Experimentally Evoked Itch Response to a Newly Developed Hand-Held Mobile Device Delivering Non-Noxious Heat, Cold, and Vibration: A Pilot Study in Healthy Humans
Anders Lindby Nørgaard Hansen1,
Parisa Gazerani2*
1School of Medicine
and Health, Faculty of Medicine, Aalborg University, Aalborg, Denmark
2Biomedicine, Department of Health Science and Technology, Faculty
of Medicine, Aalborg University, Aalborg,Denmark
*Corresponding author: Parisa Gazerani, Biomedicine,
Department of Health Science and Technology, Faculty of Medicine, Aalborg
University, Fredrik Bajers Vej 3B, 9220 Aalborg, Denmark. Tel: + 4599402412;
Email: gazerani@hst.aau.dk
Received Date: 10 September, 2018; Accepted Date: 20 September,
2018; Published Date: 27 September, 2018
Citation: Hansen ALN, Gazerani P
(2018) Experimentally Evoked Itch Response to a Newly Developed Hand-Held
Mobile Device Delivering Non-Noxious Heat, Cold, and Vibration: A Pilot Study
in Healthy Humans. Clin Exp Dermatol Ther: CEDT-154. DOI: 10.29011/2575-8268/100054
1. Abstract
Introduction: Evidence demonstrates that
cold or warm temperatures can modulate itch. Noxious heat has inhibited
histamine-evoked itch in humans. A cold stimulus has also been shown to inhibit
itch in human models. However, a combination of these modalities, in form of warm-cold
stimulation on itch is less studied and has yielded conflicting outcome. For
example, short term alternating temperature has been shown to enhance
histamine-evoked itch. On the other hand, alternating temperatures delivered by
a roller device could reduce lactic acid induced-itch in humans. This
controversy in the literature stimulated our interest to further test the
pattern of evoked itch modulation by temperature modality in humans. Since
vibration has also been found with an itch relieving effect, we combined this
modality and developed a hand-held mobile device that can deliver heat, cold,
and vibration simultaneously or individually. We investigated patterns of itch
modulation in healthy volunteers undergoing experimental human model of histamine-evoked
itch in response to the newly developed device. We expected to identify
different degrees of itch modulation and an optimal combination that can
further be examined for alleviating itch in patients with pruritic conditions.
Methods: This study was approved by the North Jutland
Region Committee on Health Research Ethics (N-20170071) and was conducted in
accordance with the Declaration of Helsinki. Sixteen healthy volunteers (age
range: 18-65 years) participated in the pilot phase of the study: 8 males
(35.75 ±10.74 (28-61 years)), and 8 females (38.0 ±14.89 (24-62
years)). Skin prick test on the volar aspect of forearm was used to provoke
histamine-induced itch in a quiet room with a temperature of 23-24°C. Following
cleaning of the skin with a sterile disinfectant, a drop of 1.0% histamine
dihydrochloride (Lofarma S.p.A., Milano, Italy) was placed and a lancet with 1
mm tip was used to prick the skin through the drop. Evoked itch intensity was
rated by volunteers on a VAS scale of 0 (no itch) to 10 (the most intense
itch). The newly constructed prototype of a mobile itch-modulating device was
applied two times for each paradigm lasting for 30 seconds with a 150 sec
inter-application interval. Paradigms of non-noxious heat, cold, heat-cold,
with and without vibration were randomly applied in 4 sessions each lasting for
one-hour, separated by a minimum of 24 hrs. Application arm (dominant vs.
non-dominant) was also randomized. Data are presented as mean and standard
deviation. ANOVA tests were performed for statistical analysis by IBM-SPSS and
p<0.05 was conside red significant.
All volunteers completed the study sessions and no safety issues were
recorded or reported. Histamine-evoked itch intensity was diminished in
response to the different applied paradigms. Combined thermal application
paradigm (heat-cold) with vibration demonstrated the largest itch reduction
effect. In general, including vibration yielded a greater reduction in itch
intensity compared with no vibration for any given paradigm (heat alone, cold
alone, heat-cold combination). Overall, first application of the device at the
peak of the histamine-evoked itch intensity was more effective in itch
reduction than the second application. Small sample size and large
inter-individual variations affected the power of the statistical analysis. A
larger cohort to substantiate findings of this study is warranted.
