trk-820 and Pruritus

The prevalence of chronic pruritus (CP) in the general population is high and increases with age. Owing to high rates of comorbidities and polypharmacy in patients aged 65 or older, the clinical management of these patients is challenging.. In this review, the authors discuss the available therapy options for patients aged ≥ 65 with CP, including emollients for dry skin, topical therapies, phototherapy and systemic agents for CP of various origins.. For multimorbid patients, topical substances and phototherapy constitute the best initial options. If systemic drugs are needed, the potential side-effects need to be closely monitored. In elderly patients, multiple possible factors for CP, including dermatological and systemic diseases, may be found, complicating the treatment of the underlying cause. In these cases, or when the origin remains unknown, a step-wise symptomatic therapy is recommended. The therapeutic choices should be made on an individual basis after carefully outweighing possible risks and benefits. Novel agents such as neurokinin-1 receptor antagonists and opioid-targeting drugs show promising antipruritic effects on refractory CP and seem to be well tolerated. They may be useful for elderly patients, who cannot tolerate conventional systemic agents.

Topics: Administration, Topical; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Emollients; Histamine Antagonists; Humans; Immunosuppressive Agents; Morphinans; Neurokinin-1 Receptor Antagonists; Phototherapy; Pruritus; Spiro Compounds

Uremic itch is a frequent and sometimes very tormenting symptom in patients with advanced or end-stage renal failure, with a strong negative impact on the quality of life. According to a representative study, the point prevalence of chronic itch is 25% in hemodialysis patients but may reach more than 50% in single cohorts depending on the country and dialysis efficacy. Not much is known regarding the pathogenesis of uremic itch. Besides parathyroid hormone, histamine, tryptase, and alteration of the calcium-phosphate metabolism have been suspected. More recently, derangements in the opioid system and an inflammatory condition have been investigated as suspected players in the pathogenesis of uremic itch, but remain unproven so far. Treatment of chronic itch in dialysis patients remains difficult. Besides topical application of rehydrating or immunomodulating compounds, such as γ-linolenic acid or tacrolimus treatment with nalfurafine may be helpful. Apart from that, gabapentin and pregabalin are promising drugs to alleviate uremic itch. In many cases, UVB phototherapy is effective in reducing the intensity of itch. When treating patients, one should take into account that most of the drugs available are not licensed for the treatment of itch. Therefore, a deliberate use of therapeutic options aiming for a good risk-benefit relation should be adopted. In very severe and refractory cases, patients suitable for renal transplantation might be switched to 'high urgency' status, as successful renal transplantation cures uremic pruritus in most of the cases.

Topics: Acupuncture Therapy; Amines; Analgesics, Opioid; Anticonvulsants; Calcineurin Inhibitors; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; gamma-Linolenic Acid; Humans; Kidney Failure, Chronic; Morphinans; Narcotic Antagonists; Pregabalin; Pruritus; Receptors, Opioid, kappa; Receptors, Opioid, mu; Renal Dialysis; Spiro Compounds; Tacrolimus; Ultraviolet Therapy; Uremia

Uremic pruritus or chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and compromising symptom in patients with advanced or end-stage renal disease, strongly reducing the patient's quality of life. More than 40% of patients undergoing hemodialysis suffer from chronic pruritus; half of them complain about generalized pruritus. The pathogenesis of CKD-aP remains obscure. Parathormone and histamine as well as calcium and magnesium salts have been suspected as pathogenetic factors. Newer hypotheses are focusing on opioid-receptor derangements and microinflammation as possible causes of CKD-aP, although until now this could not be proven. Pruritus may be extremely difficult to control, as therapeutic options are limited. The most consequential approaches to treatment are: topical treatment with or without anti-inflammatory compounds or systemic treatment with (a) gabapentin, (b) μ-opioid receptor antagonists and κ-agonists, (c) drugs with an anti-inflammatory action, (d) phototherapy, or (e) acupuncture. A stepwise approach is suggested starting with emollients and gabapentin or phototherapy as first-line treatments. In refractory cases, more experimental options as μ-opioid-receptor-antagonists (i.e., naltrexone) or κ-opioid-receptor agonist (nalfurafine) may be chosen. In desperate cases, patients suitable for transplantation might be set on 'high urgency'-status, as successful kidney transplantation will relieve patients from CKD-aP.

Topics: Acupuncture Therapy; Amines; Anti-Inflammatory Agents; Calcium Channel Blockers; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; gamma-Linolenic Acid; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Pentoxifylline; Phototherapy; Pregabalin; Pruritus; Receptors, Opioid, kappa; Renal Insufficiency, Chronic; Spiro Compounds; Tacrolimus; Thalidomide; Uremia

Several chemically diverse pruritogens, including bombesin, compound 48/80, norbinaltorphimine, and 5'-GNTI, cause rodents to scratch excessively in a stable, uniform manner and consequently provide convenient animal models of itch against which potential antipruritics may be evaluated, structure-activity relationships established, and the nature of spontaneous, repetitive behavior itself analyzed. Decreasing the number of scratching bouts in these apparently simple models has been the requisite first step in the progress of kappa opioid agonists such as nalbuphine, asimadoline, and CR845 toward clinical testing as antipruritics. Nalfurafine is the prime example of a kappa agonist spanning the developmental divide between scratching mice models and commercialization within 10 years. Patients undergoing hemodialysis and suffering from the itching associated with uremic pruritus, and potentially those inflicted with atopic dermatitis, are the beneficiaries.

