Virtual reality-assisted cognitive behavioral therapy for patients with alcohol use disorder: a randomized feasibility study.

Introduction: Cognitive behavioral therapy (CBT) is an evidence-based treatment for alcohol use disorder (AUD). Exposure to high-risk situations in virtual reality (VR) has been suggested to have a potential therapeutical benefit, but no previous study has combined VR and CBT for AUD. We aimed to investigate the feasibility of using VR-simulated high-risk environments in CBT-based treatment of AUD. Methods: We randomized ten treatment-seeking AUD-diagnosed individuals to three sessions of conventional CBT or VR-assisted CBT performed at two outpatient clinics in Denmark. In each session, patients randomized to VR-CBT were exposed to VR-simulations from a restaurant to induce authentic thoughts, emotions, physiological reactions, and craving for CBT purposes. The primary outcome measure was feasibility: Drop-out rate, psychological reactions, and simulator sickness. Secondary outcomes were assessment of preliminary short-term changes in alcohol consumption and craving from baseline to one-week and one-month follow-up. In addition, the study was conducted for training in operationalization of VR equipment, treatment manuals, and research questionnaires. Results: The majority of patients completed all study visits (90%). VR induced authentic high-risk related thoughts, emotions, and physiological reactions that were considered relevant for CBT by patients and therapists. Four of five patients randomized to VR-CBT experienced cravings during VR simulations, and most of these patients (3/5) experienced mild simulator sickness during VR exposure. The preliminary data showed that patients receiving VR-CBT had more reduction in alcohol consumption than patients receiving conventional CBT at one week- (median 94% vs. 72%) and one-month follow-up (median 98% vs. 55%). Similar results were found regarding changes in cravings. Conclusion: We demonstrated VR-CBT to be a feasible intervention for patients with AUD which supports continued investigations in a larger randomized clinical trial evaluating the efficacy of VR-CBT. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT04990765?cond=addiction%20CRAVR&rank=2, identifier NCT05042180.

The effectiveness of oxytocin for treating substance use disorders:A systematic review of randomized placebo-controlled trials.

Oxytocin is gaining traction in the treatment of various substance use disorders (SUD). We performed a systematic review assessing the efficacy of oxytocin for treating different SUD. The electronic databases MEDLINE, EMBASE, CENTRAL, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials examining the effects of oxytocin vs. placebo in SUD samples. Quality assessment was conducted using a Cochrane validated checklist. A total of 17 trials with unique samples were identified. These were conducted on participants with SUD involving alcohol (n = 5), opioids (n = 3), opioids and/or cocaine/other stimulants (n = 3), cannabis (n = 2), or nicotine (n = 4). Across the SUD-groups, oxytocin reduced withdrawal symptoms (3/5 trials), negative emotional states (4/11 trials), cravings (4/11 trials), cue-induced cravings (4/7 trials), and consumption (4/8 trials). Sixteen trials had an overall considerable risk of bias. In conclusion, although oxytocin showed some promising therapeutic effects, the findings are too inconsistent and the trials too heterogeneous to derive any firm conclusions. Sounder methodological and well-powered trials are warranted.

Virtual reality-assisted cognitive behavioural therapy for outpatients with alcohol use disorder (CRAVR): a protocol for a randomised controlled trial.

INTRODUCTION: Alcohol use disorder (AUD) is a brain disorder linked to over 200 health conditions. Cognitive behavioural therapy (CBT) is considered the best practice in the treatment of AUD, but more than 60% of patients relapse within the first year after treatment. Psychotherapy combined with virtual reality (VR) has received increasing interest in the treatment of AUD. However, existing studies have primarily investigated the use of VR for cue reactivity. We therefore aimed to investigate the effect of VR-assisted CBT (VR-CBT). METHODS AND ANALYSIS: This study is an assessor-blinded, randomised clinical trial being conducted at three outpatient clinics in Denmark. We will randomise 102 patients to 14 individual sessions of either manualised VR-CBT or CBT. The VR-CBT group will receive exposure to immersive high-risk VR situations from a pub, bar/party, restaurant, supermarket and at-home (30 videos) to activate high-risk-related beliefs and cravings for subsequent modification using CBT techniques. The treatment period is 6 months, and follow-up visits will be performed 3, 6, 9 and 12 months after inclusion. The primary outcome measure is the change in total alcohol consumption from baseline to 6 months after inclusion, measured with the Timeline Followback Method. Key secondary outcome measures include changes in the number of heavy drinking days, alcohol cravings, cognition, and symptoms of depression and anxiety. ETHICS AND DISSEMINATION: Approval has been obtained by the research ethics committee in the Capital Region of Denmark (H-20082136) and the Danish Data Protection Agency (P-2021-217). All patients will receive both oral and written information about the trial and written informed consent will be obtained from each patient before inclusion. The study results will be disseminated in peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov, NCT05042180.