Discussion: This study demonstrated that histamine-evoked itch
responded to the newly developed hand-held mobile device delivering non-noxious
heat, cold, and vibration. Different application modes of the device (heat
alone, cold alone, heat and cold combination, with and without vibration)
yielded different magnitude and pattern of reduction on the evoked itch
model. This pilot study showed that a combination of alternating thermal
stimulation paired with vibration could produce the largest anti-pruritic
effect. However, this needs to be confirmed in a larger sample size study.
2. Introduction
Itching (pruritus) is
a symptom of dermatological disease, which may be defined as a cutaneous
sensation provoking a desire to scratch or rub [1]. Atopic eczema and
psoriasis are among the most commonly described conditions that accompany
itch [2]. Besides skin diseases, itch can be a symptom of other health
conditions, for example HIV, diabetes mellitus, systemic diseases, and renal
diseases [3,4], and it is linked to both inflammatory and non-inflammatory
diseases [5]. Itch can broadly be classified to acute or chronic itch,
persisting less or more than 6 weeks, respectively [6]. Average prevalence
of chronic itch has been estimated >16% of adults [2]. Elderly
population is more likely to be affected by chronic itch [7]. However,
studies have demonstrated conflicting results and due to a large range of
variations, no significant difference can be found [2]. Quality of life in
patients with pruritus is dramatically disturbed [8]. Chronic itch has not
only been considered a burden to affected individuals, but also to health care
systems around the globe [9]. Despite the chronic itch prevalence, and its
consequences on quality of life of affected patients, current treatment
strategies for pruritus are only partially effective and pose several side
effects [10]. Lack of sufficient treatment strategies for chronic itch is
mainly associated with insufficient knowledge about itch pathways and specific
targets [11]. Considering personal, social, and economical aspects of
chronic itch and its related complications, further investigation seems
necessary in order to obtain better insights into mechanisms contributing to
development of chronic itch and identification of novel targets that can assist
in strategies or treatments for itch relief [12].
Thermal
modulation of itch has been of interest as a non-pharmacological technique to
subside itch. When the skin is stimulated by either innocuous cold, or noxious
heat, the signaling pathway is different. The cold stimuli activate innocuous
thermosensitive cold (COLD) cells [13]. The heat stimuli activate Heat,
Pinch, Cold (HPC) cells, these cells are also sensitive to mechanical and cold
stimuli [14]. This means that during innocuous cold stimulation, both COLD
and HPC cells are activated. When the skin is exposed to noxious heat stimuli,
only the HPC are activated. Collectively, based on the evidence in the
literature [15-17] and according to Chuquilin et al. [18], it
seems that heat increases itch whereas cooling relieves it and that the thermal
stimuli need to be noxious to elicit the inhibitory effect on itch. Besides the
possibility of tissue damage, noxious thermal stimulation gives rise to another
concern. Murota et al. [19] found that both in patients with atopic
dermatitis and in histamine-induced itch models in healthy individuals, itch
was experienced after either noxious heat (>45℃) or noxious cold (<5℃) stimuli. This was related to a sensitization
of the TRPV1 expressed in un-myelinated C-fibers. It is therefore of great
importance to maintain temperatures within the required interval where no
noxious stimuli occur.
Combining thermal
bars with alternating temperatures creates a Thermal Grill (TG) that is known
to provoke an illusion. TG creates a cold burning sensation despite the
temperature of both the warm and cold parts of the grill to be
innocuous [20]. The activity of the COLD and HPC cells has been tested in
relation to TG. Findings present that with cold stimuli activation of both COLD
and HPC are seen, but with warm stimuli, only HPC activation is
evident [21]. This finding presents that simultaneous application of
warm and cold causes an imbalance between firing of spinal HPC neurons and
those only responsive to cold (COLD). In response to the TG, HPC activity
increases disproportionately compared to COLD. Based on this and earlier
studies [21,22], thermosensory disinhibition hypothesis was put forward to
explain that HPC activity is centrally inhibited by COLD activity and that the
illusion of TG leads to a disinhibition or unmasking of HPC-related
percepts [21,22].