Topics: Animals; Dynorphins; Guanidines; Humans; Ligands; Mice; Morphinans; Naltrexone; p-Methoxy-N-methylphenethylamine; Peptide Fragments; Pruritus; Receptors, Opioid, kappa; Spiro Compounds

Chronic pruritus is frequently refractory to currently available treatments. Studies suggest that pruritus may arise from an imbalance of the mu- and kappa-opioid receptor system activity in either the skin or the central nervous system. Stimulation of kappa-opioid receptors by their agonists inhibits pruritus in both animals and humans. The antipruritic effect of kappa-opioid receptors agonists can currently be assumed to be related to their binding to kappa-opioid receptors on keratinocytes and cutaneous and/or central itch neurones. To date, several case reports and 2 controlled trials have demonstrated a beneficial effect of systemic kappa-opioid receptor agonists in the treatment of uraemic pruritus, prurigo nodularis, paraneoplastic and cholestatic pruritus. Nalfurafine hydrochloride (Remitch(®)), a selective kappa-opioid receptor agonist, is approved for the treatment of chronic pruritus in Japan. The aim of this review is to provide an overview of the promising role of kappa- opioid receptors and their agonist in the pathophysiology and treatment of pruritus.

Topics: Animals; Antipruritics; Butorphanol; Chronic Disease; Humans; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds; Treatment Outcome

Severe pruritus associated with end-stage renal disease is a particularly troublesome complication, because no effective treatment has been established. However, based on the findings of a recent randomized controlled trial, nalfurafine hydrochloride was officially approved in Japan for the treatment of resistant pruritus in hemodialysis patients.. This review is based upon a PubMed search and personal experience with nalfurafine hydrochloride. The pharmacokinetics and pharmacodynamics of nalfurafine hydrochloride are reviewed and its efficiency and potential adverse effects are discussed, mainly based on the findings of randomized controlled trials.. A recent long-term open trial showed that the effect of nalfurafine hydrochloride was enhanced by continuous, long-term administration. It will be of future interest to investigate its effect on excoriations, lichen simplex, prurigo nodularis and acquired perforating dermatosis (all caused by uremic pruritus), because it targets both the skin and the central nervous system. In clinical practice, it should be kept in mind that basic skin care with emollients and other topical drugs is essential for stopping the itch-scratch cycle, and the resultant skin barrier dysfunction.

Topics: Dermatologic Agents; Humans; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds

Topics: Administration, Oral; Animals; Capsules; Clinical Trials as Topic; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Morphinans; Pruritus; Receptors, Opioid; Renal Dialysis; Spiro Compounds; Uremia

Uremic pruritus in hemodialysis patients is intractable and no effective treatments have been established yet. Although the precise mechanism of the pruritus is still unclear, accumulating evidence suggests that activation of the micro-opioid receptors may induce pruritus in hemodialysis patients. On the other hand, activation of kappa-opioid receptors is known to control or inhibit the signals activated through micro-opioid receptors; therefore, it was expected that kappa-opioid receptor agonists would be able to reduce pruritus in patients undergoing hemodialysis. Nalfurafine hydrochloride is a novel derivative of the opioid receptor antagonist naltrexone. Nalfurafine hydrochloride is a selective kappa-opioid receptor agonist and has a potent antipruritic effect on various types of pruritus through central kappa-opioid receptor activation in non-clinical pharmacological studies. Moreover, clinical studies have demonstrated that nalfurafine hydrochloride possesses efficacy and safety in hemodialysis patients with uremic pruritus. In this review, we provide a detailed description of the activity of nalfurafine hydrochloride using published data of in vitro, in vivo nonclinical pharmacological and clinical studies in hemodialysis patients with uremic pruritus.

Topics: Animals; Humans; Morphinans; Pruritus; Receptors, Opioid, kappa; Renal Dialysis; Spiro Compounds; Uremia

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Kidney; Pruritus; Renal Dialysis; Renal Insufficiency, Chronic

Our previous placebo-controlled, prospective, double-blind study demonstrated that a new opioid ĸ-receptor agonist, nalfurafine hydrochloride, effectively reduced treatment-resistant pruritus in 337 hemodialysis patients. Thus, we designed this study to evaluate prospectively the efficacy, safety, addiction liability, and pharmacokinetics of nalfurafine given orally for 1 year.. This open-label study examined the effects and adverse drug reactions (ADRs) of 52-week oral administration of nalfurafine hydrochloride (5 µg/day) in 211 hemodialysis patients with a treatment-resistant itch.. Of 211 patients, 145 completed the study as scheduled. The mean pruritus value assessed by the visual analogue scale was 75.2 mm during the pre-observation period, which decreased significantly to 50.9 and 30.9 mm in week 2 and 52, respectively, indicating a long-lasting efficacy. ADRs occurred in 103 patients (48.8%). Frequent ADRs were insomnia (sleep disturbance, 19.4%), constipation (7.1%) and increased blood prolactin (3.3%), similar to previous reports. Regarding addiction liability, it appeared unlikely that nalfurafine hydrochloride was abused. After the start of treatment, plasma drug levels reached a steady state in week 2 with no apparent tendency of systemic accumulation.. Nalfurafine hydrochloride, orally administered at 5 µg/day for 52 weeks to hemodialysis patients, produced a long-term suppression of pruritus without significant safety problems.