[Virtual reality as therapy in psychiatry].

This review describes the growing research in virtual reality (VR) for healthcare purposes. In recent years, the technological improvements have expanded the possibility of investigating VR in diagnostics as well as treatment of mental and behavioural disorders. The existing literature regarding phobia, post-traumatic stress disorder, addiction, psychotic, eating and affective disorders is summarised and discussed in terms of clinical applicability.

The effect of smartphone-based monitoring and treatment on the rate and duration of psychiatric readmission in patients with unipolar depressive disorder: The RADMIS randomized controlled trial.

BACKGROUND: Patients with unipolar depressive disorder are frequently hospitalized, and the period following discharge is a high-risk-period. Smartphone-based treatments are receiving increasing attention among researchers, clinicians, and patients. We aimed to investigate whether a smartphone-based monitoring and treatment system reduces the rate and duration of readmissions, more than standard treatment, in patients with unipolar depressive disorder following hospitalization. METHODS: We conducted a pragmatic, investigator-blinded, randomized controlled trial. The intervention group received a smartphone-based monitoring and treatment system in addition to standard treatment. The system allowed patients to self-monitor symptoms and access psycho-educative information and cognitive modules. The patients were allocated a study-nurse who, based on the monitoring data, guided and supported them. The control group received standard treatment. The trial lasted six months, with outcome assessments at 0, 3, and 6 months. RESULTS: We included 120 patients with unipolar depressive disorder (ICD-10). Intention-to-treat analyses showed no statistically significant differences in time to readmission (Log-Rank p=0.9) or duration of readmissions (B=-16.41,95%CI:-47.32;25.5,p=0.3) (Primary outcomes). There were no differences in clinically rated depressive symptoms (p=0.6) or functioning (p=0.1) (secondary outcomes). The intervention group had higher levels of recovery (B=7,29, 95%CI:0.82;13,75,p=0.028) and a tendency towards higher quality of life (p=0.07), wellbeing (p=0,09) satisfaction with treatment (p=0.05) and behavioral activation (p=0.08) compared with the control group (tertiary outcomes). LIMITATIONS: Patients and study-nurses were unblinded to allocation. CONCLUSIONS: We found no effect of the intervention on primary or secondary outcomes. In tertiary outcomes, patients in the intervention group reported higher levels of recovery compared to the control group.

Reducing the rate of psychiatric re-admissions in bipolar disorder using smartphones-The RADMIS trial.

OBJECTIVES: The MONARCA I and II trials were negative but suggested that smartphone-based monitoring may increase quality of life and reduce perceived stress in bipolar disorder (BD). The present trial was the first to investigate the effect of smartphone-based monitoring on the rate and duration of readmissions in BD. METHODS: This was a randomized controlled single-blind parallel-group trial. Patients with BD (ICD-10) discharged from hospitalization in the Mental Health Services, Capital Region of Denmark were randomized 1:1 to daily smartphone-based monitoring including a feedback loop (+ standard treatment) or to standard treatment for 6 months. Primary outcomes: the rate and duration of psychiatric readmissions. RESULTS: We included 98 patients with BD. In ITT analyses, there was no statistically significant difference in rates (hazard rate: 1.05, 95% CI: 0.54; 1.91, p = 0.88) or duration of readmission between the two groups (B: 3.67, 95% CI: -4.77; 12.11, p = 0.39). There was no difference in scores on the Hamilton Depression Rating Scale (B = -0.11, 95% CI: -2.50; 2.29, p = 0.93). The intervention group had higher scores on the Young Mania Rating Scale (B: 1.89, 95% CI: 0.0078; 3.78, p = 0.050). The intervention group reported lower levels of perceived stress (B: -7.18, 95% CI: -13.50; -0.86, p = 0.026) and lower levels of rumination (B: -6.09, 95% CI: -11.19; -1.00, p = 0.019). CONCLUSIONS: Smartphone-based monitoring did not reduce rate and duration of readmissions. There was no difference in levels of depressive symptoms. The intervention group had higher levels of manic symptoms, but lower perceived stress and rumination compared with the control group.