Besides the
effect of thermal modulation on itch, vibration has long been described to
relieve itch sensation [23]. Wall and Cronly-Dillon [23] described
that the neural pathway associated with itch was overwritten with signals
stemming from vibration. Melzack and Schecter [24] tested subjects
with vibration applied on the site of itch, adjacent to the itch area, and the
opposite arm and found that applying vibration directly to the site of itch had
the largest and quickest effect. Therefore, it would be beneficial if thermal
and vibration stimuli can be combined in one device, capable of delivering
these stimuli simultaneously at itch area to potentially enhance the itch
relief. Watanabe and Kajimoto [25] were first to develop a
roller-type device capable of delivering thermal and vibration stimuli. They
tested it on healthy subjects under experimental setting of the evoked itch by
lactic acid 2.5% applied on cheek and found itch relief effects. BITE
HELPER is a small pen-shape commercially available device that has been
designed to neutralize itch and irritation following insect stings and bites
from mosquitoes, flies, bees, wasps, and ants. This device only delivers heat
and vibration for spot treatment. Considering limitations of TG roller device,
and spot itch reliever, we decided to design and produce a prototype for a
mobile, and easy to use device that is capable of producing different thermal
and/or vibrational stimuli within innocuous and non-painful range. We
considered 8 different combinations to find the most effective in relieving
histamine-evoked itch in healthy adult males and females. We hypothesized that
the different combinations of stimuli would result in different amount of itch
relief and that at least one of the eight combinations would yield an optimal
relief.
3. Methods
3.1. Design
We aimed at designing a
device that is capable of delivering both non-noxious thermal warm, thermal
cold, and vibrational stimulation. The device also had to be mobile, battery
powered, rechargeable, simple to use, and most importantly safe. We developed
several prototypes (Figure 1).
The final
design (Figure 2) resembles a spatula, with a long handle to facilitate
hard-to-reach areas on the body.
On the bottom
of the final prototype, four equal and separate aluminum plates (47mm x 40mm)
are arranged side by side in a checkboard layout (Figure 3A). These plates are
capable of producing either a warm or cold stimulus. The thermal layout of the
plates is set with switches inside the device (Figure 3B). On the top, two
external switches are placed to either turn on/off the thermal stimulation or
the vibration (Figure 3C). The charging port is placed at the end of the handle
(Figure 3D).
3.2. Settings
The device was capable of
producing four distinct temperature layouts. All warm, all cold, and two
alternating, warm-cold. One alternating was the warm and cold panels arranged
in a linear layout, and one where they were placed opposed to each other like
the black and white squares in a check board. As most literature describes and
tests the TG illusion as linear [20,21], the linear layout was chosen for
this pilot study. The device was also provided with a vibration function, which
could be turned on regardless of the thermal setting. The overview of the
device setting can be seen in Table 1.
3.3. Pilot Test
Sixteen healthy
participants, 8 males (35.75±10.74 (28-61 years)), and 8 females (38.0±14.89 (24-62
years)), participated in this pilot test. Before each experiment, the
participants were informed about the procedure, the risks involved in the
different procedures, and planned stimuli. They were also informed that they
were able to withdraw from the experiment at any time in accordance to the
version 2013 of the Declaration of Helsinki [26]. This study was
approved by the North Denmark Region Committee on Health Research Ethics
(approval no.: N- 20170071). The pilot test was conducted in a randomized
fashion for application of different settings (Table 1) and the tested arms
(dominant, non-dominant).
In the middle
of the chosen volar forearm, a standard skin prick test [27] was
performed with one drop of 1% histamine dihydrochloride (LOT# 161214, Lofarma
S.p.A., Milano, Italy) placed on the skin following cleaning with a sterile
disinfectant. A lancet with 1 mm tip was used to prick the skin through
the drop. Skin prick test was performed in a quiet room with temperature of
23-24°C. The test subjects were
asked to score itch intensity every 30 seconds on a visual analogue scale (VAS
0-10), with 0 indicated no itch, and 10, the most intense itch. Two minutes
after the prick test, the participants were asked to place the device, on top
of the prick test site, for 30 seconds. During these 30 seconds, the subjects
were asked to report their itch intensity every 15 seconds. When the device was
removed, the test subjects were again asked to record the itch intensity every
30 seconds, for the next 2.5 minutes. The device was once more placed on the
skin, on top of the prick test site, for 30 seconds. Again, the subjects rated
their itch intensity every 15 seconds and after removal of the device, itch
intensity was rated every 30 seconds for one minute. When the itch sensation
was completely vanished, no earlier than 25 minutes after the first forearm,
the process was repeated on the other forearm, with a different setting (chosen
from Table 1). The newly constructed prototype of a mobile itch-modulating
device was applied two times for each paradigm lasting for 30 seconds with a
150 sec inter-application interval. Paradigms of non-noxious heat, cold,
heat-cold, with and without vibration were randomly applied in 4 sessions each
lasting for one-hour, separated by a minimum of 24 hrs.