Topics: Aged; Double-Blind Method; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Morphinans; Patient Satisfaction; Prospective Studies; Pruritus; Receptors, Opioid, kappa; Renal Dialysis; Spiro Compounds; Surveys and Questionnaires; Treatment Outcome

Pruritus in haemodialysis patients is an intractable disease and substantially impairs their quality of life. Based on the results of our earlier clinical study, we hypothesized that the micro-(mu) opioid system is itch-inducible, whereas the kappa (kappa) system is itch-suppressive.. The efficacy and safety of nalfurafine hydrochloride (a novel kappa-receptor agonist) were prospectively investigated by randomly (1:1:1) administering 5 or 2.5 microg of the drug or a placebo orally for 14 days using a double-blind design in 337 haemodialysis patients with itch that was resistant to currently available treatments, such as antihistamines.. The mean decrease in the visual analogue scale (VAS) from baseline, the study's primary endpoint, was significantly larger in the 5-microg nalfurafine hydrochloride group (n = 114) than in the placebo group (n = 111, P = 0.0002, one-sided test at 2.5% significance level). The decrease in the VAS in the 2.5-microg group (n = 112) was also significantly larger than that in the placebo group (P = 0.0001). The incidence of adverse drug reactions (ADRs) was 35.1% in the 5-microg group, 25.0% in the 2.5-microg group and 16.2% in the placebo group. Moderate to severe ADRs were observed in 10 of the 226 patients. The most common ADR was insomnia (sleep disturbance), seen in 24 of the 226 nalfurafine patients.. This Phase III, randomized, double-blind, placebo-controlled, parallel-group, prospective study based on VAS evaluations clearly showed that orally taken nalfurafine hydrochloride effectively reduced itches that were otherwise refractory to currently available treatments in maintenance haemodialysis patients, with few significant ADRs. This novel drug was officially approved for clinical use in January 2009 by the Ministry of Health, Labour and Welfare of Japan.

Topics: Double-Blind Method; Female; Humans; Male; Middle Aged; Morphinans; Placebos; Prospective Studies; Pruritus; Receptors, Opioid, kappa; Renal Dialysis; Spiro Compounds; Treatment Outcome

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima's pruritus score. Nalfurafine hydrochloride 2.5 μg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima's pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.

Topics: Humans; Liver Diseases; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds

Nalfurafine hydrochloride is a selective kappa-opioid agonist that has antipruritic effects. Here we describe the clinical trials for treatment of uremic pruritus in dialysis patients and on hepatic pruritus in patients with chronic liver disease. Among cytochrome P-450 (CYP) isoforms in humans, CYP3A4 is the major isoform involved in metabolic decyclopropylmethylation of nalfurafine hydrochloride. Nalfurafine hydrochloride was found to be a substrate for P-glycoprotein (P-gp), but had no inhibitory effects on P-gp-mediated transport. The efficacy of oral nalfurafine hydrochloride at 2.5 and 5 μg for refractory pruritus in hemodialysis patients was observed within the first 7 days of treatment, and the effects persisted for the 52-week treatment period. Nalfurafine hydrochloride is also effective in the treatment of conventional refractory pruritus in peritoneal dialysis patients. Moreover, nalfurafine hydrochloride at 2.5 and 5 μg is effective for the treatment of refractory pruritus in chronic liver disease patients within the first 7 days of drug administration. In all the clinical trials, most adverse drug reactions (ADRs) were mild and resolved quickly and there was no clinical safety problem. Following 52 weeks of treatment, hemodialysis patients did not develop physical or psychological dependence, indicating no addiction risks. In summary, nalfurafine hydrochloride administered orally at doses of 2.5 and 5 μg was safe and effective for treatment of refractory pruritus in patients undergoing hemodialysis or peritoneal dialysis and in chronic liver disease patients.

Topics: Humans; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds

Pruritus is known to be a common complication in hepatitis patients, but the exact frequency and degree are not fully elucidated. Thus, we evaluated pruritus of 450 patients with chronic liver disease at our hospital. Pruritus was observed in 240 (53%) of the patients. Pruritus was significantly associated with males (OR = 1.51, P = 0.038) and patients with alkaline phosphatase (ALP) ≥ 200 U/L (OR = 1.56, P = 0.0495) and was significantly less in HBsAg-positive patients (OR = 0.449, P = 0.004). Seasonally, there was no difference in the frequency of pruritus between summer and winter. Of the 24 refractory pruritus patients treated with nalfurafine, 17 (71%) indicated improvement of itch, which is defined as a decrease in the visual analog scale score ≥ 30 mm. Pruritus was improved by nalfurafine both during daytime and nighttime in the Kawashima's scores evaluation. All patients who received nalfurafine exhibited improved Kawashima's scores ≥ 1 point during the daytime or nighttime. In conclusion, pruritus occurred in > 50% of patients with chronic liver disease, and predictors of pruritus were males and ALP ≥ 200 U/L. Nalfurafine may be useful for pruritus, regardless of whether daytime or nighttime.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; End Stage Liver Disease; Female; Humans; Male; Middle Aged; Morphinans; Pruritus; Spiro Compounds; Treatment Outcome; Young Adult