Early intervention with non-ablative fractional laser to improve cutaneous scarring-A randomized controlled trial on the impact of intervention time and fluence levels.

BACKGROUND AND OBJECTIVES: Laser treatment in the early phases of wound healing may reduce scar formation. However, little is known on when in the early wound healing phases laser exposure most optimally should be provided and at which fluence levels. This study investigates the clinical effect of non-ablative-fractional-laser (NAFL) performed at three early time points at a range of fluence levels versus untreated control scars. MATERIALS AND METHODS: A randomized, controlled, intra-individual trial with erbium-glass 1,540 nm NAFL versus no laser treatment on sixteen subjects receiving 10 standardized full-thickness punch-biopsy wounds. A single NAFL-exposure was applied to test-wounds 1 day before, immediately after, or 2 weeks after wounding. Three fluence levels provided deep and superficial energy depositions (range 30-70 mJ/microbeam). Primary outcome comprised the total-score of the observer part of Patient-Observer-Scar-Assessment-Scale (POSAS), performed by blinded on-site assessment at 3 months follow-up. Secondary outcomes were clinical evaluation on visual-analogue-scale (VAS), reflectance measurements, and histology. RESULTS: NAFL-treatment applied 1 day before, immediately after or 2 weeks after wounding had the potential to offer subtle but detectable improvement in clinical scar appearance compared to untreated controls. Thus, NAFL-exposure 1 day before wounding (POSAS-total: median of 15 vs. control-median of 16, P = 0.03, VAS: median 4.1 vs. control-median 5.5, P = 0.03, medium-fluence), as well as immediately-, and 2 weeks after wounding (POSAS-total: P ≤ 0.05, low-fluence) induced improvement compared to untreated controls. No significant differences in dyschromia were detected between NAFL-treated and control scars. Histology showed subtle changes towards more mature interwoven bundles of collagen in NAFL-treated scars as compared to controls. CONCLUSIONS: This study indicates that a single NAFL-treatment at low to medium fluence performed 1 day prior, or in the early phases of wound healing, may have the potential to optimize scar formation in full thickness wounds. Lasers Surg. Med. 50:28-36, 2018. © 2017 Wiley Periodicals, Inc.

Skin reactions after photodynamic therapy are unaffected by 839 nm photobiomodulation therapy: A randomized, double-blind, placebo-controlled, clinical trial.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is associated with erythema and edema. Photobiomodulation (PBM) therapy may stimulate the skin recovery process. We investigated the potential of PBM to reduce PDT-induced skin reactions. STUDY DESIGN AND METHODS: Healthy volunteers (n = 20) were randomized to receive left- or right side PBM (near-infrared 839/595 nm) or placebo-PBM (595 nm) on their buttocks. Corresponding test areas were exposed to standardized PDT reactions, using ablative fractional laser-assisted PDT (AFXL-PDT) with methyl-aminolevulinate (MAL) incubated for 30, 90, and 180 minutes before red-light illumination. Each buttock received PBM and placebo-PBM for five consecutive days, starting one day before PDT interventions. Follow-up visits were performed 4 and 11 days after PDT. Outcome measure included blinded, observer-assessed skin reactions, substantiated by objectively measured erythema and pigment percentages and skin temperatures. RESULTS: PDT interventions induced a standardized range of erythema and edema in all subjects. Skin reactions were clinically unaffected by PBM throughout the active treatment period and at all subsequent follow-up visits (PBM vs. placebo-PBM, P = 1.000). Clinical results were supported by similar erythema intensities and skin temperatures in PBM and placebo-PBM treated skin: median erythema 28.1% versus 30.3% (AFXL-PDT with 30 minutes MAL-incubation), 36.1% versus 35.2% (90 minutes MAL-incubation) and 39.4% versus 40.9% (180 minutes MAL-incubation) (Day 4, P > 0.05). No differences in clinical hyperpigmentation or pigment percentages were observed between corresponding test areas in any subject on the final 11-day follow-up. CONCLUSION: Under the current study conditions, PDT-induced skin reactions were unaffected by PBM. Lasers Surg. Med. 49:810-818, 2017. © 2017 Wiley Periodicals, Inc.