3.4. Statistical Analysis
Two sets of data were
analyzed. First, the change in itch intensity under stimulation from the
device. This was calculated by taking the average itch intensity just before,
and right after the stimulation (at 90 seconds, and at 180 seconds, and also at
270 seconds, and at 360 seconds) and deducting the average itch intensity
during stimulation (at 120, 135, and 150 seconds, and also at 300, 315, and 330
seconds). Also, the absolute change in the VAS score was timed with percentage
change (VAS%). This would ensure that participants with a high absolute change,
but low percentage change would not outweigh participants with a small absolute
change but large percentage change, and vice versa. These data would give
insight to how effective the different settings performed when stimulating the
itch area.
Second, the
area under the VAS score curve (AUC) from 90 to 390 seconds was calculated.
This would give insight to how the anti-pruritic effect of the settings would
work both during and after stimulation. From these data sets (VAS score, change
in VAS%, and AUC), it was tested if the different setting had equal starting
point at 90 seconds, if any of the 8 settings (Table 1) differed from each
other, and lastly if the 4 settings with vibration varied from the 4 settings
without.
All data from
the pilot test were checked for normal distribution by performing tests of
normality (Shapiro-Wilk). One-way analysis of variance (ANOVA) followed by a
Tukey post-hoc test was used when data were normally distributed to compare
means of 16 independent groups with setting as a factor (Linear, Linear with
vibration, Warm, Warm with vibration, Cold, Cold with vibration, Off, and Off
with vibration). When the data were not normally distributed, The
Kruskal-Wallis H test also called the one-way ANOVA on ranks was used. The data
from the analyses are presented as mean ± standard deviation (SD) and
significance level was set at p≤0.05.
4. Results
All participants completed
the pilot test and no safety issue was reported or recorded. All participants
generated a flare response to the histamine application. Regarding the two
off-settings, almost every participant reported a cold sensation. After the first
and second stimulation by both warm settings, around half of the participants
reported that it felt like the itch sensation had spread out from the site of
the prick test to a larger area. A few participants described the vibration
similar to scratching act.
4.1. Itch intensity
The primary
outcome of this pilot study was to find out the effect of 8 settings delivered
by the hand-held mobile device. Overall, all type of stimuli followed a similar
pattern, meaning that all settings presented with a peak of effect on itch
intensity 90 seconds after the histamine prick (when the itch was at its
maximum). A remarkable itch relief was seen at this time point when the device
was applied, and the effect was regardless of the setting (Figure 4).
4.2. Itch Intensity Alterations
The average
changes in itch intensity times the percent wise changes in itch intensity
(Figure 5) were tested for normal distribution. Only two settings (linear and
cold with vibration) were normally distributed (Table 3). The Off-setting
showed the smallest change whereas the linear setting with vibration showed the
largest. Six out of eight groups were not normally distributed. A one-way
nonparametric ANOVA was run to compare the average change with confidence
interval set to 95%. In the comparison of Linear with vibration and Off,
significant difference was found with a p-value of 0.048. The power was
calculated and found as 81.2%.
4.3. Area Under the Curve
The mean AUC from 90-390 seconds (Figure 6) was
calculated for the 8 settings and tested for normal distribution. The AUC had
the largest value in the warm setting with no vibration, whereas the cold
setting with vibration showed the lowest value (Table 4). Seven out of 8
settings had normally distributed data. One-way ANOVA was run to compare the
average AUC followed by a Tukey post-hoc test, with settings as variable, with
confidence interval set to 95%. No comparisons yielded
p-values ≤ 0.05. The power was calculated and found as 46.6%.
4.4. Vibration
In order to identify whether vibration was an
important factor in reduction of itch, data from the change in itch intensity
and the AUC were grouped to represent either vibration on or off. The data
showed a larger change in itch intensity when vibration was on (Table 5). Two
sample t-test was performed for both
data sets of itch intensity and AUC, but none of those yielded any significant
difference with p-values ≤ 0.05. The power was 17% for the change in
itch intensity, and 13% for the AUC.