In this study, we investigated the severity and frequency of uremic pruritus and itch-associated insomnia in patients with end-stage renal disease (ESRD) or chronic kidney disease (CKD).. This questionnaire-based study included outpatients with ESRD or CKD who were attending Tokorozawa Renal Clinic in Saitama Prefecture or Musashi Ranzan Hospital and were stable on treatment. The questionnaire was completed by patients on hemodialysis (HD) before a dialysis session and by patients on peritoneal dialysis (PD) or conservative treatment at the time of an outpatient hospital visit.. Itching was reported by 61.6% of patients on HD, 61.5% on PD, and 43.2% on conservative CKD management. There was no statistically significant difference in the severity or frequency of itch according to whether patients were on HD for ESRD, PD for ESRD, or receiving conservative treatment for CKD. However, insomnia was significantly more common in the PD group than in the HD and conservative CKD groups.. Better skin management is needed for itch in patients with ESRD or CKD. Moisturizing and lifestyle factors are important. Topical or oral medications may also be used. Nalfurafine, a κ receptor agonist, is now available in Japan for the treatment of uremic pruritus in these patients.

Topics: Aged; Aged, 80 and over; Female; Humans; Japan; Kidney Failure, Chronic; Male; Middle Aged; Morphinans; Peritoneal Dialysis; Prevalence; Pruritus; Renal Dialysis; Sleep Initiation and Maintenance Disorders; Spiro Compounds

Nalfurafine is a G protein signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G protein signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or ß-arrestin-signaling-biased KOR agonists.. This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior.. Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli).. Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS.. These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Depression; Dose-Response Relationship, Drug; Japan; Male; Morphinans; Pain; Pruritus; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Self Stimulation; Spiro Compounds

Patients with primary biliary cholangitis (PBC) frequently suffer from pruritus, which can severely impair their health-related quality of life (HRQOL). Nalfurafine hydrochloride, a selective κ-opioid receptor agonist, was recently approved in Japan for refractory pruritus in patients with chronic liver diseases, but it still remains unclear whether this treatment improves the patient-reported outcome (PRO) in PBC patients with refractory pruritus. Herein, we conducted a multicenter, post-marketing, single-arm prospective study to investigate the efficacy of nalfurafine in terms of PRO, and the associations of the efficacy with any clinical characteristics.. After screening for pruritus in 496 patients with PBC using PBC-40 and the visual analog scale (VAS), we identified 141 patients with moderate to severe pruritus; these were invited to participate in the study. The participants received 2.5 μg nalfurafine once daily for 12 weeks, and pruritus and HRQOL were assessed in week 12 of this treatment. Generic HRQOL, short form 36, blood chemistries, and serum autotaxin levels were also measured at baseline and at week 12.. Forty-four patients participated in this study. The mean PBC-40 itch domain scores and VAS declined during the study period, from 8.56 to 7.63 (P = 0.041) and from 42.9 to 29.3 (P = 0.001) at baseline and at week 12, respectively, indicating a significant effect of nalfurafine. The other domains of PBC-40 and all domains of SF-36 were not significantly altered by this treatment. We failed to find any association between the change in VAS and PBC-40 itch scores and any clinical variable. Serum autotaxin levels were significantly increased during the study period.. This study demonstrated that nalfurafine improved pruritus in patients with PBC, independent of their clinical characteristics, but had a limited effect on the PRO.

Topics: Aged; Analgesics, Opioid; Biomarkers; Female; Follow-Up Studies; Humans; Japan; Liver Cirrhosis, Biliary; Male; Middle Aged; Morphinans; Patient Reported Outcome Measures; Phosphoric Diester Hydrolases; Prospective Studies; Pruritus; Quality of Life; Receptors, Opioid, kappa; Spiro Compounds; Statistics, Nonparametric; Treatment Outcome

Among various symptoms accompanied with chronic liver disease, pruritus affects the quality of life of patients, causing physical and mental stress, and worsens hepatic function. Recently, κ-opioid receptor agonist, nalfurafine hydrochloride was approved to treat central pruritus in patients with liver disease in Japan. This study aimed to assess the long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients.. A patient-reported outcome using questionnaire-based methods was used for 41 liver disease patients with or without pruritus symptoms. Nalfurafine hydrochloride (2.5 μg/day) was orally administered to 18 patients suffering from pruritus symptoms and whose current treatment was not effective. The same questionnaires and visual analogue scales (VAS) were repeatedly followed up for the patients for the entire follow-up period, and biochemical analyses were performed to evaluate the safety of the treatment.. Pruritus completely disappeared in seven of 18 cases, and VAS scores showed a decreasing trend over time from the start of nalfurafine hydrochloride administration in all patients who received the medication. Among 11 patients who were followed up for more than 12 weeks, nine patients showed continuous improvement of symptoms, and this progress was still apparent at ≥20 weeks after starting administration (p < 0.0001). The medication was discontinued in four patients because of progression of primary disease, high cost, oral dryness, and anemia. No significant toxicity was observed on the serum biochemical analyses.. Nalfurafine hydrochloride contributed to long-term suppression of pruritus without significant safety problems.

