Novel Target for the Treatment of Itch (Pruritus) and Pruritus-Related Pain of Different Origin

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 15806

Special Issue Editors

Department of Pharmacodynamics, Faculty of Pharmacy, Medical College, Jagiellonian University, PL 30-688 Krakow, Poland
Interests: research into pharmacological mechanisms of analgesia and antipruritic activity; basic and preclinical studies into memory-enhancing molecules; drug design and development in analgesia and cognition; searching for new mechanisms of action of small molecules impacting endothelial dysfunction, atherogenesis, platelet aggregation
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna Street, PL 30-688 Krakow, Poland
Interests: searching for new mechanisms of action of small molecules to treat hypertension and metabolic syndrome; inflammation and insulin signaling; obesity; adipose tissue; endothelial integrity; endothelial dysfunction; arterioscerosis; platelet aggregation; ligands of adrenergic, histamine, serotonin, and cannabinoid receptors; isolated organ studies
Special Issues, Collections and Topics in MDPI journals
Department of Pharmacological Screening, Jagiellonian University Medical College, 9 Medyczna Street, PL 30-688 Krakow, Poland
Interests: searching for new mechanisms of action of small molecules to reduce body mass or compensating for disorders of the circulatory system or leveling depression-like disorders; pharmacology developments towards new therapeutic approaches for obesity, diabetes and selected metabolic disorders, hypertension, atherosclerosis, depression; ligands of adrenergic, histamine, serotonin, adenosine and cannabinoid receptors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Both itching and pain draw the attention of the organism to potentially dangerous stimuli, and are associated with protective motor responses. However, both of these somatosensations have been widely recognized as a significant clinical problem responsible for decreased quality of life in patients suffering from their associated conditions, particularly when chronic. Pain and itching, though distinct, share many similar attributes. Pain and itching may share some anatomical and physiological features, including transmission via the spinothalamic tract, involvement of neurons responding to both pruritic and nociceptive stimuli, and overlap in the brain areas activated. They also have in common mediators and receptors, mechanisms of peripheral and central sensitization, neuroimmune and neuroglial interactions, and potentially others. Although there are distinct neuronal circuitries for pain and itching in the peripheral and central nervous system (CNS), the circuits are engaged in cross-modulation in the spinal cord and brain. Furthermore, phenomena such as the attenuation of itches via painful stimulation, such as scratching, and the induction of itching via pain-relieving opioids, show the antagonistic nature of these processes.

These observations reveal the fascinating nature of research into different pharmacological interventions impacting pain and itching, which may also be beneficial in clinical conditions. The search for new and better therapeutic targets for the treatment of pain and itching, as well as specific agents that affect these targets, is essential.                    The journal Pharmaceuticals invites both reviews and original articles which will increase knowledge on the pharmacology and medicinal chemistry of pain and pruritus. Papers on the interaction between pain and itching will be considered particularly valuable.

Dr. Szczepan Mogilski
Dr. Monika Kubacka
Dr. Magdalena Kotańska
Guest Editors

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Keywords

  • pain
  • pruritus
  • itch,
  • drugs
  • analgesia
  • antipruritic

Published Papers (6 papers)

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Research

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27 pages, 3899 KiB  
Article
Efficacy of the Multi-Target Compound E153 in Relieving Pain and Pruritus of Different Origins
by Szczepan Mogilski, Monika Kubacka, Artur Świerczek, Elżbieta Wyska, Katarzyna Szczepańska, Jacek Sapa, Katarzyna Kieć-Kononowicz and Dorota Łażewska
Pharmaceuticals 2023, 16(10), 1481; https://doi.org/10.3390/ph16101481 - 17 Oct 2023
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Abstract
Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and [...] Read more.
Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or μ receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood–brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism. Full article
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Review

