Itch and pain modulation in patients with chronic itch before and after inpatient treatment

Patients suffering from chronic physical symptoms, such as chronic pain and
itch, have a lot in common, for example, the mechanisms of peripheral and
central sensitization of itch and pain are partly characterized by
corresponding patterns.
Conditioned Pain Modulation (CPM) is a pain modulatory mechanism, supposed to
be one of the mechanisms that partly explain the susceptibility of chronic pain
disorders. CPM is a phenomenon in which one noxious stimulus (the conditioning
stimulus) inhibits the pain produced by another. Results showed that CPM is
impaired in patients with chronic pain, possibly because of dysregulation of
endogenous analgesic systems. We recently showed that itch can be similarly
modulated, by a phenomenon called Conditioned Itch Modulation (CIM). Both CPM
and CIM has been shown to be impaired in patients with chronic pruritus, which
is possibly a consequence of a dysregulation of endogenous itch modulatory
systems.
It is known that CPM in chronic pain patients can improve after successful
treatment. However, whether CIM and CPM can be improved in patients with
chronic itch has not been investigated yet.
Therefore, the aim of this pilot-study is to investigate whether CIM and CPM
can be improved after effective treatment of itch. Furthermore, since there are
indications that also CPM is dysregulated in chronic itch, a secondary goal is
to investigate whether CPM can improve after effective treatment of itch. We
hypothesized that CIM and CPM would improve after effective treatment of
chronic itch. When these hypotheses are supported, the results of this study
can possibly lead to improved diagnostics and care in patients with chronic
itch in the long term.

Analyses should indicate whether, in line with our hypotheses, CIM and CPM are
improved after effective treatment in patients with chronic itch. When the
hypotheses are supported, the study provides preliminary evidence for possible
treatment developments for chronic itch to improve diagnostics and care in
these patients.

Subjects and procedures
The study has an observational design without invasive measurements. All
measurements will be conducted with approximately 25 patients with chronic itch
due to skin conditions (e.g. atopic dermatitis, psoriasis) who are admitted in
the clinic. The patients are 18 years or older and have no serious physical or
psychiatric co-morbidity that severely interfere with the study protocol.
Assessments of itch and pain modulation by using quantitative sensory testing
(QST) will take place twice: once within the first three days and once within
the last three days during the inpatient treatment.
Power calculations are based on a repeated measures design within one group
with an alpha of 0.05. Main effects with an effect size (f) of 0.30 yield a
beta of 0.80 and a sample size of 25. The dependent variable in this
calculation is the difference in pain induced by electrical stimulation before
and after conditioning stimulation.

Self-report measures
Before the first assessment of QST, self report measures which could be related
to itch and pain modulation will be assessed e.g. psychological vulnerability
factors of neuroticism, hypervigilance and worrying. In addition, validated
questionnaires will be used to measure the itch- and health-related quality of
life during the past month.


Quantitative sensory testing (QST) of itch and pain modulation

All measures have been previously validated in healthy controls and patients
with chronic itch and pain by the research group.
Methodological background: The QST measures are short stimuli of moderate
intensity that are experienced as little burdensome. QST stimuli will be
applied before and after treatment to investigate CIM and CPM. QST is a
frequently applied method to assess central sensitization in chronic pain using
different stimulus modalities and has also been validated for chronic itch. QST
is also a frequently used method to demonstrate reduced CPM. In the present
study, short electrical test stimuli will be applied before and after the
conditioning stimulus for either itch or pain.
Electrical stimulation: After applying cutaneous electrodes, the electrical
perception, the unpleasantness and tolerance threshold will be determined in
twofold. The maximum stimulation is 15 mA. Short electrical test stimuli are
applied to investigate the change in itch and pain resulting from the itch and
pain conditioning stimuli, respectively. Patients will first receive threshold
measurements and short electrical stimuli of low intensity to familiarize with
the stimuli.
CIM: Itch conditioning stimulation is done by application of 0.5% histamine,
applied to the subject*s dominant arm by means of iontophoresis with an
intensity of 0.4 mA during 2.5 minutes. Before and after the histamine
application (itch conditioning stimulation), electrical test stimuli will be
used to measure (altered) CIM.
CPM: Pain conditioning stimulation is done by using a cold pressor test.
Patients are asked to immerse their dominant hand up to the wrist in water of 4
°C. Patients are instructed to keep their hand in the water as long as possible
until it becomes intolerable (with a maximum of 3 minutes). Before and after
the cold pressor test (pain conditioning stimulation), electrical test stimuli
will be used to measure (altered) CPM.
Dependent measures: Patients are asked to indicate on a VAS scale the
intensities of itch and pain evoked by the electrical test stimuli as well as
during the itch and pain conditioning stimulation.

Analysis
The data will be analyzed using SPSS. Variables will be checked for normal
distribution. To test the main hypothesis, itch and pain scores before and
after applying the conditioning stimuli will be analyzed at both measuring
points (at the start and at the end of the inpatient treatment), using repeated
measures ANOVAs for itch and pain separately.
In addition, Pearson correlation coefficients will be calculated between change
scores for itch and pain evoked by the electrical test stimuli, and the
following variables: age, gender, educational level, itch and pain scores
evoked by the conditioning stimuli (histamine and cold pressor), cold pressor
immersion time, individual characteristics, the current skin disease severity
and VAS itch and pain on the day of testing.

The burden for the patients consists of two QST measurements of 1 hour and
completing validated questionnaires one time (30 minutes) (in total 2,5 hours).
The validated QST measurements with short stimuli were not considered a burden
by patients in the past (e.g. Laarhoven et al., 2007, 2010).