Retrospective Evaluation of Moderate Sedation Visits That Used Oral Meperidine and Hydroxyzine With Oral or Intranasal Midazolam.

Purpose: To examine the influence of substituting intranasal (IN) midazolam (MID) for oral (PO) MID, within the three-drug combination of meperidine (MEP), hydroxyzine (H) and MID, on sedation treatment outcomes. Methods: A retrospective, cross-sectional analysis examined patient variables and sedation outcomes in 508 pediatric dental patients sedated by single- and multi-drug sedation regimens (MEP-H; MEP-H-(PO)-MID; MEP-H-(IN)-MID; single-agent MID). The outcome assessment examined sedation visit effectiveness, sedation treatment completion, treatment time and medication administration to discharge time. Multivariable logistic regression analyses assessed predictive variables associated with sedation visit effectiveness. Results: Both three-drug combinations (MEP-H-(PO)-MID; MEP-H-(IN)-MID) were used for behavior guidance in children of a similar age (median age=7.1 and 6.5 years, respectively, for the two drug combinations) and weight (median weight = 23.7 and 23.5 kg, respectively, for the two drug combinations). These three-drug combinations had a higher likelihood of sedation effectiveness over the reference sedation regimen of single-agent midazolam (MEP-H-(PO)-MID adjusted odds ratio [OR] = 2.65; 95 percent confidence interval [95% CI]=1.09 to 6.45; P=0.032; and MEP-H-(IN)-MID OR=2.08; 95% CI=1.03 to 4.18; P=0.039). MEP-H-(IN)MID was associated with a shorter medication administration to discharge time for patients by 23 minutes (interquartile range [IQR]=9.5 to 34 minutes) compared to MEP-H-(PO) MID (P<0.05) while providing a comparable number of teeth treated (median=five). All sedation drug regimens, including MEP-H-(IN)MID, had high levels of oxygen saturation during all sedation appointments. Conclusion: Substituting IN for PO MID in MEP-H-MID was associated with a shorter total time to discharge while demonstrating comparable efficacy during sedation.

Are antimuscarinic effects common in hydroxyzine overdose? A cohort analysis of antimuscarinic effects in hydroxyzine and diphenhydramine-poisoned patients.

INTRODUCTION: Exposures to hydroxyzine, a first-generation H1 antihistamine, have increased rapidly over the last two decades. Many assumptions about hydroxyzine poisoning are based on other antihistamines, like diphenhydramine. However, the receptor affinities of hydroxazine suggest that there should be fewer antimuscarinic findings than diphenhydramine. METHODS: This was a cohort study that compared hydroxyzine and diphenhydramine exposures reported to the National Poison Data System between January 1, 2000, and December 31, 2020, and the Toxicologic Investigators Consortium Core Registry between January 1, 2010, and December 31, 2020. The primary outcome was to assess for antimuscarinic findings in hydroxyzine-poisoned patients, using diphenhydramine-poisoned patients as a comparison group. The secondary outcomes were to assess for markers of overall toxicity. Inclusion criteria were single-substance exposures with known outcomes. Exclusion criteria for National Poison Data System exposures were chronic exposures, unintentional exposures, and patients younger than 12 years old. There were no exclusion criteria for exposures reported to the Toxicologic Investigators Consortium Core Registry. RESULTS: There were 17,265 hydroxyzine and 102,354 diphenhydramine exposures reported to the National Poison Data System and 134 hydroxyzine and 1,484 diphenhydramine exposures reported to the Toxicologic Investigators Consortium Core Registry that met inclusion criteria. In both datasets, hydroxyzine-poisoned patients had lower rates and relative risk of developing antimuscarinic findings or receiving physostigmine, with the exception of hyperthermia in the Toxicologic Investigators Consortium Core Registry dataset. Coma/central nervous system depression (major), respiratory depression, seizures, ventricular dysrhythmias, intubation, and benzodiazepine administration were less likely in hydroxyzine-poisoned patients, but central nervous system depression (mild) was more likely in exposures reported to the National Poison Data System. The mortality in hydroxyzine-poisoned patients was rare: 0.02% and 0.8% of exposures reported to the National Poison Data System and Toxicologic Investigators Consortium Core Registry, respectively. DISCUSSION: The clinical manifestations of hydroxyzine exposures are consistent with the pharmacology of hydroxazine. The clinical effects were consistent across two United States national datasets. Clinicians should not generalize the illness script of diphenhydramine exposures to hydroxyzine exposures. CONCLUSIONS: Hydroxyzine-poisoned patients were less likely to develop antimuscarinic findings than diphenhydramine-poisoned patients. Hydroxyzine-poisoned patients were more likely to have mild central nervous system depression than an antimuscarinic toxidrome.

