Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase.

BACKGROUND: Treatment of prurigo nodularis (PN) is challenging and new treatment options are needed. OBJECTIVE: To evaluate the efficacy and safety of two oral doses of the kappa opioid agonist and mu opioid antagonist nalbuphine extended release (NAL-ER) tablets in a phase 2, multicentre, randomized, double-blind, placebo-controlled trial with an open-label, 50-week extension phase. METHODS: Subjects with moderate-to-severe PN were randomized to NAL-ER 81 mg (NAL-ER81) or 162 mg (NAL-ER162) tablets twice-daily or placebo for 8 weeks of stable dosing following a 2-week titration period. Subjects completing Week 10 with a Worst Itch Numerical Rating Scale (WI-NRS) score ≥5 at the time of rollover (or during the observation period) were eligible for open-label treatment. RESULTS: Of 63 randomized subjects, 62 were treated and comprised the modified intent-to-treat population (MITT), 50 completed 10 weeks of treatment. In the MITT analysis, 8 subjects (44.4%) treated with NAL-ER162 (P = 0.32) and 6 (27.3%) treated with NAL-ER81 (P = 0.78) achieved ≥30% reduction from baseline in 7-day WI-NRS at Week 10 (primary efficacy endpoint) vs. 8 (36.4%) in the placebo group. Itch reduction was significant among 8/12 (66.7%) subjects completing Week 10 treated with NAL-ER162 vs. placebo (8/20, 40.0%; P = 0.03). Additionally, 6 subjects (33.3%) treated with NAL-ER162 and 3 (13.6%) treated with NAL-ER81 achieved ≥50% reduction from baseline in 7-day WI-NRS at Week 10 (coprimary endpoint). Extended open-label treatment was associated with further improvements in itch reduction and favourable changes in PN lesion activity as assessed by Prurigo Activity Score. Adverse events occurred predominantly during dose titration and were of mild-to-moderate severity. The safety profile did not change with extended open-label treatment. CONCLUSION: In adult subjects with PN, oral treatment with NAL-ER 162 mg twice daily provided measurable anti-pruritic efficacy in subjects completing ≥10 weeks of treatment and was well tolerated (ClinicalTrials.gov: NCT02174419).

Prevalence, pathophysiology and management of itch in epidermolysis bullosa.

Epidermolysis bullosa (EB) is a highly diverse group of inherited skin disorders, resulting from mutations in genes encoding proteins of the dermoepidermal junction. Itch (pruritus) is one of the most common symptoms across all EB subtypes. It occurs in blistered or wounded sites, or manifests as a generalized phenomenon, thereby affecting both intact skin and healing wounds. The mechanism of pruritus in EB is unclear. It is likely that skin inflammation secondary to barrier disruption, wound healing cascades and dysregulated activation of epidermal sensory nerve endings are all involved in its pathophysiology on the molecular and cellular level. Understanding these mechanisms in depth is crucial in developing optimized treatments for people with EB and improving quality of life. This review summarizes current evidence on the prevalence, mechanisms and management of itch in EB.

Impact of acute stress on itch sensation and scratching behaviour in patients with atopic dermatitis and healthy controls.

BACKGROUND: Patients with atopic dermatitis (AD) often report that stress aggravates their itch. However, no study has investigated if and how acute stress influences itch sensation and scratching behaviour in these patients. OBJECTIVES: We evaluated the impact of acute stress on experimentally induced cowhage itch perception and scratching behaviour in 16 healthy subjects and 15 patients with AD. METHODS: The Trier Social Stress Test (TSST) was used to induce acute stress. The itch sensation, provoked by applying cowhage to the forearms, and off-site scratching behaviour (not directed at the cowhage application site) were compared before and after performing the TSST or the control condition (watching a video of landscape scenes). RESULTS: In patients with AD, stress induced by TSST caused a significant reduction of cowhage-evoked itch but significantly increased off-site scratching behaviour. Such changes in itch perception and scratching behaviour were not observed in healthy controls. In addition, a significant positive correlation was noted between stress induced by TSST and clinical severity of eczema. CONCLUSIONS: We speculate that psychological stress increases spontaneous scratching in patients with AD, which may enhance the vicious cycle of itching and scratching, resulting in aggravation of the skin eczema. These results provide new insights on the mechanism of acute stress-related exacerbation of itch in patients with AD.

