ARTICLE
Scabies is a contagious disease caused by the mites Sarcoptes scabiei
[1]. It is generally associated with poor living conditions but it is
also common in hospitals and nursing homes. It is calculated that around
300 million people worldwide suffer from scabies, each year [2].
In the elderly and immunocompromised subjects a severe form of scabies
may be seen (Norwegian type). Infestation can cause considerable discomfort.
Intense itching, especially at night, is a very common symptom of this
skin infestation [3]. Topical application of antiscabetic agents is standard
practice. Lindane, crotamiton, benzyl-benzoate, permethrin and oral invermectin
are commonly utilised treatments [4]. Evidence-based medicine data show
that permethrin 5 % cream has to be considered as the gold standard
therapy for this condition [5]. However, local tolerability and low patient
compliance are the main limiting factors of the traditional topical formulations
(i.e. creams, lotions) used in the treatment of scabies. A new formulation
of natural pyrethrins (0.16 %), synergised with pyperonil butoxide
(1.65 %), (Milice&circR;) (Mipharm, Italy), in thermo
labile foam, is now available [6]. After application on the skin, the
foam rapidly evaporates without residues with a good patient’s acceptability
[7]. This formulation is particularly suitable for application of the
active compounds on large body surfaces as is required for the treatment
of patients with scabies. So far, this product is indicated exclusively
in the treatment of head and pubic lice. In vitro and in vivo
studies have shown that this pharmaceutical formulation allows a better
and faster penetration of active compound through head lice involucres
with a greater ovulocidal activity in comparison with permethrin 1 %
rinse [6]. An experimental study conducted on human cadaver skin model
has demonstrated that this foam technology increases the penetration of
the active compound through skin layers in comparison with a traditional
topical formulation [7]. No data are available, so far, regarding the
efficacy and safety profile of this thermo labile foam formulation in
the treatment of scabies.
Study aims
This trial was conducted to evaluate the efficacy and tolerability of
a new synergised natural pyrethrins foam formulation in comparison with
permethrin cream 5 % in patients with scabies. The primary end point
of the trial was to assess the presence of clinical signs of scabies at
2 and 4 weeks after treatment. Secondary end points of the trial
were the evaluation of itching, the concomitant use of antihistamine drugs
and the incidence of secondary skin infections.
Participants and methods
Local ethics committee approved the study protocol in February 2001.
Between March 2001 and October 2001, 65 patients with scabies
were screened for the study. A total of 40 patients (19 men
and 21 women; age mean ± SD: 44 ± 17 years)
were enrolled in the trial. All patients gave written informed consent.
Inclusion criteria were: immunocompetent men and women, aged 18-75 years
with microscopic confirmed uncomplicated scabies. Skin scrapings were
examined for mites, eggs, or scybala. Exclusion criteria were: HIV-positive
subjects, severe (i.e. plasma creatinine > 2.5 mg/dL)
renal failure, liver insufficiency (ALT and/or AST > 3 UNL),
acute or chronic leukaemia or lymphoma, use of antiscabetic preparations
in the previous 30 days and pregnant or lactating women. The study
was a prospective, randomised, parallel-group, investigator-blinded, comparative
trial. Randomisation was performed using a computer-generated randomisation
list (Arcus Quickstat; Cambridge, UK). Treatment allocation concealment
was obtained using a phone-call centralised procedure for each eligible
patient. Primary end points of the study were clinical evolution of scabetic
lesions and itching intensity assessed with semi quantitative scores.
Secondary end points were the percentage of patients with complete relief
of itching at week 2 and week 4, use of anthistamine drugs and secondary
skin infections. Clinical grading (CG) of scabies and itching score (IS)
were measured using a 5-point scale (0 = no lesion, no itch;
4 = 100 or more lesions, severe itch) and evaluated at
baseline, at week 2 and 4. Twenty patients (9 men, mean age:
44 ± 15 years) were treated with permethrin cream
5 % (P) applied to the entire body surface, except for the head,
for 8 hours (overnight) for two consecutive days. The same treatment
was repeated after 14 days. Twenty patients (10 men, mean age:
44 ± 19 years) were randomised to natural synergised
pyrethrins thermo labile foam (F) with a similar treatment schedule.
