of scabies: A systematic
review and meta-analysis of
randomized controlled trials
To the Editor: Scabies, an intensely pruritic ectopar-
asitic skin infestation, affects over 130 million people
and hampers quality of life.1,2 Permethrin is consid-
ered the most effective topical treatment for scabies.3
Ivermectin is the only oral alternative and can also be
applied topically. Because randomized controlled
trials comparing oral or topical ivermectin with
topical permethrin have been inconclusive, we
performed a meta-analysis.
On March 21, 2017, we searched PubMed,
Embase, Cochrane Library, and references of
included articles using the terms ‘‘scabies’’ and
‘‘permethrin’’ and ‘‘ivermectin’’ for peer-reviewed
randomized controlled trials comparing oral or
topical ivermectin with topical permethrin in
patients with scabies. Two authors independently
selected studies, extracted data, and assessed study
quality using the Cochrane Risk of Bias Tool. The
primary outcome was treatment failure as defined
in the individual studies, although we required that
the definition include persistent lesions, new
lesions, or confirmation of a live mite. Secondary
outcomes were persistence of itch and adverse
effects. We calculated pooled risk ratios (RRs) and
95% confidence intervals (CIs) using a random
effects model.
Our search identified 461 potential articles. We
ultimately included 15 randomized controlled tri-
als, which contained 2172 patients. Table I sum-
marizes the main study characteristics. In terms of
dose regimens, oral ivermectin (200 g/kg) was
given as a single dose in 5 trials and repeat doses
in 9 trials. Topical ivermectin (1%) was given as
repeat applications in 2 trials. Topical permethrin
(5%) was given as a single application in 5 trials
and repeat applications in 9 trials, while topical
permethrin (2.5%) was given as repeat applications
in 1 trial.
Oral ivermectin was associated with a signifi-
cantly increased risk of treatment failure
compared with topical permethrin (RR 1.33, 95%
CI 1.04-1.72, I2 ¼ 0%, treatment failure rate: 14%
[122/860] vs 10% [85/831], n ¼ 1691) (Fig 1). Meta-
regression revealed no significant heterogeneity
by various study characteristics: length of follow-
up, treatment of family or close contacts, repeti-
tion of ivermectin dose, itch in definition of
treatment failure, and microscopy in definition of
treatment failure. Visual inspection of the funnel
plot and Egger’s test (P ¼ .19) revealed no
Table I. Main characteristics of studies comparing oral or topical ivermectin with topical permethrin
Author, country
Usha et al, India, J Amer Acad
Dermatol. 2000;42:236-40.
Bachewar et al, India, Indian
J Pharmacol. 2009;41:9-14.
Mushtaq et al, Pakistan, Journal
of Pakistan Association of
Dermatologists. 2010;20:227-31.
Sharma et al, India,* Indian J
Dermatol Venereol Leprol.
2011;77:581-6.
Goldust et al, Iran, Journal of
Dermatology. 2012;39:545-7.
Saqib et al, Pakistan, Journal
of Pakistan Association of
Dermatologists. 2012;22:45-9.
Number
of
subjects Interventions
85 Group A: OI, single dose,
repeated at week 2 for
nonresponders
Group B: Pa, applied overnight,
repeated at week 2 for
nonresponders
55 Group A: OI, single dose,
repeated at week 1 for
nonresponders
Group B: Pa, applied overnight,
repeated at week 1 for
nonresponders
86 Group A: OI, single dose,
repeated at week 2 for
nonresponders
Group B: Pa, applied over
12 hours, repeated at week
2 for nonresponders
117 Group A: OI, single dose
Group B: OI, single dose,
repeated at week 2
Group C: Pa, applied overnight
242 Group A: OI, single dose
Group B: Pa, applied over
12 hours, repeated at week 1
120 Group A: OI, single dose
Group B: Pa, applied over
10-12 hours
VOLUME 78, NUMBER 1
J AM ACAD DERMATOL
Primary
outcome,
treatment Secondary Important additional
failure outcomes Cointerventions exclusion criteria
I1PNL1LM Adverse effects Treated family and/or close i) Age \5 years
contacts 1 washed clothes ii) Pregnant and lactating
and bedding 1 antibiotic women
if infection
PNL None Treated family and/or close i) Age \12 years
contacts 1 antibiotic ii) Pregnant and lactating
if infection women
iii) Immunocompromised
iv) Crusted scabies
I1PNL1LM Adverse effects None i) Age \2 and [60 years
Itch persistence ii) Pregnant and lactating
women
iii) Immunocompromised
I1PNL1LM Adverse effects Treated family and/or close i) Age \5 years
Itch persistence contacts 1 washed ii) Pregnant and lactating
clothes and bedding women
iii) Immunocompromised
iv) Crusted scabies
PNL1LM Adverse None i) Age \2 years
effects ii) Pregnant and lactating
women
iii) Immunocompromised
iv) Crusted scabies
I1PNL1LM None Treated family and/or close i) Age \18 and [60 years
contacts 1 washed
Research Letters 195
ii) Pregnant and lactating
clothes and bedding 1 women
antihistamine 1 antibiotic
if infection
Continued
Table I. Cont’d