5. Discussion
The aim of this study was
to design and test a mobile device with an antipruritic effect. The goal was to
develop a prototype that can be easy to use and capable of producing a thermal
and vibrational stimulation simultaneously. After developmental and production
phase, the final prototype was tested to identify an optimum setting for
antipruritic effect in an experimental model of itch in healthy humans.
Findings showed the optimal setting for antipruritic effect to be linearly
arranged alternating thermal stimulation paired with vibration. This setting
showed the greatest drop in itch intensity under the condition of this pilot
study. Larger studies are required to substantiate the findings. Below, design
modifications for prototypes and the identification of optimal setting with the
final prototype are discussed.
5.1. Design of Prototypes
The first prototype of a
mobile thermal grill roller was made in the spring of 2017. Thermoelectric
peltier elements (Thermonamic Electronics (Jiangxi) Corp., Ltd., China) of 40mm
x 40mm were placed on the outside of a hexagon tube. The tube width was 44mm on
each side, and the length was 58mm. Six thermoelectric elements were placed
with alternating warm and cold side facing out. On the inside of the cooling
elements a heat sink radiator was placed to conduct the excess heat from the
surface (Figure 7).
Lids were cut
from a Polyoxymethylene (POM) blank. Six holes were drilled in each POM lid to
accommodate ventilation, and a ball bearing was fitted in the center. The
bottom lid was fitted, and a cast was made around the contraption to create a
round surface. The cast was made from Epoxy 091108-1M1 (Resin Design, LLC, MA
01801, USA) and set to dry overnight (Figure 8).
When cast was
set, excess epoxy was removed, and the top lid was fitted. Inside, a double AA
battery holder was fitted in parallel circuit to the cold elements, and a
double AAA battery holder was fitted in parallel circuit to the warm elements.
An on/off switch was also fitted (Figure 9).
A detachable
handle was made from aluminum and POM, and resulted in the final roller (Figure
10).
The surface
temperature of the roller was tested three times. A preliminary test was
performed without the epoxy cast and using a controlled power with fixed
voltage and amps (1.6 volts and 1.4 amps for the three cold elements, and 1.6
volts and 1.3 amps for the warm elements). This was done to get an
approximation of the current needed and monitored to investigate whether the
peltier elements would overheat. Next test, was the test with the cast and a
battery power source, but without the wires soldered and the detachable fitted
lid. This was done to test the set up with epoxy cast and batteries as power
source. Finally, a test was performed with a full test run with epoxy cast,
soldered wires, a switch, detachable lid and the attached handle. This test run
was carried out for a longer timeframe to also test the capacity of the
batteries. Before the tests new batteries were installed to ensure comparable
and optimal conditions. Figure 11 shows the results.
Major issues
with this prototype consisted of battery life, non-rechargeable batteries,
overheating of peltiers, and the fact that the roller was to be disassembled to
be turned on/off.
The 2nd prototype of the roller was made
at the beginning of autumn 2017. This time, the roller was constructed from a
3D model, using Rhinoceros 5.4 software (Robert McNeel & Associates,
Seattle, WA, USA), printed using a Makerbot Replicator+ (Makerbot Industries,
Brooklyn, NY, USA) (Figure12). To improve some of the issues from the previous
model, the 2nd prototype had 4
LG 3.6V, 2600mAh rechargeable lithium battery packs (LG Chem mobile energy
division, Seoul, South Korea) installed. A 5V micro USB 1A Lithium Battery
18650 Charging Board Charger Module LED TP4056 (NedRo, Eindhoven, Netherland),
was used to charge the batteries. A switch was attached to the outside of the
cylinder making it possible to turn the roller on/off without having to
disassemble it.
To both the
warm and cold circuits, individual resistors were fitted to ensure that the
correct amount of current was delivered to the peltier elements. The peltier
elements were fitted inside the cylinder, in the same arrangement as on the
first prototype. Rectangular holes were made on the backside of the peltier
elements facing the cold side out, to accommodate the cooling bridges to be
fitted directly onto the warm surface. Holes were fitted in both ends of the
cylinder to enable air flow and hopefully provide sufficient cooling. When
testing the surface temperature of the roller, two major issues were noticed.