Topics: Adult; Aged; Aged, 80 and over; Antipruritics; Chronic Disease; Female; Humans; Liver Diseases; Male; Middle Aged; Morphinans; Patient Reported Outcome Measures; Pruritus; Quality of Life; Spiro Compounds; Surveys and Questionnaires; Treatment Outcome

Pruritus is a major symptom of several dermatological diseases but has limited therapeutic options available. Animal models replicating the pathophysiology of pruritus are needed to support the development of new drugs. Induction of pruritus by chloroquine (CQ) in mice is widely used, although, as with similar models, it has low throughput and does not distinguish between antipruritic effects and confounding factors such as sedation. To overcome these issues, we incorporated into the model an automated system that measures both scratching and locomotor behaviour simultaneously. We combined this system with the determination of CQ levels in different tissues to understand the impact of the route of CQ administration on the pruritogenic response. We concluded that whereas oral CQ does not induce pruritus due to insufficient skin levels, the bell-shaped curve of pruritus observed following subcutaneous administration is due to toxicity at high doses. We validated the model with several drugs currently used in humans: nalfurafine, aprepitant, cyproheptadine and amitriptyline. By comparing the effects of the drugs on both scratching and locomotor activity, we concluded that nalfurafine and aprepitant can exhibit efficacy at doses devoid of central effects, whereas central effects drove the efficacy of the other two drugs. This was further confirmed using non-brain-penetrant drugs. Moreover, as anticipated, anti-inflammatory drugs showed no efficacy. In conclusion, the use of an automated integrated behavioural assessment in CQ-induced pruritus makes the assay suitable for screening purposes and allows for a correct interpretation of the antipruritic effect of the compounds evaluated.

Topics: Administration, Oral; Amitriptyline; Animals; Anti-Inflammatory Agents; Antidepressive Agents, Tricyclic; Antipruritics; Aprepitant; Behavior, Animal; Chloroquine; Cyproheptadine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Morphinans; Morpholines; Motor Activity; Narcotic Antagonists; Neurokinin-1 Receptor Antagonists; Pattern Recognition, Automated; Pruritus; Signal Processing, Computer-Assisted; Skin; Spiro Compounds; Vibration; Video Recording

Uremic pruritus in patients on hemodialysis is associated with depression, lower quality of life, and mortality. We studied the prevalence, awareness, and treatment of pruritus to assess how well this important condition is currently managed internationally.. Data from 35,452 patients on hemodialysis in up to 17 countries from the Dialysis Outcomes and Practice Patterns Study were analyzed to describe pruritus prevalence from 1996 to 2015. Data from 6256 patients and 268 medical directors in 17 countries in 2012-2015 were analyzed to describe predictors, effects, medical directors' awareness, and treatment of pruritus.. Patients very much or extremely bothered by itching declined from 28% in 1996 to 18% in 2015. In 2012-2015, among patients nearly always or always bothered by itching, pruritus had a major effect on work and social life; 18% used no treatment for pruritus, and 17% did not report itching to health care staff. In total, 69% of medical directors underestimated the prevalence of pruritus in their unit. Managing high serum phosphorus and low Kt/V was ranked as the most important intervention, but no relationship was found between these factors and pruritus; 57% of medical directors used oral antihistamines for first-line chronic treatment of pruritus. Gabapentin was used by 45% as first-, second-, or third-line treatment. Nalfurafine was only used in Japan.. The prevalence of pruritus in people on hemodialysis is decreasing but remains underestimated. Large numbers of patients on hemodialysis with severe pruritus do not receive treatment. There is wide variation in the use of unlicensed medications for the treatment of pruritus. These data provide a benchmark for initiatives to improve the management of uremic pruritus.. This article contains multimedia at https://vimeo.com/49458473This article contains multimedia at vimeo.com/49455976.

Topics: Aged; Aged, 80 and over; Amines; Antipruritics; Chronic Disease; Cyclohexanecarboxylic Acids; Female; Gabapentin; gamma-Aminobutyric Acid; Health Knowledge, Attitudes, Practice; Histamine Antagonists; Humans; Hyperphosphatemia; Internationality; Male; Middle Aged; Morphinans; Nephrology; Practice Patterns, Physicians'; Prevalence; Pruritus; Renal Dialysis; Risk Factors; Spiro Compounds; Surveys and Questionnaires; Uremia

Nalfurafine is a moderately selective kappa opioid receptor (KOR) analgesic with low incidence of dysphoric side effects in clinical development for the treatment of uremic pruritis. The basis for its reduced dysphoric effect compared to other KOR agonists is not clear, but prior studies suggest that the aversive properties of KOR agonists require p38α MAPK activation through an arrestin-dependent mechanism. To determine whether nalfurafine is a functionally selective KOR agonist, we measured its potency to activate the G protein-dependent early phase of Extracellular Signal-Regulated Kinase (ERK1/2) phosphorylation and the arrestin-dependent late phase of p38 MAPK signaling. Nalfurafine was approximately 250 fold more potent for ERK1/2 activation as compared to p38 MAPK activation in human KOR (hKOR) expressing HEK293 cells, and approximately 20 fold more potent for ERK1/2 activation than p38 activation in rodent KOR (rKOR) expressing HEK293 cells. The 10-fold greater G-bias at the hKOR than rKOR was unexpected, however the G protein biased effect of nalfurafine is consistent with its reduced dysphoric effects in human and rodent models. Although nalfurafine is reported to have low receptor selectivity in radioligand binding assays, its antinociceptive effect was blocked by the selective KOR antagonist norbinaltorphimine. Nalfurafine pretreatment also resulted in a KOR-dependent and mu opioid receptor-independent reduction in scratching induced by 5'-GNTI. These findings suggest that nalfurafine is a functionally selective KOR agonist and that KOR agonists able to selectively activate G protein signaling without activating p38α MAPK may have therapeutic potential as non-dysphoric antipruritic analgesics.

