Treatment of apomorphine-induced skin reactions: a pilot study

Levodopa as gold-standard treatment of Parkinson*s disease (PD) is associated
with the occurrence of motor complications in the long term. After 5 years of
levodopa treatment 50% of the patients develop motor response fluctuations and
dyskinesia, and 80% after 10 years (Chase et al., 1993; Schrag & Quinn, 2000).
Continuous infusion of apomorphine has shown to be very efficacious in treating
these motor response fluctuations and dyskinesia (Fox et al., 2011). However, a
common side effect of apomorphine infusion is the formation of subcutaneous
nodules (Deleu et al., 2004). It may cause distress due to discomfort such as
redness, itchiness or tenderness (van Laar et al., 1998). Subcutaneous nodules
interfere with the absorption rate and may cause *flip-flop* kinetics (Neef &
van Laar, 1999), which limits the duration and effectiveness of apomorphine.

The histopathology of the nodules is poorly understood. Four studies were found
performing biopsies of subcutaneous nodules induced by continuous subcutaneous
apomorphine infusion (Stibe et al., 1988; Acland et al., 1998; van Laar et al.,
1998; Pot, 2005) of which only two performed multiple biopsies (Acland et al.,
1998; van Laar et al., 1998). Acland and coworkers (1998) took biopsies in ten
patients from lesions resulting from the previous day*s infusion site. Six out
of ten biopsies showed a predominantly eosinophilic infiltrate into the
subcutaneous fat. Van Laar and coworkers (1998) took multiple biopsies in three
patients varying from 1 to 14 days after termination of continuous subcutaneous
apomorphine infusion. The biopsies showed an infiltrate, which was loaded with
melanin-like pigment. This pigment was supposed to be related to quinone
breakdown products of apomorphine. Apomorphine is auto-oxidized into
o-quinones. O-quinones can undergo conjugation reactions or can be polymerized
into dark melanin-like pigments (van Laar et al., 1998). The contribution of
o-quinones to nodule formation is not known. The formation of nodules was
considered to be a hypersensitivity reaction either of a delayed type IV or a
late form of the immediate type I reaction (Acland et al., 1998; van Laar et
al., 1998). Apomorphine as a derivative of morphine and having a close
structural similarity to morphine, could have the same allergenic properties as
morphine (van Laar et al., 1998). Patch testing did not support a type IV
hypersensitivity reaction, which could have been the result of an insufficient
concentration of apomorphine (Acland et al., 1998).

Since the histopathology of the nodules is poorly understood, treatment options
are limited and suggestive. Authors suggested the use of ultrasound, massage,
the use of silicon patches and 50% dilution of apomorphine with 0.9% normal
saline to significantly reduce nodule formation (Bowron et al., 2004; Deleu et
al., 2004; Colzi et al., 1998; Lees et al., 2002; Poewe & Wenning, 2000). Only
the use of ultrasound has been studied in a small-sample randomized controlled
trial which showed a beneficial effect on tenderness and hardness compared to a
sham ultrasound, however this did not reach significance (Poltawski et al.,
2009). In the Netherlands, the use of ultrasound is not integrated in the
treatment of apomorphine-induced skin reactions for practical reasons.

The University Medical Center Groningen (UMCG) uses massage, dilution and
hydrocortisone administration, dermally or subcutaneously, in the treatment of
apomorphine-induced skin reactions. However, evidence for one of these
treatment options is lacking. Neither the benefits nor the risks have been part
of research. The planned pilot study is intended to investigate the efficacy of
these treatment options to provide such evidence.

The primary objective of this pilot study is to determine the effectiveness of
four treatment options for local skin reactions induced by continuous
subcutaneous apomorphine infusion, as compared to no treatment.
The primary endpoint is the measured absolute change on the global perceived
effect (GPE) scale after treatment with one of these options.
The secondary objective of this study is to investigate the role of allergy in
these apomorphine-induced skin reactions.
Secondary endpoints are therefore changes in nodule and erythema size, changes
in histological skin tissue characteristics (presence of eosinophils,
melanine-like pigment, fibrosis, macrophages, histiocytes and lymphocytes),
extend of eosinophilia, personal and family history of allergies and atopic
constellation.

This pilot study is designed as an open label crossover trial of four
treatments in a fixed sequence in 20 PD patients showing skin reactions to
continuous subcutaneous apomorphine infusion. The study will comprise 1
screening visit to confirm subjects* eligibility. The duration of inclusion is
6 months. The sequence of treatments for each patient eligible will be
administered over a period of 4 months. The overall duration of the study is
four months + one week. All patients receive four therapeutic interventions,
each with a duration of 14 days. After each period of two weeks two deep punch
biopsis will be taken to assess the secondary endpoints, one biopsis of a
lesion treated for three days and one biopsis of a lesion after being treated
for two weeks.

The investigational treatment options are part of the current standard
treatment of skin reactions in Parkinson*s disease patients treated with
continuous subcutaneous apomorphine infusion. Subjects are standard instructed
to take the following measures:
• Strict hygiene;
• Daily rotation of insertion site, making use of the whole abdominal wall.

The investigational treatment options will be given in a fixed sequence:
1. Massage: Start massage of nodule with a spikey ball. Massage nodules three
times a day for 2 minutes. After 14 days, determine nodule size and erythema
size of lesions treated for 3 and 14 days, take a picture with scale of lesions
and whole abdominal skin. Perform a deep punch biopsy of nodules after 3 and 14
daysof treatment and take blood sample. Administer global perceived effect
(GPE) scale;
2. Topical administration of hydrocortisone: Start with treatment of the nodule
with hydrocortisone cream 1% 1 time a day. After 14 days, determine nodule size
and erythema size of lesions treated for 3 and 14 days, take a picture with
scale of lesions and whole abdominal skin. Perform a deep punch biopsy of
nodules after 3 and 14 days of treatment and take blood sample. Administer GPE
scale;
3. Dilution: Start dilution of apomorphine. Dilute apomorphine 0.5% (5 mg/ml)
to 0.25% (2.5 mg/ml) by addition of same volume 0.9% NaCl (physiological
saline). After 14 days, determine nodule size and erythema size of lesions
treated for 3 and 14 days, take a picture with scale of lesions and whole
abdominal skin. Perform a deep punch biopsy of nodules after 3 and 14 days of
treatment and take blood sample. Administer GPE scale;
4. Subcutaneous administration of hydrocortisone: Start with pre-treatment with
Solu-Cortef 10mg. After 14 days, determine nodule size and erythema size of
lesions treated for 3 and 14 days,take a picture with scale of lesions and
whole abdominal skin. Perform a deep punch biopsy of nodules after 3 and 14
days of treatment and take blood sample. Administer GPE scale.

Risks
Apomorphine-induced skin reactions may be the result of an allergic reaction
(Acland et al., 1998; van Laar et al., 1998). Safety endpoints include
evaluation of liver enzymes to anticipate on a chronic allergic reaction which
is potentially harmful. Eventually, patients need to stop apomorphine
treatment.
The extra invasive procedures (i.e. deep punch biopsies and blood samples at
each visit) are considered as low risk procedures. The risk of bleeding is
minimal even when using anti-coagulantia.

Benefits
For the patients the benefit lies in the possibility of a therapeutic effect,
and with their participation in the trial all patients contribute to a
scientific understanding and treatment of apomorphine-induced skin reactions.