Validation of 'ItchApp©' in Poland and in the USA: multicentre validation study of an electronical diary for the assessment of pruritus.

BACKGROUND: Although chronic pruritus affects a large part of the population, its reliable assessment remains difficult. Electronical diaries (eDiaries) are often used in multicentre clinical trials. The ItchApp© for Android was developed to assess itch intensity and course and was validated for the German language in 2017. OBJECTIVE: To validate ItchApp© for the use in the Polish and US English languages. METHODS: Fifty-three subjects in Poland and thirty subjects in the USA with chronic pruritus completed the paper-based and app-based questionnaires. These questionnaires contained items for measuring the itch intensity, including a numerical rating scale (NRS) and verbal rating scale (VRS), and for detecting the change of pruritus since the beginning of treatment. RESULTS: The ItchApp© showed a high level of test-retest reliability [Intraclass correlation, Kappa and Kendall-Tau B coefficients: 0.915-1.000 (Poland) and 0.863-1.000 (USA)]. The convergent validity showed strong correlation between the itch intensity scales on the ItchApp© (Items II-IV = VRS mean, NRS mean and NRS worst) and the paper-based itch intensity scales (mean and worst: VRS, NRS, VAS) [Spearman-Rho and Pearson correlation coefficients: 0.710-0.987 (Poland) and 0.646-0.954 (USA)]. The ItchApp© items moderately correlated with the ItchyQol scores [Spearman-Rho and Pearson correlation coefficients: 0.303-0.554 (Poland) and 0.275-0.447 (USA)]. After completing the ItchApp© questionnaire, a feasibility questionnaire was completed and showed that subjects feel the app is well suited for assessing pruritus. CONCLUSION: We provide evidence for the ItchApp© as a validated eDiary for the assessment of pruritus in Polish and US English languages, enabling its use in multicentre international clinical trials.

Pathophysiology of pruritus in primary localized cutaneous amyloidosis.

BACKGROUND: Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatosis prevalent among Southern Chinese and South American populations. Pruritus is frequently present and can be debilitating; its pathophysiology is largely unknown. OBJECTIVES: To investigate if small-fibre neuropathy (SFN), which results in a reduction of intraepidermal nerve fibres (IENF) and abnormalities in quantitative thermal sensory testing (QST), is present in PLCA. METHODS: Twenty Chinese patients (10 men) and 20 ethnicity-, sex- and age-matched controls underwent QST assessments. The patients' warm detection threshold (WDT) and heat pain threshold at the typical lesional sites were determined. Serum interleukin (IL)-31 levels were measured. Lesional biopsies were stained for IENF, IL-31 and its receptor's subunits [IL-31RA and oncostatin M receptor-ß (OSMRß)], and nerve growth factor (NGF) and its receptor [tropomyosin receptor kinase A (TrkA)], and were compared with normal skin obtained from archival paraffin-embedded specimens. RESULTS: WDT was significantly higher in patients at all sites and correlated with itch scores (r = 0·59; P < 0·01). Patient biopsies revealed lower IENF counts (P < 0·01 using protein gene product 9.5, ß3-tubulin and Neurofilament 200 stains) and increased epidermal expression of OSMRß (P < 0·01) and IL-31RA (P < 0·01). Cutaneous IL-31, NGF and TrkA stains were not significantly increased in patients. Serum IL-31 was not significantly higher in patients. CONCLUSIONS: SFN is present in PLCA. Pruritus in PLCA is likely associated with hypersensitivity of cutaneous nerve fibres, which may be related to an increased expression of epidermal IL-31 receptors. Targeting IL-31 receptors is therefore a potential therapeutic approach.