196 Research Letters

Primary
Number outcome,
of treatment Secondary Important additional
Author, country subjects Interventions failure outcomes Cointerventions exclusion criteria
Chhaiya et al, India, Indian J 300 Group A: OI, single dose, PNL Adverse Antihistamine i) Age \5 and [80 years
Dermatol Venereol Leprol. repeated at week 1 and 2 for effects ii) Pregnant and lactating
2012;78:605-10. nonresponders Itch women
Group B: TI, applied for at least persistence iii) Immunocompromised
8 hours, repeated at week 1 iv) Crusted scabies
and 2 for nonresponders
Group C: Pa, applied for at
least 8 hours, repeated at week
1 and 2 for nonresponders
Ranjkesh et al, Iran, Ann Parasitol. 60 Group A: OI, single dose, PNL1LM Adverse Treated family and/or i) Age \2 years
2013;59:189-94. repeated at week 2 for effects close contacts ii) Pregnant and lactating
nonresponders women
Group B: Pa, 2 applications 1 iii) Immunocompromised
week apart, repeated at week iv) Crusted scabies
2 for nonresponders
Goldust et al, Iran, Ann Parasitol. 380 Group A: TI, 2 applications PNL1LM Adverse Treated family and/or i) Age \2 years
2013;59:79-84. 1 week apart, repeated at effects close contacts ii) Pregnant and lactating
week 2 for nonresponders women
Group B: Pb, 2 applications 1 iii) Immunocompromised
week apart, repeated at iv) Crusted scabies
week 2 for nonresponders
Aggarwal et al, India, Natl J Integr 88 Group A: OI, single dose I1PNL1LM None Treated family and/or i) Age \10 and [60 years
Res Med. 2014;5:57-60. Group B: Pa, applied overnight close contacts ii) Pregnant and lactating
women
iii) Immunocompromised
iv) Crusted scabies
Manjhi et al, India, J Clin Diagn Res. 120 Group A: OI, single dose PNL Itch None i) Age \5 and [60 years
2014;8:HC01-4. Group B: Pa, applied overnight persistence ii) Pregnant and lactating
women
Maurya et al, India, International 120 Group A: OI, single dose, I1PNL Adverse Treated family and/or i) Age \12 years

J AM ACAD DERMATOL
Journal of Pharmacology and repeated at week 1 effects close contacts 1 ii) Pregnant and lactating
Clinical Sciences. 2014;5:15-21. Group B: Pa applied over washed clothes and women
12 hours, repeated at week 1 bedding

JANUARY 2018
Kanwar et al, India, Int J Basic Clin 199 Group A: OI, single dose PNL Itch None i) Age \5 and [60 years
Pharmacol. 2016;5:1234-8. Group B: Pa, applied overnight persistence ii) Pregnant and lactating
women
J AM ACAD DERMATOL Research Letters 197
VOLUME 78, NUMBER 1

I, Itching; LM, live mite confirmed on microscopy; OI, oral ivermectin 200 g/kg; Pa, 5% permethrin cream; Pb, 2.5% permethrin cream; PNL, persistent or new lesions; TI, 1% topical ivermectin cream.
ii) Pregnant and lactating evidence of small-study effect. Oral ivermectin

ii) Pregnant and lactating

i) Age \5 and [60 years

i) Age \2 and [50 years

iii) Immunocompromised

iii) Immunocompromised
was associated with a nonsignificant increased
risk of persistent itch compared with topical
iv) Crusted scabies

iv) Crusted scabies

permethrin (RR 1.32, 95% CI 0.91-1.93, I2 ¼ 0%,
persistent itch rate: 13% [57/432] vs 10% [39/389],
n ¼ 821).
women

women Topical ivermectin was associated with a nonsig-

nificant increased risk of treatment failure
compared with topical permethrin (RR 1.49, 95%
CI 0.88-2.51, treatment failure rate: 10% [30/291] vs
contacts 1 washed clothes

7% [20/289], I2 ¼ 0%, n ¼ 580). One trial by Chhaiya

and bedding 1 antibiotic
Adverse effects Treated family and/or close

et al found no significant difference in itch persis-

tence between both agents.4
The number of adverse effects were few: 4.3%
(26/604) for oral ivermectin, 4.6% (35/758) for
if infection

topical permethrin, and 6.9% (20/291) for topical

ivermectin. There were no serious adverse
effects.
None

Several other topical treatments are available for

scabies: benzyl benzoate, lindane, crotamiton, mal-
Itch persistence

athion, and sulfur. A previous systematic review

found topical permethrin to be the most effective
effects
Adverse

current scabicide.3 Although the authors found much

higher treatment failures with oral ivermectin
compared with topical permethrin than in our study,
the review only included two small trials (n ¼ 140)
PNL1LM