Fractional laser-assisted drug uptake: Impact of time-related topical application to achieve enhanced delivery.

BACKGROUND AND OBJECTIVE: Ablative fractional laser (AFXL) is acknowledged to increase uptake of topically applied agents in skin. AFXL channels gradually close over time, which may impair this capability. The time frame for applying a drug after AFXL exposure remains to be established. The aim of this study, was to investigate the importance of time-related topical application after AFXL exposure and to relate resultant uptake in skin with AFXL channel morphology and skin integrity. STUDY DESIGN/MATERIALS AND METHODS: Buttock skin of healthy volunteers (n = 11) was exposed to 10,600 nm fractional CO2 laser using 5% density, 120 µm beam diameter, 15 mJ pulse energy. Sodium fluorescein (NaF) a small, hydrophilic molecule (370 MW, log P = -1.52) was applied under standardized conditions at specific time points after laser exposure (0, 2, 5, 10, 30, 60, 90 minute, 6, 24, and 48 hours). Fluorescence photography collected fluorescence images up to 180 minute after NaF application. Optical coherence tomography (OCT) assessed AFXL channel dimensions and transepidermal water loss (TEWL) estimated loss of skin integrity. RESULTS: Fluorescence intensities (FI) were significantly elevated when NaF was applied up to 6 hours after laser exposure compared to non-laser-processed skin (median FI 1947 arbitrary units [interquartile range 1,246-3,560] versus 1,004 [350-1,538], P < 0.02). The highest FI occurred when NaF was applied within 30 minute after laser exposure and similar FI were reached for applications at 0, 2, 5, 10, and 30 minute after AFXL exposure (0 minute: 3,866 [3,526-4,575], 30 minute: 3,775 AU [3,070-4,484], P > 0.1). NaF application later than 30 minute after AFXL exposure resulted in gradually decreasing FI, becoming similar to intact skin when applied at 24-48 hours after AFXL exposure (P > 0.2). OCT images demonstrated that AFXL channels closed over time (100% [100-100%] open up to 30 minute, 75% [4-86%] at 6 hours and 3% [0-15%] at 24-48 hours after AFXL exposure). TEWL measurements proved loss of skin integrity up to 6 hours after AFXL exposure, while integrity was similar in laser-exposed and non-laser-exposed skin at 24-48 hours. CONCLUSIONS: The time frame to maintain enhanced drug delivery sustained for several hours after AFXL exposure, corresponding to channel morphology and loss of skin integrity. Lasers Surg. Med. 49:348-354, 2017. © 2016 Wiley Periodicals, Inc.

Side effects from intense pulsed light: Importance of skin pigmentation, fluence level and ultraviolet radiation-A randomized controlled trial.

BACKGROUND AND OBJECTIVE: Intense pulsed light (IPL) is a mainstream treatment for hair removal. Side effects after IPL are known, but risk factors remain to be investigated. The objective of this study was to assess the contribution of skin pigmentation, fluence level, and ultraviolet radiation (UVR) on IPL-induced side effects. METHODS: The study was a blinded, randomized intra-individual controlled trial including 16 healthy subjects with Fitzpatrick Skin Types (FST) II-V. Three test areas were each divided into four sites, randomized to a single IPL exposure of 22, 34, 46 J/cm2 or triple stacking of 46 J/cm2 . Areas were subsequently randomized to no UVR or single solar-simulated UVR exposure of 3 Standard Erythema Dose at 30 minutes or 24 hours after IPL. Each area had a corresponding control, resulting in 15 treatment sites. Follow-up visits were scheduled up to 4 weeks after IPL. Outcome measures were: (i) blinded clinical skin reactions; (ii) objectively measured erythema and pigmentation; (iii) pain measured by visual analog scale (VAS); (iv) histology (H&E, Fontana-Masson); and (v) mRNA-expression of p53. RESULTS: Fifteen subjects with FST II-IV completed the protocol. IPL induced a wide range of skin reactions, including erythema (87% of subjects), purpura (27%), blisters (20%), edema (13%), crusting (13%), hyper- (60%), and hypopigmentation (20%). Darker skin pigmentation and increasing IPL fluence were determinants for IPL-induced side effects (P ≤ 0.002), while a single exposure of UVR did not exacerbate side effects (P ≥ 0.180). Clinical findings were confirmed objectively by reflectance spectrometry and qualitatively by histological changes in skin architecture, inflammatory infiltration, and pigmentation. Marker of cellular DNA damage, that is, p53, did not increase after IPL (P ≥ 0.24). CONCLUSIONS: Skin pigmentation and IPL fluence are major determinants of side effects after IPL exposure, while a single exposure to three SED of UVR at 30 minutes or 24 hours after IPL, does not amplify such side effects. Lasers Surg. Med. 49:88-96, 2017. © 2016 Wiley Periodicals, Inc.