Topics: Animals; Drug Tolerance; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; GTP-Binding Proteins; HEK293 Cells; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Morphinans; p38 Mitogen-Activated Protein Kinases; Pruritus; Receptors, Opioid, kappa; Receptors, Opioid, mu; Signal Transduction; Spiro Compounds

The kappa-opioid agonist, nalfurafine, has been approved in Japan for treatment of itch in patients with chronic kidney disease. We presently investigated if systemic administration of nalfurafine inhibited ongoing or touch-evoked scratching behavior (alloknesis) following acute intradermal injection of histamine or the non-histaminergic itch mediator, chloroquine, in mice. We also investigated if nalfurafine suppressed spontaneous or touch-evoked scratching in an experimental model of chronic dry skin itch. Nalfurafine reduced scratching evoked by histamine and chloroquine. Following acute histamine, but not chloroquine, low-threshold mechanical stimuli reliably elicited directed hindlimb scratching behavior, which was significantly attenuated by nalfurafine. In mice with experimental dry skin, nalfurafine abolished spontaneous scratching but had no effect on alloknesis. Nalfurafine thus appears to be a promising treatment for acute itch as well as ongoing itch of dry skin.

Topics: Animals; Antipruritics; Behavior, Animal; Chloroquine; Disease Models, Animal; Histamine; Ichthyosis; Male; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Morphinans; Pressure; Pruritus; Skin; Spiro Compounds; Time Factors

Topics: Aged; Aged, 80 and over; Anxiety; Dermatologic Agents; Female; Humans; Male; Middle Aged; Morphinans; Pain Measurement; Pruritus; Quality of Life; Renal Dialysis; Severity of Illness Index; Spiro Compounds; Treatment Outcome

Pharmacological characterization of the main metabolites of nalfurafine hydrochloride ((E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; a selective κ-opioid receptor agonist and an antipruritic for uremic pruritus in hemodialysis patients in Japan) such as 17-decyclopropylmethylated nalfurafine (de-CPM), 3-glucuronide of nalfurafine (NFA-G) and 3-glucuronide of 17-decyclopropylmethylated nalfurafine (de-CPM-G) was performed in vitro (human opioid receptor radioligand binding assay and forskolin-stimulated cyclic adenosine monophosphate (cAMP) assay) and in vivo (substance P-induced scratching behavior in mice). These main metabolites of nalfurafine showed the low affinities for human κ-, μ- and δ-opioid receptors except for the affinity of de-CPM to κ-opioid receptor (inhibition constant (Ki) values: 5.95nmol/l), which was 24 times lower than that of nalfurafine. Moreover, the main metabolites of nalfurafine had much lower agonistic activities than that of nalfurafine for three opioid receptors in forskolin-stimulated cAMP assays. In the substance P-induced mouse scratching behavior, the subcutaneous administration of each metabolite did not statistically significantly reduce the scratching behavior at doses up to 1000μg/kg which was 100 times higher than the effective dose of nalfurafine. These findings suggest that the main metabolites of nalfurafine do not make any contribution to its pharmacological actions including antipruritic effects in vivo.

Topics: Animals; Antipruritics; Behavior, Animal; HEK293 Cells; Humans; Male; Mice; Morphinans; Pruritus; Receptors, Opioid; Spiro Compounds; Substance P

Gastrin-releasing peptide (GRP) has been implicated in the itch-scratch cycle. We investigated if this gut-brain-skin peptide plays a role in the compulsive, hindleg scratching of the neck of mice by 5'-guanidinonaltrindole (GNTI), the kappa opioid receptor antagonist, and in the antipruritic activity of nalfurafine, the kappa opioid agonist. Previously, we showed that GNTI (0.03-1mg/kg, s.c.) elicits dose-related scratching and that nalfurafine (0.001-0.02mg/kg, s.c.) inhibits this behavior in mice. Utilizing immunohistochemistry, GRP positive nerve fibers were detected in mouse skin and superficial layer of the dorsal horn of the spinal cord as well as GRP positive cells in the dorsal root ganglion. Pretreating mice with either a pseudopeptide GRP receptor antagonist, RC-3095 (10-30mg/kg, s.c. at -15min), or a peptide GRP receptor antagonist, [d-Phe(6)]bombesin(6-13) methyl ester (2-100nmol, i.t. at -10min), did not suppress GNTI-induced scratching. However, pretreating mice with either antagonist inhibited scratching precipitated by the GRP receptor agonist, GRP(18-27) (2nmol, i.t.). Pretreating mice with a muscarinic M(1) receptor agonist, McN-A-343 (1.5-15μg/5μl, i.t. at -10min) antagonized GNTI-induced scratching. Norbinaltorphimine (20mg/kg, i.p. at -18 to -20h), a kappa opioid antagonist, countered the antiscratch activity of nalfurafine. We conclude that (a) the GRP receptor system does not mediate GNTI-induced scratching and (b) the kappa opioid system is involved, at least in part, in the scratch suppressing activity of nalfurafine.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Animals; Bombesin; Compulsive Behavior; Ganglia, Spinal; Gastrin-Releasing Peptide; Grooming; Guanidines; Locomotion; Male; Mice; Morphinans; Naltrexone; Nerve Fibers; Peptide Fragments; Pirenzepine; Pruritus; Receptor, Muscarinic M1; Receptors, Bombesin; Receptors, Opioid, kappa; Skin; Spinal Cord; Spiro Compounds

