Navarixin

Itch reduction using immersive virtual reality—An experimental pilot study

Albert Baschong1 | Florian Spiess2 | Philippe C. Cattin2 |
Alexander Navarini1
Image | Simon M. Mueller1

Abstract
In a previous proof-of-concept study we have demonstrated that visual exposure to specific colors results in pruritic or antipruritic effects. To determine the effect of
“antipruritic” colors when using immersive virtual reality (VR) and to assess whether
psychometric values correlate with the response to the color exposure. In this cross-sectional interventional single-center study, itch patients were exposed to their sub- jective “antipruritic color” (defined by the Manchester Color Wheel) in a virtual monochromatic room for 10 min using a head-mounted display. Itch intensity rating(0–10 numerical rating scale [NRS]) was repeated at 1-min intervals. Additionally, dermatology life quality index, itch-related quality of life and the Hospital Anxiety and Depression Scale questionnaires were completed. Twenty-two patients (mean age 51.9 ± 23 years, 13 females) participated in the study. Following color exposure for 10 min itch intensity was significantly reduced compared to baseline (exactWilcoxon signed-rank test, mdn-NRS 4.5 vs 3.0; z = —3.025, p = 0.001), confirmed
by the area under the curve (z = —3.118; p = 0.001). No significant correlation between itch reduction and questionnaire scores was found (Spearman’s Rho for all questionnaires). Visual exposure to the “antipruritic color” using immersive VR resulted in a significant decrease in itch intensity. This aligns with previous findingson the influence of colors on itch perception. The response of the intervention appeared independent of psychometric values. Thus, color exposure using immersive VR is a promising, low-cost, rapidly-acting, easily-applicable, non-pharmacological experimental antipruritic method.

KE YWOR DS
antipruritic, colors, itch, pruritus, virtual reality
1Department of Dermatology, University Hospital Basel, Basel, Switzerland
2Department of Biomedical Engineering, University of Basel, Basel, Switzerland

Correspondence
Albert Baschong, Department of Dermatology, University of Basel, Petersgraben 4, 4056 Basel, Switzerland.
Email: [email protected]

|INTRODUCTION

“Quod pruritus […] sit tristis sensatio, desiderium scalpendi excitans […]”1—The itch […], is [this] unpleasant sensation which elicits the desire to scratch […]. This first definition of itch proposed by
Hafenreffer in 1660 still holds true to today.2 Itch (synonymous pruri- tus) is the commonest skin-related symptom caused by numerous dermatological and non-dermatological conditions.3-5 Chronicpruritus, defined as itch lasting over 6 weeks, has a substantial burden of disease and a negative impact on quality of life comparable to that of chronic pain.6 Treatment of itch is often challenging and unsatis- factory for several reasons such as involvement of various itch media- tors (e.g., psoriasis),7 multifactorial itch causes in a single patient (e.g., iron deficiency, chronic kidney disease, xeroderma, drugs), latency of the treatment effect (e.g., antipruritic antidepressants, anti- inflammatory treatment), lack of evidence
of unknown origin),8 or lack of coverage by the health insurer due off-label use.9
Inspired by the phenomenon of contagious itch, which indicates that itch can be modified by visual cues,10 we have previously investi- gated the effect of colors, being evolutionary visual cues, on itch per- ception.11 In that proof-of-concept study, most patients had
considered red as a “pruritic” and blue or green as “antipruriticcolors.” Exposure to these colors on an LED-screen during 10 min resulted in a significant decrease (blue or green) and increase of itch
intensity (red), respectively.11 Yet it appeared possible that some patients were distracted by the colors surrounding the LED-screen potentially limiting the effect of color exposure.

Therefore, we sought to investigate the effect of colors on itch when using a virtual three-dimensional room allowing patients to
“immerse” themselves in the colors of interest. Furthermore, we
aimed to assess patient factors potentially influencing the response to color exposure- an aspect not addressed in the previous study. Fol- lowing this previous proof-of-concept study which confirmed that colors can modulate itch, the primary study goals of this subsequent study was to investigate the effect and feasibility of exposure to the
“antipruritic” color applied by virtual reality immersion (i.e., through a
head-mounted VR-display). The secondary study goals were to assess
whether specific itch qualities (“burning,” “prickling,” “painful,” “sting- ing”), skin- and itch-related quality of life, anxiety, and depression, and pleasantness of the intervention correlate with the response to color exposure.