Repeated Treatments with Ingenol Mebutate Prevents Progression of UV-Induced Photodamage in Hairless Mice.

BACKGROUND AND AIM: Ingenol mebutate (IngMeb) is an effective treatment for actinic keratosis. In this study, we hypothesized that repeated treatments with IngMeb may prevent progression of UV-induced photodamage, and that concurrent application of a corticosteroid may reduce IngMeb-induced local skin responses (LSR). METHODS: Hairless mice (n = 60; 3 groups of 20 mice) were irradiated with solar simulated ultraviolet radiation (UVR) throughout the study. Five single treatments with IngMeb were given at 4-week intervals (Days 21, 49, 77, 105, and 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to each IngMeb application, as well as 6 h and 1 day post treatment. One week after IngMeb treatment No. 1, 3, and 5 (Days 28, 84, and 140), biopsies from four mice in each group were collected for histological evaluation of UV-damage on a standardized UV-damage scale (0-12). LSR (0-24) were assessed once daily (Days 1-7) after each IngMeb treatment. RESULTS: IngMeb prevented progression of photodamage in terms of keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage with a lower composite UV-damage score on day 140 (UVR 10.25 vs. UVR+IngMeb 6.00, p = 0.002) compared to UVR alone. IngMeb induced LSR, including erythema, flaking, crusting, bleeding, vesiculation, and ulceration. Concurrent CP increased LSR (max LSR Tx 1-5: UVR+IngMeb+CP 3.6-5.5 vs. UVR+IngMeb 2.6-4.3) and provided better prevention of photodamage compared to IngMeb alone (Day 140: UVR+IngMeb 6.00 vs. UVR+IngMeb+CP 3.00 p < 0.001). CONCLUSION: Repeated field-directed treatments with IngMeb prevent progression of cutaneous photodamage in hairless mice, while CP cannot be used to alleviate IngMeb-induced LSR. The findings suggest that IngMeb may potentially serve as a prophylactic treatment for UV-induced tumors.

Repeated treatments with ingenol mebutate for prophylaxis of UV-induced squamous cell carcinoma in hairless mice.

BACKGROUND AND AIM: The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application of a corticosteroid would reduce IngMeb-induced local skin responses (LSRs) without affecting tumor postponement. METHODS: Hairless mice (n=150; 6 groups á 25 mice) were irradiated with solar simulated ultraviolet radiation (UVR) until SCC developed. During UV-irradiation and before tumor development, five single treatments (Tx) with IngMeb were given at four-week intervals (days 21, 49, 77, 105, 133). Clobetasol propionate (CP) was applied once daily for 5days prior to IngMeb, as well as 6h and 1day post treatment. Tumor formation was evaluated weekly for 52weeks. LSR (scale 0-24) were assessed at baseline, 1h, 6h, 1-, 2-, 3-, 4-, 5-, 6-, and 7days after each IngMeb treatment. RESULTS: IngMeb significantly delayed tumor development compared to UVR alone (UVR day 168 vs. UVR+IngMeb day 189; p=0.025). LSR included erythema, flaking, crusting, bleeding, vesiculation, and ulceration. The composite LSR-scores were of moderate intensity in non-UV irradiated skin (max LSR IngMeb Tx 1-5: 1.5-2.5) and more pronounced in photodamaged skin (max LSR Tx 5; IngMeb 1.5 vs. UVR+IngMeb 1.8; p<0.001). LSR intensity correlated with tumor development by means of greater composite LSR-score resulted in longer tumor-free survival (r(2)=0.257, p<0.001). Contrary to our hypothesis, concurrent CP increased LSR (max LSR Tx 1-5: UVR+CP+IngMeb 3.2-4.9 vs. UVR+IngMeb 1.3-2.2, p<0.001) and postponed tumor development compared to IngMeb alone (UVR+CP+IngMeb day 217 vs. UVR+IngMeb day 189, p<0.001). CONCLUSION: Repeated field-directed treatments with IngMeb delay development of UV-induced SCC in hairless mice, and increased IngMeb induced LSRs correlated with improved clinical outcomes. The findings highlight the potential of IngMeb as a prophylactic remedy for SCC in humans.