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15 pages, 1869 KiB  
Review
Treatment Options for Troublesome Itch
by Sumika Toyama, Mitsutoshi Tominaga and Kenji Takamori
Pharmaceuticals 2022, 15(8), 1022; https://doi.org/10.3390/ph15081022 - 19 Aug 2022
Cited by 5 | Viewed by 2565
Abstract
Itch (or pruritus) is an unpleasant sensation, inducing the desire to scratch. It is also a major and distressing symptom of many skin and systemic diseases. The involvement of histamine, which is a major itch mediator, has been extensively examined. Recent studies suggest [...] Read more.
Itch (or pruritus) is an unpleasant sensation, inducing the desire to scratch. It is also a major and distressing symptom of many skin and systemic diseases. The involvement of histamine, which is a major itch mediator, has been extensively examined. Recent studies suggest that histamine-independent pathways may play roles in chronic itch. Therefore, antihistamines are not always effective in the treatment of patients with chronic itch. The development of biologics and κ-opioid receptor (KOR) agonists has contributed to advances in the treatment of itch; however, since biologics are expensive for patients to purchase, some patients may limit or discontinue their use of these agents. Furthermore, KOR agonists need to be prescribed with caution due to risks of side effects in the central nervous system. Janus kinase (JAK) inhibitors are sometimes associated with side effects, such as infection. In this review, we summarize antidepressants, antineuralgics, cyclosporine A, antibiotics, crotamiton, phosphodiesterase 4 inhibitor, botulinum toxin type A, herbal medicines, phototherapy, and acupuncture therapy as itch treatment options other than antihistamines, biologics, opioids, and JAK inhibitors; we also explain their underlying mechanisms of action. Full article
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21 pages, 882 KiB  
Review
Druggable Targets and Compounds with Both Antinociceptive and Antipruritic Effects
by Hao-Jui Weng, Quoc Thao Trang Pham, Chia-Wei Chang and Tsen-Fang Tsai
Pharmaceuticals 2022, 15(7), 892; https://doi.org/10.3390/ph15070892 - 19 Jul 2022
Viewed by 3106
Abstract
Pain and itch are both important manifestations of various disorders, such as herpes zoster, atopic dermatitis, and psoriasis. Growing evidence suggests that both sensations have shared mediators, overlapping neural circuitry, and similarities in sensitization processes. In fact, pain and itch coexist in some [...] Read more.
Pain and itch are both important manifestations of various disorders, such as herpes zoster, atopic dermatitis, and psoriasis. Growing evidence suggests that both sensations have shared mediators, overlapping neural circuitry, and similarities in sensitization processes. In fact, pain and itch coexist in some disorders. Determining pharmaceutical agents and targets for treating pain and itch concurrently is of scientific and clinical relevance. Here we review the neurobiology of pain and itch and discuss the pharmaceutical targets as well as novel compounds effective for the concurrent treatment of these sensations. Full article
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Other