2 | METHODS

In this investigator-driven, single-center, interventional pilot study subjects were enrolled from in and out-patient care of the Depart- ment of Dermatology, University Hospital Basel, Switzerland. Inclu- sion criteria were: suffering from a mean itch intensity of ≥4 on a
numerical rating scale (0–10 NRS; 0 = no itch; 10 = worst itch imagin-
able) during the past 7 days and age ≥16 years. Exclusion criteria were: a history of color-blindness, itchy or contagious skin conditions on the scalp/forehead, and illiteracy. Patients were recruited between November 2019 and March 2020.
All patients provided informed consent, the study was approved by the Ethics Committee North-Western and Central Switzerland (EKNZ Req_2017-1—Amendment, ClinicalTrials.gov Identifier: NCT03928223).

2.1 | Experimental protocol

2.1.1 | Assessment of itch, itch-related colors, skin- and itch-related quality of life, anxiety and depression

Four different qualities of itch perception (“burning,” “prickling,” “painful,” “stinging”) were rated on a NRS from 0 (not present) to 10 (most intense quality imaginable).
In analogy to our previous study,11 patients were thereafter asked to answer the question “What color is your itch?” by matching their itch with a color shade of the Manchester Color Wheel (MCW, a vali-
dated tool consisting of 38 colors).12 The MCW was developed by Carruthers et al. as a method to assess color choices in different clini- cal situations (Supporting Information).12 The patient’s color choice
defined the patient’s “pruritic color.” Thereafter, patients were asked
to answer the question “What color should a room be painted in to reduce your itch, if only one color can be chosen?”. The patient’s color choice in the MCW defined the patient’s “antipruritic color.”
Patients were then asked to complete the dermatology life quality index (DLQI),13 itch-related quality of life (German-ItchyQoL)14 and the Hospital Anxiety and Depression Scale (HADS-D)15 respectively.

2.1.2 | Virtual reality system

The 2018 HTC VIVE Pro was used as a stereoscopic head-mounted display (HMD). It has a dual AMOLED 3.500 diagonal display with a res- olution of 1440 × 1600 pixels per eye, displayed at 90 Hz and a field of view of 110◦. For color exposure we used a proprietary app that allowed participants to immerse themselves in a virtual monochro- matic room developed in the Unity engine version 2019.2.1f1 (Figure 1). To give a better sense of orientation and counteract the possibility of virtual reality induced side-effects (VRISE)16 the floor was shaded darker.

2.1.3 | Color exposure

Patients were seated in upright position during the experiment. The individually chosen “antipruritic” color was matched through RGB (red, green, and blue) values and adjusted in shade, saturation and
brightness through patient feedback until the best match of the imag- ined color could be found. After the color was set, patients were asked to close their eyes for 1 min. to standardize start conditions. Five seconds before this minute passed, patients had to rate theirmomentary itch intensity on the 0–10 NRS, this value was used as the baseline itch intensity. Subsequently, patients had to open their eyes for color exposure, during which itch intensity was reassessed at 1-min intervals throughout the 10 min of color exposure. At the end of the experiment patients had to rate the pleasantness of the colorexposure on a —10 to +10 NRS (—10: highest unpleasantness imagin-
able; 0: neutral; + 10: highest pleasantness imaginable).