First, the electronics overheated despite the cooling holes. The overheating
was even greater compared to the first prototype. This was assigned to the
newly fitted resistors. The resistors work by releasing the excess current from
the batteries as heat. This created a great deal of heat inside the cylinder
overheating the peltier’s after only 3-4 minutes. Second, as the second
prototype was made entirely from the plastic compound used by the 3D printer, the
temperature generated by the peltiers was not conducted through to the surface
of the cylinder. Facing these issues, no further testing was made.
The 3rd prototype was also a 3D printed
roller consisting of 5 parts. Design changes were made to create a more
conducting surface. Holes were made in the surface of the cylinder, on for each
peltier element, and six aluminum plates were cut to fit the holes (Figure 13).
To fit flush with the cylinder, the plates had one curved side (Figure14). The
plates were attached using heat conducting tape, to ensure thermal conduction
from the peltier elements.
The simple
resistors were replaced with buck resistors. These regulate current through
pulsation, as they turn the circuit on and off continually. As this would create
an uneven current, a capacitor is fitted. The capacitor function by collecting
the current released by the buck regulator, and releasing it at a steady pace,
much like a water tank with a fosset attached. As the current is down regulated
by essentially turning the batteries on and off instead of releasing the excess
energy as thermal energy, less overheating should occur, and battery life
should be increased.
This prototype
was tested on the skin of few participants, but it failed to live up to the set
criteria, of delivering warm and cold thermal stimulation simultaneously. This
was due to the physical design, where the size of the aluminum plat and the
diameter of the cylinder did not allow for simultaneously stimulation of warm
and cold. The major issue was that the roller type was not able to deliver
alternating temperature of cold and heat at the same time of application to the
skin.
Therefore,
roller design was changed to a spatula like design (Figure 15) to ensure that
both warm and cold stimulation could be delivered simultaneously. The 4th prototype, featured the same
electronics as the 3rd. The peltiers
were now placed in a checkerboard like arrangement, alternating warm and cold.
Hole were made on the backside of the cold peltiers to make room for the
cooling bridges, and a 2mm thick aluminum plate was taped to the outside of all
six peltier elements.
This prototype
was able to deliver both warm and cold thermal stimulation simultaneously. It
would overheat, but this could be solved by increasing the thickness of the
plate creating a larger internal space and putting 2mm diameter holes all over
the design to accommodate ventilation. Two of the six peltier elements removed
to make space for additional switches inside the final device to be able to
have heat or cold alone as well. Finally, a vibration function was added to the
final device to test if it can enhance the antipruritic effect.
5.2. Optimal Setting
The 8 different settings were tested to find
pattern of anti-pruritic effect in response to each setting. By looking at the
recorded itch intensity over time, it is clear that all settings generally
followed a similar pattern. All settings produced a clear decrease in itch
intensity during the 30 seconds stimulations at 120 and 300 seconds. The
setting with both thermal stimulation and vibration turned off (Off), was then
used as a baseline. Using this setting instead of just itch intensity without
intervention from the device was chosen to isolate the thermal and vibrational
stimulation from any physical stimulation interference from simply placing the
device overlying the skin. In addition, there was a risk that some participants
might have pressed the device against the test site on the skin, although it
was instructed to just place it without pressing. By using “Off” setting as the
baseline, difference between participants would become less influential.
Following the data analysis, one setting (Linear with vibration) showed a
significantly larger deduction in itch intensity from the baseline (Off), at
-1.24 VAS% ±0.89 vs. -0.61 VAS% ±0.74, with a p-value of 0.048 and
power of 81.2%. This suggests that the most likely the optimal setting is
linear with vibration. This fits well with the results we obtained earlier with
our non-mobile device where we found that alternating non-painful temperatures
of warm and cold had the greatest effect of subsiding histamine-evoked itch.
However, there is still a small chance of 18.8% (considering the study power)
that the findings would be either false positive or false negative. Therefore,
it is still possible that another setting would differ significantly from the
baseline if the sample size would have been larger. This requires further
investigation. Vibration is most likely an important element to be included in
the optimal setting [23,24].
Measurement of
AUC allowed us to gain insights into the itch experience during the entire
experimental time. This would therefore help in identifying which settings
would be capable of creating a lasting anti-pruritic effect. The power analysis
showed a low power for this analysis, 46.6%, and no significant difference was
found between the 8 settings. Increasing the sample size would therefore be of
great interest to identify any difference between the settings. It was suspected
to find difference between warm and cold settings [18] as they were
visually differed in data plotting. In particular, cold with vibration looked
to have a lasting anti-pruritic effect when comparing to the other settings.
