Concise report CED

Clinical and Experimental Dermatology

An observational analysis of low-dose thalidomide in recalcitrant

prurigo nodularis
K. Sardana, A. Gupta and S. Sinha
Department of Dermatology, Post Graduate Institute of Medical Education and Research (PGIMER) Dr Ram Manohar Lohia hospital, New Delhi, India

doi:10.1111/ced.14015

Summary Thalidomide has been used as an effective treatment for prurigo nodularis (PN) with
a median dose of 200 mg, but the risk of peripheral neuropathy precludes long-term
use. We analysed the efficacy of low-dose thalidomide (< 100 mg) in 17 patients
with recalcitrant PN. Patients were initiated on thalidomide 50 mg on alternate
days, and the dose was increased (doubled) in a stepwise manner, if needed, until a
≥ 50% reduction in score (partial response; PR) on a visual analogue scale (VAS)
was achieved. Thalidomide then was continued at the same dose for 4 weeks to
achieve ≥ 90% decrease in VAS score; if this was not achieved, the dose was
increased to a maximum of 100 mg and continued until complete resolution of
lesions (complete response; CR). Four patients discontinued thalidomide due to
adverse effects. Four patients achieved PR, while 9 patients (n = 2 with 50 mg,
n = 7 with 100 mg) achieved CR. No patient developed neuropathy. In addition,
complete responders achieved an earlier ≥ 50% reduction in VAS score. Two
patients relapsed after 12 months but responded to thalidomide 50 mg.

Prurigo nodularis (PN) is a distinctive reaction pattern
to incessant scratching due to various predisposing
factors. Studies have shown an increase in nerve fibre
density with increased expression of nerve growth fac-
tor and its receptor, tyrosine kinase A, along with the
release and accumulation of neuropeptides such as
substance P and calcitonin gene-related peptide, sug-
gesting a role of agents working at the neural level in
the management of PN.1 T-helper (Th)2 cytokines and
interleukin (IL)-31 have also been implicated in the
pathogenesis of PN.
Thalidomide acts as an antipruritic agent owing to
its central depressant, anti-inflammatory and neuro-
modulatory effects, and has been found to be effective
for PN with a median dose of 200 mg.2 However, this
Correspondence: Dr Aastha Gupta, Department of Dermatology, PGIMER
Dr Ram Manohar Lohia Hospital, Baba Kharak Singh Marg, New Delhi
110001, India
E-mails: aasthagupta11@gmail.com
, age except those who had completed their families.
article.sardana@gmail.com
Conflict of interest: the authors declare that they have no conflicts of
interest.
Accepted for publication 12 October 2018
dose can lead to adverse effects (AEs), preventing long-
term use. There are conflicting reports on the use of
low-dose thalidomide for the treatment of PN
(Table 1).3–8 We analysed our experience of the effi-
cacy and relapse rates of low-dose thalidomide
(< 100 mg) in patients with recalcitrant PN.
Report
In total, 17 consecutive patients (10 men, mean age
28 years; 7 women, mean age 36 years) with recalci-
trant PN, defined as patients not responding to sys-
temic and topical treatments given for at least
3 months, were enrolled from a tertiary care hospital
over a 2-year period. Prior to commencing treatment,
detailed history, examination and investigations were
performed. All systemic drugs except antihistamines
were stopped. Topical emollients were continued. We
did not administer the drug to women of child-bearing
The patients were initiated on thalidomide in accor-
dance with the published guidelines (http://www.thalo
midrems.com/). An 11-point visual analogue scale
(VAS) (0 = no pruritus, 1–3 = mild pruritus, 4–

ª 2019 British Association of Dermatologists Clinical and Experimental Dermatology 1

Analysis of low-dose thalidomide in recalcitrant PN  K. Sardana et al.

Table 1 Review of studies on the use of low-dose thalidomide for the treatment of prurigo nodularis.

No of Dose of Duration of
Author patients thalidomide therapy Response AEs Recurrence