2.2 | Statistical analyses

AUC for the baseline was computed by plotting the baseline NRS- Multiple systemic antihistamines 1 (4.5%)
values onwards for 10 min. Again, the exact Wilcoxon signed-rank Antihistamines (t + s) 1 (4.5%)
test was used to test the median AUC against the median baseline Steroids (t) + antihistamines (t + s) 1 (4.5%)
AUC. The significance level was set a priori to α = 0.05. Extensive itch therapya 1 (4.5%)

The sample size estimation was based on two previous studies: (a) In the study by Leibovici et al.17 who reported itch reduction using vir- tual reality immersion for the first time, the sample consisted of 24 patients and (b) in our previous study using color exposure, the sample size of 10 patients was sufficient to reach statistically signifi- cant itch reduction.11 Comparison of the median itch intensity before and after 10 min of color exposure was performed using an exact Wilcoxon signed-rank test. Additionally, linear area under the curve (AUC) was calculated for itch NRS-values during 10 min of exposure.
TABL E 1 Diagnosis and current itch treatment n = 22

Diagnosis Patients
Pruritus on non-diseased skin 5 (22.7%)
Atopic dermatitis 3 (13.6%)
Psoriasis
Non-atopic eczema 3 (13.6%)
2 (9.1%)

Nummular eczema 2 (9.1%)

Paraviral exanthema
1 (4.5%)

Urticaria 1 (4.5%)

Erythema multiforme
1 (4.5%)

Pityriasis lichenoides chronica 1 (4.5%)

Lupus erythematodes
1 (4.5%)

Pigmented purpuric dermatosis 1 (4.5%)
Itch treatment
None 13 (59.1%)
Steroids (t) 3 (13.6%)
Levocetiricine only 2 (9.1%)

Balanitis of unknown origin 1 (4.5%)

Itch reduction (as expressed by ΔNRS and ΔAUC) was correlated with baseline itch intensity as well as with the itch intensity of the
past 7 days using Spearman’s Rho correlation coefficient. Likewise itch reduction was correlated with the ratings of the itch qualities
“burning,” “prickling,” “painful,” “stinging,” the scores of the DLQI,
ItchyQoL, HADS and (un)pleasantness of the intervention. We did not correct for multiple testing, but all tests are reported. Statistical analy- sis was computed using IBM SPSS version 26.0.0.

3 | RESULTS

3.1 | Patient characteristics

Twenty-five patients were recruited for this study, three of which
dropped out due to time constraints (n = 1), incomplete question- naires (n = 1), and feeling uncomfortable wearing the headset (n = 1).
Twenty-two patients were included in the final analysis (13 females, mean age of 51.9 ± 23 years. SD, range 18–89 years) who reported a mean itch intensity of 5.8 NRS ± 1.8 in the past 7 days (mdn 5.5). Of 21, 13 patients (61.9%, information in one patient incon- clusive), suffered from chronic itch. Table 1 lists the patients’ diagnosis and the itch treatments patients were on (9/22, 40.9%).

3.2 | Questionnaire ratings

The mean DLQI was 14 ± 7.7, reflecting a “very large effect on patients life.” The mean ItchyQoL-score was 65.5 ± 19.8 also reflecting a considerable impairment of itch-related quality of life.

Note: Itch treatment is further classified into: (t): topical, (s): systemic.
aCombination of photo-therapy, whole body dressings, topical steroids.

4 | DISCUSSION

In this study we investigated the effect of color exposure on itch per-
ception by using a virtual three-dimensional color-room. Indeed, vir- tual immersion in the “antipruritic color” resulted in a significant decrease in itch intensity. This further supports the hypothesis, thatthe perception of itch can be mitigated by color exposure and alignswith our previous findings on the influence of color on itch percep- tion.11 The preference for red shades to match “pruritic colors” and blue, green, and yellow shades to match “antipruritic colors” corre-spond exactly to the patients’ color choices in our previous study.11 In the current study, we did not find a significant correlation between the itch reduction, psychometric assessments including itch-related quality of life, dermatology-related quality of life, hospital-related anx- iety and depression, and pleasurability of the intervention. However, we found a correlation between itch intensity and itch reduction: the higher itch intensity, the better the response to the antipruritic response was.
The distribution of gender and age in our study is similar to other study populations with itch patients,4 the baseline itch intensity simi- lar to a previous study using virtual reality.17