Sample size and statistical
analysis
Previous controlled studies have shown that permethrin 5 % cream
induces a cure rate ranging from 89 % and 93 % [8-10]. We hypothesized
a 90 % reduction of the clinical grading score in the permethrin
group (i.e. from 3.5 ± 0.5 at baseline to 0.4 ±
0.3 at the end of the study, an absolute difference of the
clinical grading score of 3.1). The sample size was based on the assumption
that an absolute difference of the clinical grading scores at the end
of the study of 0.4 between treatments groups should be considered
clinically relevant. Therefore, with a power of 95 % and a type I
error of 0.05, at least 36 patients had to be recruited in the trial.
The unpaired T-test was used to compare continuous variables and the Wilcoxon
and the median tests were used to compare ordinal variables. Chi-square
and Fisher’s exact tests were used to compare proportions. All performed
tests were two-tailed. A P value of < 0.05 was considered
significant.
Results
All 40 randomised patients concluded the 4-week study duration
and were evaluable for efficacy and safety analysis. Figure
1 shows the trial profile. At baseline, mean scabies lesions were
83 ± 23 and 74 ± 25 in P and
F group, respectively. Table I
summarises patients’ characteristics at baseline. Table II
reports the main results of the study. As compared with baseline values,
both treatments reduced significantly CG and IS scores. All patients,
in both groups, were completely free of scabies at week 4. As compared
to P group, the IS in F group treated patients, at week 2, was significantly
(P < 0.0013; Wilcoxon rank test) lower (0.4 ± 0.6 vs.
1.4 ± 1.1). At week 2, 60 % (95 % CI: 36-80 %)
of F group and 15 % (95 % CI: 3-37 %) of P group treated
patients presented a complete disappearance (i.e. IS = 0) of
itching (P < 0.003; two-sided Fisher’s exact test).
At the end of the study, 100 % (95 % CI: 83-100 %) of the
F group and 80 % (95 % CI: 56-94 %) of the P group treated
patients had a complete relief of pruritus (P = 0.05). Mean
treatment duration of anti-histamine drugs was 13 ± 6 days
in F group and 26 ± 12 in P group (P < 0.0008;
unpaired T-Test with Welch correction). Secondary skin infections, requiring
antibiotic treatments, were observed in 2 and 10 patients in
the foam and permethrin cream groups, respectively (P < 0.013;
Fisher’s exact test).
CONCLUSION
The results of our study show that this new thermo labile foam formulation
of synergised natural pyrethrins is at least as effective as permethrin
5 % cream in the treatment of scabies. Permethrin cream 5 %
is considered more effective than lindane, crotamiton and oral invermectin
in achieving clinical cure rate in patients with scabies [5]. Permethrin
is considered the gold standard therapy for this clinical condition. In
comparison with lindane, permethrin induces a greater reduction in itch
persistence [11]. Our study showed that the foam formulation has a similar
efficacy to permethrin cream but, in addition, it induced a more rapid
and complete resolution of itching. However, an important study limitation
has to be taken in account in assessing our results. This was not a double-blind
trial and therefore it is important to consider whether the non-blinded
nature of the study may have biased our results. The primary study end
points were the clinical global score of scabetic lesions and the itching
intensity score. An investigator unaware of treatments allocation performed
these evaluations. Regarding the clinical grading score, the pyrethrins
foam was as effective as permethrin cream. Regarding pruritus, the foam
formulation was shown to induce a faster and more complete disappearance
of itching. While scabies is not a life-threatening condition, the severe,
persistent itch can often debilitate patients [12]. Therefore a positive
and rapid effect on itch is an important goal for therapy. The 95 %
Confidence Intervals of the difference of itching scores at week 2 and
at week 4, in comparison to baseline values, confirm the significantly
more rapid effect in reducing itching with natural pyrethrins foam formulation
in comparison with permethrin cream. The reason for this effect is not
clear at the moment and it could be a matter of speculation. In addition,
the positive effects on itching of the foam formulation were in agreement
with the anti-histamine drug sparing effect and the lower incidence of
secondary skin infections we found in this study. In patients with scabies,
secondary skin infections are considered a complication of compulsive
scratching [1]. In comparison with this new natural pyrethrin foam formulation,
permethrin cream application on the entire body surface area is time-
and cost-consuming. Furthermore, foam formulation has a greater patient
acceptability [13]. Foam formulation is also particularly suitable for
the treatment of the scalp and face, which could be involved in scabies
in children and immunocompromised subjects [3]. Therefore we believe that
the results of this study could be applicable to the every-day clinical
scenario of scabies treatment.
This trial was supported by an unrestricted grant from Mipharm SpA
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