Lan et al., 6 100 mg, then 1.5–15 months All patients reported early No patient developed One patient
20033 tapered and marked reduction in neuropathy. 2 patients had recurrence
according to pruritus. Complete reported sedation and 1 and was
clinical response resolution of lesions was had generalized erythema treated
seen in 5 patients, while 1 with lower leg oedema, successfully
patient was lost during which resolved on with a second
follow-up tapering the drug course
Taefehnorooz 13 50–100 mg for 3–142 months 7 had complete resolution 2 patients discontinued –
et al., 20114 12 patients; after a mean of 3 months, treatment due to
150–200 mg with 4 on maintenance peripheral neuropathy (at
for 1 patient treatment at the most 8 and 20 months), while 2
recent follow-up. 4 other patients had other
patients showed slight AEs: 1 had renal toxicity
improvement while and 1 had sedation and
treatment was unsuccessful dizziness
in 2
Johnke and 22 50–300 mg daily 2 weeks to 20 patients had immediate The therapy was –
Zachariae, 5 years relief from pruritus, and a discontinued in 13
19935 significant decrease in size patients due to AEs, of
and number of skin lesions which 5 had neuropathy
after 1–2 months of
treatment
Crouch et al., 5 100 mg in 4 1–8.5 months 2 showed mild 3 patients stopped –
20026 patients, improvement and 1 treatment due to AEs;
200 mg in 1 showed marked peripheral neurotoxicity in
patient improvement (required a 2, and dizziness, angina
second course for and worsening diabetes in
10 months at the same 1
dose but with reduced
effect) of pruritus and
lesions, and 2 had no
change. Complete
clearance was not seen in
any patient
Doherty and 12 100 mg tapered > 1 month 30% had mild (no Numbness, constipation –
Hsu, 20087 to 50 mg if worsening and 25% and sedation
early clinical improvement), 60% had
improvement moderate (25–90%)
improvement, and 1 (8%)
had complete
(90%) improvement
Andersen and 42 100 mg daily. 26 months 6 patients had mild 25 developed peripheral –
Fogh, 20118 Dose was (mean improvement, 25 had neuropathy (at 89 weeks
decreased to duration) significant improvement, average), 9 had sedation,
50 mg in 4 and 1 had complete 7 had dizziness, and 5
patients due to clearing. 6 had no had a skin rash
gastrointestinal improvement while in 4
AEs the effect could not be
determined

AE, adverse effect.

6 = moderate pruritus, 7–8 = severe pruritus and 9– Thalidomide was started at 50 mg on alternate days
10 = very severe pruritus) for itching was used at in all patients. The medication was taken at night to
baseline and every follow-up visit to measure reduce daytime sedation. Patients were followed up
response. every 2 weeks and the dose of thalidomide was

2 Clinical and Experimental Dermatology ª 2019 British Association of Dermatologists

 Analysis of low-dose thalidomide in recalcitrant PN  K. Sardana et al.
increased in a stepwise manner (50 mg on alternate
days for 2 weeks, followed by 50 mg daily for
2 weeks, then 100 mg daily) if needed, until > 50%
reduction in VAS (VAS50) was achieved [i.e. the dose
of thalidomide was increased in patients with < 50%
reduction until they achieved VAS50, which was con-
sidered partial response (PR)]. Thalidomide 100 mg
was given for a maximum of 4 weeks, and if VAS50
was not achieved even after 8 weeks of thalidomide, it
was considered treatment failure (Fig. 1). The drug
was continued for another 4 weeks at the same dose
(at which PR was achieved) with the goal of achieving
≥ 90% decrease in VAS score, failing which the dose
was increased to a maximum of 100 mg. Treatment
was continued with the same dose until complete reso-
lution of the lesions (complete response; CR). This
fixed-dose escalating regimen was dependent on VAS
score and the dose of 100 mg was not exceeded in
any patient. The aim of the stepwise increase was to
ascertain any AEs that were considered disabling by
the patient; if so, the treatment was stopped or modi-
fied accordingly. Nerve conduction velocity (NCV)
studies were performed at 3 months and thereafter
every 6 months. After CR, the drug was stopped and
the patients were asked to apply topical emollients and
continue oral antihistamines if needed. Patients were
followed up monthly for 12 months and any signs of
peripheral neuropathy or relapse were noted. In case
of relapse, thalidomide was restarted.
Duration of disease varied from 3 to 6 years, with a
mean of 4.58 years. Two patients had diabetes melli-
tus, one had hypothyroidism and one had acquired
immunodeficiency syndrome. Previous treatments
received included potent topical corticosteroids and
sedative antihistamines in all patients and systemic
medications, namely, oral steroids (n = 3), gabapentin
(n = 5), pregabalin (n = 4), methotrexate (n = 2) and
ciclosporin (n = 1). Mean pre-treatment VAS score
was 7.75 (range 7–9).
Of the 17 patients, 4 discontinued therapy due to AEs
(Fig, 1). The remaining 13 patients received the drug
for at least 8 weeks, with 4 showing PR with low-dose
thalidomide (VAS50), but not responding subsequently,
while the other 9 (69.23%) patients (n = 2 with 50 mg,
n = 7 with 100 mg) had complete resolution of lesions
(mean duration 16 weeks) (Fig. 1). The encouraging
results in our study were akin to the studies by Lan
et al. (6 patients) and Taefehnorooz et al. (7/13) who
found a favourable response to low-dose thalidomide
treatment (50–100 mg/day) in patients with PN.3,4
The lack of response in four of our patients could be due
to the lack of effect of thalidomide on IL-31, which has
ª 2019 British Association of Dermatologists
been implicated in PN . Possibly a higher dose given for
a longer duration might have helped the partial respon-
ders. Additionally, genetic polymorphism in thalidomide
metabolism may account for the variability of response
and lack of efficacy seen in some of our patients.9
At the 12-month follow-up, 2 patients had relapsed,
but responded promptly within 1 month of restarting
with thalidomide 50 mg, indicating that there is a
consistently predictable response of the drug.
Marked reduction in itching (VAS50) was noted
after 4.58 weeks with > 90% reduction in itching by
11 weeks. Interestingly, in patients who achieved PR,
VAS50 was achieved in 7 weeks, compared with
3.67 weeks in the patients who achieved CR, suggest-
ing that patients exhibiting an early marked reduction
in itching are likely to respond completely to treat-
ment. Similarly, Jøhnke and Zachariae found immedi-
ate pronounced alleviation of pruritus with significant
reduction in lesions after 1–2 months following treat-
ment with thalidomide at 50–300 mg.5 The clinical
morphology of PN is consequent to the incessant
scratching, and the effect of thalidomide on itching
may be due to Wallerian degeneration in the type C
unmyelinated fibres, as well as a direct analgesic effect
via inhibition of the peripheral vanilloid receptor [tran-
sient receptor potential vanilloid (TRPV-1)] channel.10
In the current study, only minor AEs were noted
(sedation, constipation, dizziness, urticaria) with no
case of drug-induced neuropathy (clinically or on
NCV). Sedation is the most common AE, and it gener-
ally decreases with continued use of thalidomide as
was seen in our patients. The major disadvantage with
thalidomide use is the development of neuropathy,
leading to treatment discontinuation in many patients.
The lack of neuropathy in our series was possibly due
to the fact that the risk of thalidomide-associated neu-
ropathy is related to the daily dose regardless of the
duration of treatment, and usually appears after
6 months of treatment.10 In our series, total clearance
was seen in 16 weeks, thus the shorter duration and
lower dose probably accounted for the lack of neu-
ropathy.
Our work suggests that an escalating, low dose of
thalidomide can alleviate itching and cause resolution
of lesions in PN without leading to neuropathy. Addi-
tionally, patients showing an early marked reduction
in itching are likely to respond completely to treat-
ment. The limitations of our work include the small
number of patients, the low maximum dose (100 mg)
and the arbitrary cut-off (8 weeks) to determine treat-
ment failure. The variation in the response to thalido-
mide and reasons for relapses are also unclear. The
Clinical and Experimental Dermatology 3
Analysis of low-dose thalidomide in recalcitrant PN  K. Sardana et al.