Both warm
settings were reported as spreading of itch sensation to surrounding areas.
This is also visually noticeable by looking at data plots, where the itch
intensity seems elevated compared with the other settings. It is known that
elevation in skin and underlying muscle temperature leads to increased blood
flow [28]. Considering this phenomenon, it seems plausible that the
increased blood flow generated from warm thermal stimulation could have
increased diffusion of the histamine into the surrounding tissue from the application
point. However, the changes seen are not significant therefore, no conclusion
can be made.
When only
evaluating the effect of vibration, it was expected that this would have an
anti-pruritic effect [23,24]. In this study, however, no difference was
found when looking at both the VAS% and AUC data. This might be due to the low
power of 17% and 13% for these two parameters, respectively. A larger sample
size would confirm or disprove the finding from this study.
When
evaluating the anti-pruritic effect of the different settings it is important
to consider what type of relief is the most desirable. In general, the two
major wishes are being instant and long lasting, and a combination of these
two, if possible, would be the optimal. Instant itch relief seems desirable but
perhaps only for brief and recurrent itch periods. However, as described by
Twycross, et al. [29], chronic itch originates from either a
malfunctioning pruritic neuron or a pruritogen stimulating the nerve and it is
long lasting. A lasting effect would be desirable for chronic conditions to
allow patients benefit from anti-pruritic effect while not being forced to
perform the stimuli frequently over time.
While the
focus has been clinically on inhibiting itch, it would be of great interest to
identify if the anti-pruritic stimulation not only affect the itch but also the
underlying cause. Inflammation, plays a significant role in some of diseases
causing secondary itch, for example psoriasis, and atopic eczema. Inhibiting
inflammatory response leads to less scratching [30]. Interleukin-4 and -10
(IL-4 and IL-10), are cytokines involved in this response, and have a
suppressing role to reverse the inflammatory response [31]. Elevation
of level of these cytokines by cold thermal modulation, could not only produce
a local direct anti-pruritic response, but potentially an inhibitory effect on
the underlying mechanism promoting itch.
When studying
the whole spectrum of itch, it might not be possible to identify only one
optimal setting for the device, because different settings might yield
different optimal anti-pruritic effect based on different types of itch. It
also seems very important to test the device for different itch related
diseases, as the specific underlying causes of the itch might also be
influenced differently by the thermal and vibrational stimulation.
5.3. Limitations and Methodological Considerations
Even though the device was
easy to use and mobile, and functioned sufficiently to carry out the pilot
test, it still faced some limitations. This device runs on rechargeable
batteries, which are charged using a 5V micro USB charger, identical to most
current smart phones. Battery life was not tested, but in average, the device
could run for maximum one hour. This limits the mobility indirectly as charging
would be necessary. Having only two switches, one for thermal stimulation and
one for vibration, it would seem easy to use. It is noted that if vibration is
found to be turned on in the optimal setting, this could be linked to the same switch
as the thermal stimulation, simplifying the device even further. In regard to
the thermal stimulation, the device faced some limitations. This was due to
overheating of the device and consequently, the peltier elements inside it.
These would warm up the device regardless of the setting if the device left
turned on for longer periods of time. Overheating has been a problem throughout
the design process, and has been faced by other researchers [25]. A fan
attached to the top of the device would help; but, could also decrease the
battery life.
As already
mentioned, the Off was used as baseline to remove bias and isolate the thermal
and vibration stimulation as factors. The pilot test was done in a room with a
temperature of 23-24°C, whereas the
surface temperature of the skin in the arms are just over 32°C under stable conditions [32]. This
explains why this setting was reported, by the participants, as cold, and it
can create a bias. For future research, it will be of interest to match the
surface temperature of the device to the skin of the participant. This might be
feasible by placing the device in an incubator set to 32°C
before testing is initiated. Another point to consider is that this study has
only tested histaminergic itch response in healthy participants; but, future
studies should also focus on other modalities of itch in both models and real
patients.
6. Conclusion
The study was
successful in designing and producing a mobile, and easy to use prototype of an
antipruritic device. The prototype device, however, needs some improvements, as
it tends to overheat and is challenging to use it for long periods due to a
limited battery life.