In terms of skin-related (DLQI) and itch-related (ItchyQoL) impair- ment of quality of life our population was also within the range of pre- vious studies.19 However, in contrast to previous studies,20,21 the level of anxiety and depression (as measured by the HADS-A/D) was not increased in our population. This difference may be explained by the fact that we did not only include patients with chronic itch- which is known to be associated with anxiety and depression20-22 but also patients with acute itch, which may have had only minor negative effects on psychological wellbeing so far.
Based on previous assumptions,11,23 we hypothesize that the effect
of the colors on itch perception may be explained by two theories. According to the “color arousal theory” colors with longer wavelengths (ca. 560–580 nm), such as the colors yellow, orange, and red, mayinduce higher arousal than colors with shorter wavelengths like blue (430–480 nm), or green (490–540 nm).23-25 Alternatively, the “color-in-context theory” postulates that the colors evoke specific memories,
emotions or expectations (e.g., blue might reflect cold/cooling, red fire/ warmth or inflamed itchy skin) which thus influence perception.23,26
Some of our patients reported to have such associations during exposure to their “antipruritic color” (e.g., blue: swimming pool, green: meadow, yellow: sandy beach), but others could not verbalize associa-ions or memories. More detailed questionnaires could help to further elucidate this aspect in future studies. It has been described that mere imagination of itch can evoke real itch sensations.27 Thus, it is con- ceivable vice versa may apply by the imagination of itch relief and possibly colors and/or VR have facilitating effects in this respect.
To our knowledge, only one study using virtual reality immersion has been published so far: Leibovici et al.17 successfully reduced itch within 10 min by distraction techniques in patients with chronic itch. Thus, distraction from itch may theoretically be a further explanation for the itch reduction. However, we consider this effect to be unlikely in our setting as our patients were asked to rate and focus on itch at 1-min intervals, whereas in the study by Leibovici et al.,17 the patientsdid not rate itch intensity for 10 min (the assessment “during” virtual
reality immersion was made retrospectively). This assumption is supported by two patients who complained about itch being salient during our experiment. Thus, we can hypothesize that exposure to the“antipruritic color” might even be more efficacious, if itch assessments
were not required at 1-min intervals.

Considering the tangible itch reduction within only 3 min, expo- sure to the “antipruritic color” could act as a rapidly acting non- pharmacological intervention. It may serve to promptly reduce “itch-peaks” and/or to bridge the onset of the effect of topical or systemic therapies. This assumption should be studied in larger populations including the effect of repetitive and long-term color therapy in itch.
The mean itch reduction (ΔNRS) was higher in the previous study with the color exposure via LED-screen (mean = —2.3 ± 1.49)11 than in this study using immersive virtual reality (mean = —1.225 ± 1.571). This may be explained by differences in study populations
(e.g., diagnoses, mean itch intensities at baseline). However, it could also indicate that the visual “quantity” of the “antipruritic color” does not influence the success as much as thought. A head-to-head cross-over study design with the LED-screen exposure and the immersive virtual reality could help clarify these points.

Our secondary study goals were to assess whether specific itch qualities, skin- and itch-related quality of life, anxiety or depression,
and pleasantness of the intervention correlate with the response to color exposure. Remarkably, the response to the “antipruritic color” did not seem to significantly correlate with any of these variables. A
study with healthy volunteers indicated that the degree of visual itch contagion correlated with neuroticism—a variable that could be con- sidered in future studies using color exposure.28

As none of the qualities “burning,” “prickling,” “painful,” “sting-
ing” correlated with the response to the “antipruritic color,” we assume that itch quality is not a decisive factor in this context. In con-
trast, we found that higher itch intensity at baseline seems to corre- late with a stronger response to the “antipruritic color.” The reason for this is unclear, but it may be conceivable that incremental changes
are differently perceived and rated depending on the level of intensity at baseline. Moreover, the duration of itch could play a role in this point with possibly more treatment responsiveness in shorter duration.