The aims of the present study were to establish if nalfurafine, a kappa opioid agonist, inhibits compulsive scratching in mice elicited by the s.c. administration (behind the neck) of 5'-guanidinonaltrindole (GNTI), a kappa opioid antagonist; to assess if nalfurafine prevents c-fos expression provoked by GNTI or compound 48/80, two chemically diverse pruritogens; and to distinguish on the basis of neuroanatomy, those neurons in the brainstem activated by either GNTI-induced itch or formalin-induced pain (both compounds given s.c. to the right cheek). Pretreatment of mice with nalfurafine (0.001-0.03 mg/kg s.c.) attenuated GNTI (0.3 mg/kg)-evoked scratching dose-dependently. A standard antiscratch dose of nalfurafine (0.02 mg/kg) had no marked effect on the spontaneous locomotion of mice. Tolerance did not develop to the antiscratch activity of nalfurafine. Both GNTI and compound 48/80 provoked c-fos expression on the lateral side of the superficial layer of the dorsal horn of the cervical spinal cord and pretreating mice with nalfurafine inhibited c-fos expression induced by both pruritogens. In contrast to formalin, GNTI did not induce c-fos expression in the trigeminal nucleus suggesting that pain and itch sensations are projected differently along the sensory trigeminal pathway. Our data indicate that the kappa opioid system is involved, at least in part, in the pathogenesis of itch; and that nalfurafine attenuates excessive scratching and prevents scratch-induced neuronal activity at the spinal level. On the basis of our results, nalfurafine holds promise as a potentially useful antipruritic in human conditions involving itch.

Topics: Afferent Pathways; Analgesics, Opioid; Animals; Antipruritics; Biomarkers; Disease Models, Animal; Guanidines; Male; Mice; Morphinans; Naltrexone; Narcotic Antagonists; Nociceptors; p-Methoxy-N-methylphenethylamine; Pain Measurement; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Pruritus; Receptors, Opioid, kappa; Sensory Receptor Cells; Spinal Cord; Spiro Compounds; Treatment Outcome

Topics: Humans; Kidney Failure, Chronic; Morphinans; Pruritus; Renal Dialysis; Spiro Compounds; Uremia

In atopic dermatitis patients, pruritus is a severe symptom that is difficult to treat. It is previously reported that TRK-820, a kappa-opioid receptor agonist, reduces murine scratching behavior induced by an intradermal injection of histamine or substance P or an intracisternal injection of morphine. It is also reported that TRK-820 ameliorates the intractable pruritus in hemodialysis patients. However, it is still unclear whether TRK-820 possesses antipruritic effects on the pruritus in dermatitis patients. Therefore, the effect of TRK-820 on scratching behavior in NC/Nga mice maintained in a conventional environment, an animal model of atopic dermatitis, was examined. Oral TRK-820 (10-100 microg/kg) inhibited the scratching behavior but did not affect the locomotor activity. On the other hand, ketotifen (3-30 mg/kg, po), an antihistamine, did not attenuate the scratching behavior. TRK-820 showed the highest selectivity and activity for kappa-opioid receptor among all human opioid receptors. Release of various inflammatory mediators from a variety of cells and activity of nitric oxide synthase were not altered by TRK-820. This compound showed much lower affinities for other receptors than that for opioid receptors. These results suggest that TRK-820 is effective against antihistamine-resistant pruritus in atopic dermatitis patients via the kappa opioid receptor.

Topics: Animals; Behavior, Animal; Dermatitis, Atopic; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Inbred Strains; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds

Scratching is the behavioral manifestation of pruritus. The pruritus of cholestasis can be severe, intractable and affect the quality of life. We investigated if ethynylestradiol (EE)-induced cholestasis is associated with scratching in rats and if nalfurafine, a kappa opioid receptor agonist with antipruritic effects in human uremic pruritus, would antagonize such scratching. Chronic injection of EE (2 mg/kg, s.c., for 14 days) induced cholestasis as documented by increased serum concentrations of bile acids and caused a higher incidence of body scratching compared to vehicle, thus providing an animal model to study scratching behavior secondary to cholestasis. Pretreating the rats with nalfurafine (0.005-0.04 mg/kg, s.c.) inhibited EE-induced scratching dose-dependently with an A(50) value of 0.013 (0.009-0.021) mg/kg. Serum levels of dynorphin A and nitric oxide were decreased in rats with cholestasis compared to control animals. Our data suggest that (a) nalfurafine has the potential to relieve cholestatic pruritus and (b) both kappa opioid and nitric oxide systems are involved, at least in part, in mediating the pruritus of cholestasis.