Thalidomide 50 mg on
alternate days for 2 weeks
(n = 17)

Paents disconnued treatment due to side

effects [dizziness (n = 1) and urcaria (n = 1) ]

VAS < 50%

VAS > 50%* (n = 15)
(n = 0) Thalidomide increased to
50 mg OD for 2 weeks

Paents disconnued treatment due to side effects

[sedaon (n = 1) and conspaon (n = 1) ]

VAS < 50% (n = 4)

VAS > 50%* Thalidomide increased to
(n = 9) 100 mg OD ll VAS > 50 (for
maximum 4 weeks)

*VAS > 50% or paral response (PR) connue the

drug at the same dose for 4 weeks
VAS < 50% even aer 8 weeks of
(n = 9 with 50 mg and n = 4 with 100 mg) VAS > 50%*
thalidomide (treatment failure )
(n = 4)
(n = 0)

PR seen but VAS > 90% not achieved

VAS > 90% achieved
(n = 7 with 50 mg)
(n = 2 with 50 mg and n = 4 with
100 mg) Increase the dose to maximum 100 mg
OD

Connue the drug at same dose

ll complete clearance of lesions VAS > 90% achieved PR achieved but VAS > 90%
or complete response not achieved (n = 4)
(n = 3)
(n = 2 with 50 mg and n = 7 with Paral responders
100 mg)

Figure 1 Flowchart depicting the use of fixed dose escalating regimen dependent on the visual analogue scale (VAS) score and the
results of our experience with low-dose thalidomide in 17 patients with prurigo nodularis. *Patients achieving VAS > 50% denoting
partial response.

ideal dose and duration for the minority of patients • However, development of peripheral neuropa-
who did not respond adequately will require a pla- thy with thalidomide use, especially at high
cebo-controlled study with a larger number of patients doses, leads to discontinuation of treatment in
to shed light on the external validity and failure rates many patients receiving this drug.
of this low-dose regimen. • Lower doses of thalidomide given for a shorter
duration minimizes the risk of peripheral neuropathy.
• Low-dose thalidomide (< 100 mg) produces a
Learning points profound effect on the itching and is efficacious
for the treatment of PN.
• Thalidomide has been found to be effective in • An escalating low-dose regimen can be helpful
PN, usually at a dose of 200–400 mg. to reduce the incidence and severity of AEs.

4 Clinical and Experimental Dermatology ª 2019 British Association of Dermatologists

 Analysis of low-dose thalidomide in recalcitrant PN  K. Sardana et al.
• Early and marked response in itching predicts
patients are likely to have complete resolution of
lesions.
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Clinical and Experimental Dermatology 5