It is possible that additional determinants such as sex may also influence the response to the antipruritic color. Due to the small sam- ple size, we did not address this point as a study goal, but descriptive interpretation of our results may indicate that men could be more sus- ceptible to antipruritic colors than women. However, a larger sample size is needed to assess sex differences in the response to antipruritic colors.
All patients tolerated immersive VR well and rated this interven- tion as pleasant (but the success of the intervention was independent of subjective pleasantness), indicating that this method was safe and well accepted in our study population.

4.1 | Limitations

Interventional studies should ideally be designed with a placebo con- trol. However, in our setting a placebo control was not feasible as there is no such as a visual condition without a color and even achro- matic colors like black or white, could have a potential impact on itch. To better evaluate whether the color itself or rather autosuggestiofollowing “priming” (i.e., linking a potential treatment effect to a color) is the predominant mode of action, two research conditions could be added: Participants could be exposed to the color blue, green and red
without priming beforehand. In another set-up verbal suggestions by the experimenter could be used to more accurately explore the role of suggestibility to induce a reverse nocebo/placebo effect: “This bluewill intensify your itch” (reverse nocebo), “This red will relieve your itch” (reverse placebo). Furthermore, studies using functional mag- netic resonance imaging could help objectify the effect of color expo-
sure and to correlate it with activation of brain structures involved.

In terms of usability and practicability our current technical set-up (including a base station, head-mounted-display and a desktop com- puter) may limit clinical use in patient rooms. In addition, acquisition costs for specific system requirements (graphic card, memory, proces- sor, etc.) incur as VR-systems are not standard medical equipment. Development of more mobile solutions for bedside and home thera- pies is desirable. Ideally, applications and headsets allowing patients to use their own smartphones would limit the need of extra hardware.

5 | CONCLUSION

We conclude that exposure to the “antipruritic color” using immersive virtual reality resulted in a significant reduction of itch intensity within a few minutes irrespective of the quality of itch, the burden of the dis- ease and the tested psychometric assessments. Therefore, we con-
sider the combination of color exposure and virtual reality immersion a promising, rapidly acting and inexpensive, easily-applicable, non- pharmacological approach to reduce itch in patients with acute and chronic itch. Portable devices could facilitate its use in clinical routine and even allow user-friendly home-based use. Further studies are necessary to confirm our results in larger populations and to further elucidate the mechanisms leading to itch reduction in this setting.

ACKNOWLEDGMENTS
The authors are indebted to Ivana Cvijetic (study coordinator) for her organizational support in this study. We thank Tobias Erlanger (bio- statistician, Department of Clinical Research, University of Basel) for his support in statistical analysis. No external funding was involved in this study.

CONFLICT OF INTEREST
The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS
Simon M. Mueller: Conceptualization. Albert Baschong: Data curation. Albert Baschong: Formal analysis. Albert Baschong, Simon
M. Mueller: Investigation. Albert Baschong, Simon M. Mueller: Meth- odology. Simon M. Mueller: Project administration. Simon
M. Mueller, Philippe C. Cattin, Alexander Navarini: Resources. Florian Spiess: Software. Simon M. Muller, Philippe C. Cattin: Supervision. Simon M. Mueller: Validation. Albert Baschong: Visualization. Albert Baschong: Writing—Original draft. Simon M. Mueller, Philippe
C. Cattin: Writing—Review & editing. Albert Baschong, Florian Spiess, Philippe C. Cattin, Alexander Navarini, Simon M. Mueller: Final approval.

DATA AVAILABILITY STATEMENT
Research data are not shared.

ORCID
Albert Baschong Image https://orcid.org/0000-0003-1032-9822 Florian Spiess Image https://orcid.org/0000-0002-3396-1516 Philippe C. Cattin Image https://orcid.org/0000-0001-8785-2713 Alexander Navarini Image https://orcid.org/0000-0001-7059-632X Simon M. Mueller Image https://orcid.org/0000-0002-0200-4254

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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of this article.

How to cite this article: Baschong A, Spiess F, Cattin PC, Navarini A, Mueller SM. Itch reduction using immersive virtual reality—An experimental pilot study. Dermatologic Therapy.
2021;e15001. https://doi.org/10.1111/dth.15001