Ultraviolet radiation after exposure to a low-fluence IPL home-use device: a randomized clinical trial.

The prevailing advice is to avoid sun exposure after intense pulsed light (IPL) hair removal. However, no systematic evaluation of ultraviolet radiation (UVR) after IPL hair removal exits. Therefore, we investigated the occurrence of side effects in subjects receiving solar-simulated UVR after a low-fluence IPL treatment with a home-use device. Sixteen subjects with Fitzpatrick skin types (FST) II-V were enrolled. Three constitutive buttock blocks (4.4 × 6.4 cm) were each subdivided into four sites, randomized to one IPL exposure of 0, 7, 8, or 10 J/cm2 (spectral output 530-1100 nm). Blocks were randomized to no UVR or three standard erythema doses (SEDs) UVR either 30 min or 24 h after IPL. Follow-up visits were 48 h, 1 week, and 4 weeks after IPL. Outcome measures were (i) clinical skin reactions, (ii) reflectance measurements of erythema and pigmentation, and (iii) pain. Subjects with FST II-IV experienced no skin reactions up to 4 weeks after IPL, neither erythema, edema, blisters, crusting, textual, nor pigment changes. Reflectance confirmed no change in erythema and pigmentation (p ≥ 0.090). UVR exposure induced erythema and increased pigmentation. The combination of IPL and UVR induced skin reactions not different to responses from UVR (IPL-UVR vs. UVR, p ≥ 0.164). Pain was generally low (median 1, range 0-4) and correlated positively with fluence and pigmentation (Spearman's rho ≥ 0.394, p < 0.001). One subject with FST V experienced perifollicular hyperpigmentation after IPL and slightly more intense when exposed to UVR. A single UVR exposure of three SEDs either shortly or 1 day after low-fluence IPL causes no amplification of skin responses in constitutive skin of individuals with FST II-IV.

The role of natural and UV-induced skin pigmentation on low-fluence IPL-induced side effects: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: The risk of adverse skin effects following light-based hair removal is greater in pigmented skin based on the theory of selective photothermolysis. Thus sunlight-induced pigment i.e., facultative pigmentation, increases the risk of adverse skin effects, perhaps disproportionately. The aim of this study was to evaluate the influence of constitutive and facultative skin pigmentation on low-fluence intense pulsed light (IPL)-induced adverse skin effects. STUDY DESIGN/MATERIALS AND METHODS: Twenty-one subjects with Fitzpatrick skin type II-IV were enrolled. Two buttock blocks were randomized to receive 0 or 8 solar simulated ultraviolet radiation (UVR) exposures of consecutively increasing Standard Erythema Doses (2-4 SED). Each block was subdivided into four sites, randomized to receive IPL of 0, 7, 8, or 10 J/cm(2) , once a week for 3 weeks. Biopsies were taken 16-24 hours after the first IPL exposure and subjects were seen 1 and 4 weeks after the last IPL exposure. Outcome measures were: (i) skin reactions, (ii) pain, (iii) mRNA expression of pigment-markers microphthalmia-associated transcription factor (MITF) and pro-opiomelanocortin (POMC), and (iv) clinical appearance of biopsy wounds. RESULTS: Skin pigmentation increased after UVR (baseline median 13.8%, after UVR 28.1%, P = 0.0001) in all skin types. Subjects reported low pain intensities (median 1.5, scale 0-10) and experienced transient erythema immediately after IPL exposure. No persistent erythema, blisters, crusting, textual, or pigment changes were observed. The risk of erythema and pain intensities increased with IPL dose and skin pigmentation (P < 0.03). There was no difference in pain or skin reactions in skin with similar degree of natural and facultative pigmentation (P ≥ 0.104). Expression of cellular pigment-markers was not influenced by IPL exposure, neither in constitutive nor in facultative pigmented skin. Clinical appearance of biopsy wounds was unaffected by IPL exposure. CONCLUSION: The prevalence and intensity of low-fluence IPL-induced adverse skin effects depended on IPL dose and skin pigmentation regardless of the origin, i.e., constitutive versus UV induced.