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25 pages, 4579 KiB  
Systematic Review
Clinical Efficacy and Safety of Chinese Herbal Medicine in the Treatment of Uremic Pruritus: A Meta-Analysis of Randomized Controlled Trials
by Ping-Hsun Lu, Chien-Cheng Lai, I-Hsin Lin, Fu-Ming Tsai and Po-Hsuan Lu
Pharmaceuticals 2022, 15(10), 1239; https://doi.org/10.3390/ph15101239 - 09 Oct 2022
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Abstract
Uremic pruritus is a disturbing and refractory symptom in patients with advanced chronic kidney disease. Chinese herbal medicine has been reported to alleviate uremic pruritus. To investigate the effects of Chinese herbal medicine, we conducted a systematic review and meta-analysis on patients with [...] Read more.
Uremic pruritus is a disturbing and refractory symptom in patients with advanced chronic kidney disease. Chinese herbal medicine has been reported to alleviate uremic pruritus. To investigate the effects of Chinese herbal medicine, we conducted a systematic review and meta-analysis on patients with uremic pruritus. We searched databases (prior to 3 May 2022) for randomized controlled trials on the effects of Chinese herbal medicine in treating uremic pruritus. Our meta-analysis included 3311 patients from 50 randomized controlled trials. In patients with uremic pruritus, adjunctive Chinese herbal medicine significantly improved overall effectiveness (risk ratio 1.29, 95% CI 1.23 to 1.35), quality of life, renal function, reduced pruritus score, and inflammatory biomarkers compared to control groups with hemodialysis alone or with anti-pruritic treatments. Chinese herbal medicine treatment showed a time-dependent tendency in improving the visual analog scale of dialysis patients. Compared to control groups, no significantly higher risk of adverse events in patients taking Chinese herbal medicine (risk ratio 0.60, 95% CI 0.22 to 1.63). Chinese herbal medicine appears to be effective and safe in complementing the treatment of patients with uremic pruritus. Full article
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16 pages, 995 KiB  
Systematic Review
Difelikefalin in the Treatment of Chronic Kidney Disease-Associated Pruritus: A Systematic Review
by Kamila Wala and Jacek C. Szepietowski
Pharmaceuticals 2022, 15(8), 934; https://doi.org/10.3390/ph15080934 - 28 Jul 2022
Cited by 7 | Viewed by 3883
Abstract
Chronic kidney disease-associated pruritus (CKD-aP) is a chronic condition that significantly reduces the quality of life of patients with end-stage renal disease. The etiology is not fully understood, but imbalance in the activity of the opioid pathways, including downregulation of the kappa-opioid receptor, [...] Read more.
Chronic kidney disease-associated pruritus (CKD-aP) is a chronic condition that significantly reduces the quality of life of patients with end-stage renal disease. The etiology is not fully understood, but imbalance in the activity of the opioid pathways, including downregulation of the kappa-opioid receptor, may contribute to itching sensation. Difelikefalin is a selective, peripherally acting kappa-opioid receptor (KOR) agonist. Recently, difelikefalin has been approved as a first drug for the treatment of pruritus associated with chronic kidney disease (CKD) in adult hemodialysis patients. A systematic review of currently available clinical trials was performed to assess the efficacy and safety of difelikefalin in patients with uremic pruritus. A literature review was conducted in May 2022 based on the PRISMA 2020 guidelines. The analyzed clinical trials showed that difelikefalin was effective in reducing pruritus in patients as assessed by the Worst Itching Intensity Numerical Rating Scale. Improvement in quality of life assessed on the basis of the Skindex score and the 5-D itch scale was also noticed. The most commonly reported side effects were mild and included nausea, vomiting, dizziness, and diarrhea. Due to its proven efficacy and good safety profile, difelikefalin is a promising drug for the treatment of pruritus in patients with chronic kidney disease. Full article
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9 pages, 547 KiB  
Technical Note
Chronic Pruritus in Atopic Patients Treated with Dupilumab: Real Life Response and Related Parameters in 354 Patients
by Luca Mastorino, François Rosset, Federica Gelato, Michela Ortoncelli, Giovanni Cavaliere, Pietro Quaglino and Simone Ribero
Pharmaceuticals 2022, 15(7), 883; https://doi.org/10.3390/ph15070883 - 17 Jul 2022
Cited by 16 | Viewed by 1695
Abstract
Chronic pruritus is a major symptom of atopic dermatitis (AD). Its etiopathogenesis is complex, and an understanding of the driving factors of its pathogenesis allows for the development of new molecule-targeted therapies. Dupilumab, targeting and blocking interleukin-4 (IL-4) and interleukin-13 (IL-13) molecules, has [...] Read more.
Chronic pruritus is a major symptom of atopic dermatitis (AD). Its etiopathogenesis is complex, and an understanding of the driving factors of its pathogenesis allows for the development of new molecule-targeted therapies. Dupilumab, targeting and blocking interleukin-4 (IL-4) and interleukin-13 (IL-13) molecules, has shown great efficacy in treating AD symptoms such chronic itching. We performed a retrospective observational study to evaluate possible chronic-itch-related characteristics and parameters in 356 AD patients who received dupilumab. The objective of the study was to evaluate the factors associated with the level of pruritus reported by patients at each of the 1575 detections in the form of the peak pruritus numerical rating scale (NRSpp) and sleep disturbance numerical rating scale (NRSsd). We focused on: the eczema area and severity index (EASI), dermatology life quality index (DLQI), patient-oriented eczema measure (POEMS), eosinophilia, L-lactate dehydrogenase (LDH), immunoglobulin E (IgE) and the time from the start of dupilumab therapy. NRSpp fell from 8.6 (sd 1.7) at baseline to 1.7 (sd 2.3) at 36 months and NRSsd from 7 (sd 3) to 0. Regarding the parameters that correlate with NRSpp, all the parameters analysed were significantly correlated except for eosinophils (p = 0.136). In the multivariate analysis, both considering and not considering treatment duration, the parameters were correlated (p < 0.001); EASI, DLQI, POEM, and LDH significantly correlated with NRSpp (p < 0.001 for each, except for LDH p = 0.003); while IgE tot lost significance (p = 0.337). Similar results were obtained for the parameters correlating with NRSsd. Our results confirm the efficacy of dupilumab on pruritus. The use of questionnaires such as DLQI and POEM is advisable in clinical practice and is adequate for assessing the impact of itching on AD. The low correlation of IgE and eosinophils, the ambiguity of LDH levels with the level of pruritus, and a poor clinical validity and unclear correlation with disease severity suggest a progressive abandonment of monitoring of these values. Full article
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