Findings from
testing device on histamine-evoked itch in healthy humans showed that the
optimal setting for antipruritic effect is linearly arranged alternating
thermal stimulation paired with vibration stimulation. This setting showed the
greatest drop in itch intensity. Small sample size, however calls for cautious
conclusions. Further studies increasing the sample size, and testing other itch
models in healthy humans would be of great interest to systematically test the
optimal setting. Likewise, it would be of interest, to test the optimal setting
in different diseases linked to chronic itch.
7. Acknowledgements
This work was
financially supported by the School of Medicine and Health and partially by SMI®. Authors are grateful
to Kenneth Knirke, electronics mechanic at institute for Electronic
Systems, Aalborg University forhis excellent electrical and 3D-printing
assistance; Leif Jepsen, assistant engineer at the department of Health Science
and Technology, Aalborg University for aluminum plate production; and Brage
Mæhle Hult, Master of Science in architecture, at N+P Arkitektur - for his
assistance in 3D-modeling. This study was not possible without excellent
engagement and cooperation of our participants; we would like to extend our
special appreciation to all of them.
8. Conflict of Interest
None.
Figure 1: Prototypes of hand-held mobile device
delivering non-noxious heat, cold, and vibration.
Figure 2: Final spatula prototype of hand-held
mobile device delivering non-noxious heat, cold, and vibration. The main structure is made by a 3D print.
Figure 3 (A-D): A) Layout of the aluminum
plates. B) Inside view shows the circular vibration units, and the switches to
control the thermal configuration. The two switches to the left are set to
warm, and the two to the right are set to cold. C) The two switches on top of
the device (red circles). The left turns the vibration on/off, the right turns
the temperature stimulation on/off, and both are in the “off” position in this
picture. D) Charging port at the end of the handle.
Figure 4: The pattern of average itch intensity
(VAS: 0-10) recorded over time. Please note that the histamine was applied at
time 0. From this, two sets of data were
analyzed. First, the change in itch intensity under stimulation from the
device. This was calculated by taking the average itch intensity just before,
and right after the stimulation (at 90 seconds, and at 180 seconds, and also at
270 seconds, and at 360 seconds) and deducting the average itch intensity
during stimulation (at 120, 135, and 150 seconds, and also at 300, 315, and 330
seconds).
Figure 5: The average change in itch intensity
times the percent wise change in itch intensity for the 8 settings. Clamp marks
the two settings, which differed significantly. * P-value=0.048.
Figure 6: Mean area under the curve for the 8
settings.
Figure 7: A) Top view of aluminium hexagon tube with the
thermoelectric elements attached on the outside, B) Side view, C) Inside view, note the
three heat sink radiators.
Figure 8: A) Top view without epoxy, B) Side view with
epoxy, C) POM lid with six ventilation holes and a centred ball bearing.
Figure 9: Schematic
circuit of the thermal grill roller. The peltier circuit to the right (warm
circuit) are the warm panels with 2 AAA batteries as power source. The peltier
circuit to the left (cold circuit) are the cold panels with 2 AA batteries as
power source.
Figure 10: Alternating warm-cold roller prototype.
Figure 11: Average
temperature ± SD. measurements from the
preliminary, 1st , and 2nd tests. Red lines represent warm panels, and
blue ones represent cold panels. The temperature at 0 minutes were 26.9±0.09, 27.83±0.12, and
24.13±0.08 for preliminary, test 1 and test 2,
respectively. SD: standard deviation.
Figure 12: 3D rendering of the 2nd prototype. The main structure was made
completely from a 3D print, and it consisted of 5 parts.
Figure 13: 3D rendering of the 3rd prototype. The main structure was still made from a
plastic 3D print, and it consisted of 5 parts, but holes were added to the
surface to accommodate curved aluminium plates to improve thermal conduction. |
Table 1: Overview of the eight settings applied with the final prototype of hand-held mobile device delivering non-noxious heat, cold, and vibration.
Table 2: Mean ± SD of the itch intensity (VAS) at 90 seconds. SD: standard deviation.
Table 3: Means ± SD of the changes in itch intensity times the percent wise change for the 8 settings. SD: standard deviation.
Table 4: Means ± SD of the area under the curve from 90 - 390 seconds. SD: standard deviation.
Table 5: Comparison of vibration off vs. on. Left panel) means ± SD of the change in itch intensity times the percent wise change in itch intensity. Right panel) means ± SD of the area under the curve from 90 - 390 seconds. SD: standard deviation.