and data from the earliest follow-up visit. Indeed,

I1PNL

several studies have noted a slower response with

oral ivermectin.5 Of note, our meta-regression ana-
lyses found no significant difference between trials
nights, repeated at week 1 for
Group B: Pa, applied overnight,

using single and multiple doses of oral ivermectin

Group B: Pa for adults, applied
overnight for 5 consecutive

(Pheterogeneity ¼ .46). However, given ivermectin’s

*Results for both ivermectin groups were combined in the final pooled estimate.
repeated at week 1 for

repeated at week 1 for

repeated at week 1 for

Group A: OI, single dose,

Group A: OI, single dose,

limited ovicidal activity and short half-life, it would

be prudent to administer 2 doses at least 4 days
apart.6
nonresponders

nonresponders

nonresponders

nonresponders

Other factors could also affect choice of agent.

Ivermectin is cheaper, and oral administration
might improve adherence.5 However, oral iver-
mectin is not approved for use in young children
and pregnant or lactating womenekey groups that
most trials excluded. It should be noted that the
basis for therapeutic recommendations should not
100

100

be made solely on a meta-analysis. Our study was

limited by the lack of patient-level data; potential
performance bias (assessment of study quality
Wankhade et al, India, Indian J

revealed absence of blinding in most trials); and

Pb used for children \10 years.
Abdel-Raheem et al, Egypt,y
Pharmacol. 2013;45:S202.

trial exclusion of subjects with crusted scabies,

which generally requires combination therapy.
J Dermatolog Treat.

Our findings, however, suggest that combination

therapy with oral ivermectin and topical
2016;27:473-9.

permethrin is presumably safe and, in typical

scabies, might potentially enhance efficacy.
In summary, oral ivermectin is less effective than
topical permethrin. Topical ivermectin may have a
similar efficacy to topical permethrin, but further
y
198 Research Letters
Fig 1. Forest plot for treatment failure comparing oral ivermectin with topical permethrin. See
Table I for reference information.
trials are warranted given the small sample size used
for this comparison. All 3 agents, however, have low
treatment failure rates and are well tolerated.
Ashar Dhana, MBBCh, MPH,a Hsi Yen, MD,
MPH,b,c Jean-Phillip Okhovat, MD, MPH,d
Eunyoung Cho, ScD,e,f,g NaNa Keum, ScD,h
and Nonhlanhla P. Khumalo, FC Derm, PhDa
From the Division of Dermatology, Groote Schuur
Hospital and University of Cape Town, Cape
Town, South Africaa; Department of Derma-
tology, Chang Gung Memorial Hospital Linkou
and Taipei Branch, Taoyuan, Taiwanb; College
of Medicine, Chang Gung University, Taoyuan,
Taiwanc; Department of Medicine, Beth Israel
Deaconess Medical Center, Harvard Medical
School, Boston, Massachusettsd; Department of
Dermatology, Warren Alpert Medical School,
Brown University, Providence, Rhode Islande;
Department of Epidemiology, Brown University
School of Public Health, Providence, Rhode
Islandf; Channing Division of Network Medicine,
Department of Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston,
Massachusettsg; and Department of Nutrition,
Harvard T.H. Chan School of Public Health,
Boston, Massachusettsh
Funding sources: None.
Conflicts of interest: None declared.
Reprints not available from the authors.
J AM ACAD DERMATOL
JANUARY 2018
Correspondence to: Ashar Dhana, MBBCh, MPH,
Division of Dermatology, Groote Schuur Hospital
and University of Cape Town, Cape Town, South
Africa, 7935
E-mail: ashardhana@live.com
REFERENCES
1. Currie BJ. Scabies and global control of neglected tropical
diseases. New Engl J Med. 2015;373:2371-2372.
2. Jackson A, Heukelbach J, Filho AF, et al. Clinical features and
associated morbidity of scabies in a rural community in
Alagoas, Brazil. Trop Med Int Health. 2007;12:493-502.
3. Strong M, Johnstone PW. Interventions for treating scabies
(update). Cochrane Database of Systematic Reviews. 2010.
Available at: http://onlinelibrary.wiley.com/doi/10.1002/ebch.
861/full. Accessed October 2, 2017.
4. Chhaiya SB, Patel VJ, Dave JN, Mehta DS, Shah HA.
Comparative efficacy and safety of topical permethrin, topical
ivermectin, and oral ivermectin in patients of uncomplicated
scabies. Indian J Dermatol Venereol Leprol. 2012;78:605-610.
5. Mounsey KE, McCarthy JS. Treatment and control of scabies.
Curr Opin Infect Dis. 2013;26:133-139.
6. Golant AK, Levitt JO. Scabies: a review of diagnosis and manage-
ment based on mite biology. Pediatr Rev. 2012;33:e1-e59.
http://dx.doi.org/10.1016/j.jaad.2017.09.006
Cantharidin for treatment of facial
molluscum contagiosum: A retrospective
review
To the Editor: Molluscum contagiosum (MC) papules
are self-limited, resolving within months to years.
Active nonintervention is a common management