Topics: Animals; Behavior, Animal; Cholestasis; Ethinyl Estradiol; Injections, Subcutaneous; Male; Morphinans; Pruritus; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Spiro Compounds

Topics: Humans; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds; Uremia

Pruritus is a common, distressing and difficult to manage complication of many autoimmune diseases. A suitable animal model of autoimmune disease associated pruritus would contribute to a better understanding of the pathophysiology of this symptom and lead to the development of safe and effective antipruritic agents. We noticed spontaneous scratching behavior in aged MRL/lpr mice, a model of autoimmune disease. This scratching behavior was observed in a specific pathogen-free environment and was more frequent in female mice. In contrast to animal models of dermatitis; NC/Nga mice, the serum IgE and IgG1 levels in MRL/lpr mice were not elevated. These features indicate that this scratching behavior is similar to human autoimmune disease associated pruritus. The antipruritic effects of an antihistamine (chlorpheniramine), an opioid receptor antagonist (naltrexone), and a novel kappa-opioid receptor agonist (nalfurafine hydrochloride [TRK-820]) were evaluated. The frequency of scratching was not reduced by oral administration of chlorpheniramine, suggesting that the behavior is antihistamine-resistant. The oral administration of nalfurafine and subcutaneously administered naltrexone inhibited the scratching behavior without causing gross behavioral changes. In conclusion, MRL/lpr mice scratching behavior is a suitable model of pruritus that occurs in autoimmune diseases, and nalfurafine was shown to be efficacious against this behavior suggesting that it may be beneficial in patients with autoimmune disease associated pruritus.

Topics: Age Factors; Animals; Antipruritics; Autoimmune Diseases; Behavior, Animal; Chlorpheniramine; Dermis; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Immunoglobulin E; Immunoglobulin G; Male; Mice; Mice, Inbred ICR; Mice, Inbred MRL lpr; Mice, Inbred Strains; Morphinans; Naltrexone; Pruritus; Receptors, Opioid, kappa; Sex Factors; Spiro Compounds

The inhibitory effects of kappa-opioid receptor agonists on systemic skin scratching induced by the intravenous administration of morphine, a micro-opioid receptor agonist, were investigated in rhesus monkeys. Intravenous pretreatment with kappa-opioid receptor agonists, either TRK-820 at 0.25 and 0.5 microg/kg or U-50488H at 64 and 128 microg/kg, inhibited systemic skin scratching induced by morphine at 1 mg/kg, i.v. in a dose-dependent manner. By the intragastric route, apparent inhibitory effects on morphine-induced systemic skin scratching were evident following pretreatment with TRK-820 at 4 microg/kg but not with U-50488H from 512 to 2048 microg/kg. These results suggest that TRK-820 produces antipruritic effects on i.v. morphine-induced systemic skin scratching and is more readily absorbed intragastrically than is U-50488H, resulting in high bioavailability in the intragastric route.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Dose-Response Relationship, Drug; Macaca mulatta; Morphinans; Morphine; Motor Activity; Observation; Pruritus; Receptors, Opioid, kappa; Spiro Compounds; Statistics, Nonparametric

The role of central mu- and kappa-opioid receptors in the regulation of itch sensation was examined using pruritogen-induced mouse scratching behavior model. Intracerebroventricular administration of beta-funaltrexamine, a selective mu-opioid receptor antagonist, inhibited the scratching behavior induced by intradermal substance P, but subcutaneous administration of beta-funaltrexamine did not. Similarly, the scratching inhibitory activity of subcutaneously administered TRK-820, (-)-17-(cyclopropylmethyl)-3, 14beta-dihydroxy-4, 5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride, a kappa-opioid receptor agonist, was antagonized by intracerebroventricular administration of nor-binaltorphimine (10 microg/site), a kappa-opioid receptor antagonist, but was not by subcutaneous administration of nor-binaltorphimine. In addition, the scratching induced by the direct activation of central mu-opioid receptor by intracisternal morphine was significantly and dose-dependently inhibited by subcutaneous administration of TRK-820. Taken all together, it is suggested that the central mu-opioid receptors play a role in the processing of itch sensation, and the activation of central kappa-opioid receptors antagonize the central mu-opioid receptor mediated itch processing, thereby suppressing itch sensation.

Topics: Animals; Antipruritics; Behavior, Animal; Injections, Intraventricular; Injections, Subcutaneous; Ketotifen; Male; Mice; Morphinans; Morphine; Motor Activity; Naltrexone; Narcotic Antagonists; Pruritus; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spiro Compounds; Substance P

The effects of the kappa-opioid receptor agonist, TRK-820, (-)-17-(cyclopropylmethyl)-3, 14beta-dihydroxy-4, 5alpha-epoxy-6beta-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride, on the itch sensation were compared with those of histamine H1 receptor antagonists, using the mouse pruritogen-induced scratching model. Peroral administration of TRK-820 reduced the numbers of substance P- or histamine-induced scratches dose dependently. No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments, indicating that the inhibition of scratches was not due to the effect on general behavior. Furthermore, the scratching inhibitory activity of TRK-820 was dose dependently antagonized by the specific kappa-opioid receptor antagonist, nor-binaltorphimine, suggesting that the inhibitory activity was mediated via kappa-opioid receptors. Histamine H1 receptor antagonists, chlorpheniramine and ketotifen, did not inhibit substance P-induced scratches, or did so only partially. Both antihistamines inhibited the histamine-induced scratches completely. These results suggest that TRK-820 has antipruritic activity which is mediated by kappa-opioid receptors, and is effective in both antihistamine-sensitive and -resistant pruritus.

Topics: Animals; Antipruritics; Chlorpheniramine; Disease Models, Animal; Histamine; Histamine H1 Antagonists; Ketotifen; Male; Mice; Mice, Inbred ICR; Morphinans; Motor Activity; Naltrexone; Pruritus; Receptors, Opioid, kappa; Spiro Compounds; Substance P