Vanadium-Containing Anionic Chelate for Spectrophotometric Determination of Hydroxyzine Hydrochloride in Pharmaceuticals.

Four azo dyes known to form anionic complexes with V(V) were investigated as potential liquid-liquid extraction-spectrophotometric reagents for the antihistamine medication hydroxyzine hydrochloride (HZH). A stable ion-association complex suitable for analytical purposes was obtained with 6-hexyl-4-(2-thiazolylazo)resorcinol (HTAR). The molar absorption coefficient, limit of detection, linear working range, and relative standard deviation in the analysis of real pharmaceutical samples (tablets and syrup) were 3.50 × 104 L mol-1 cm-1, 0.13 µg mL-1, 0.43-12.2 µg mL-1, and ≤2.7%, respectively. After elucidating the molar ratio in the extracted ion-association complex (HZH:V = 1:1), the ground-state equilibrium geometries of the two constituent ions-HZH+ and [VO2(HTAR)]--were optimized at the B3LYP level of theory using 6-311++G** basis functions. The cation and anion were then paired in four different ways to find the most likely structure of the extracted species. In the lowest-energy structure, the VO2 group interacts predominantly with the heterochain of the cation. A hydrogen bond is present (V-O···H-O; 1.714 Å) involving the terminal oxygen of this chain.

Efficacy and safety of hydroxyzine for sleep in adults: Systematic review.

OBJECTIVE: The purpose of this systematic review is to assess the efficacy and safety of hydroxyzine for insomnia in adults. METHODS: A comprehensive literature search of PubMed, Embase, and CENTRAL databases was conducted to identify relevant published studies through October 2022 using the search terms: hydroxyzine and sleep, insomnia, sleep disorder or sleep initiation and maintenance disorders. Studies identified for review included prospective, interventional designs or cohort trials that reported impact of hydroxyzine on sleep in adults. Animal studies, case reports, non-English articles, letters to the editor, case studies, and conference abstracts were excluded. Data were extracted using a standardized systematic process. RESULTS: Five articles were identified for inclusion, including 1 open-label and 4 randomized controlled trials, evaluating a total of 207 patients receiving hydroxyzine 25 mg, 50 mg, or 100 mg at bedtime. Mixed efficacy was demonstrated in the sleep measures of sleep onset, sleep maintenance, and sleep quality. The most common adverse drug effect was dry mouth, although 4 of the 5 studies did not report safety outcomes. CONCLUSIONS: The studies in this review suggest hydroxyzine could be considered as a short-term treatment option for adults with insomnia for whom previous therapy was ineffective, not tolerated, or contraindicated. Additional long-term studies with an active comparator are needed to further establish its role in insomnia treatment.

Dermatitis asteatósica o de craquelé. A propósito de un caso / Asteatotic or Craquelé Dermatitis. A Case Study

La dermatitis de craquelé o dermatitis asteatósica es una enfermedad cutánea caracterizada por piel eritematosa, pruriginosa, seca y agrietada, que afecta preferentemente a personas de edad avanzada, siendo el tipo de eccema más común en pacientes ancianos. Entre los factores que contribuyen a su aparición, destacan la edad, el clima estacional y los hábitos del baño, que pueden favorecer la alteración del estrato córneo y la aparición de fisuras.(AU)

Craquelé dermatitis or asteatotic dermatitis is a skin disease characterized by erythematous, itchy, dry and cracked skin, which preferentially affects the elderly and is the most common type of eczema in elderly patients. Among the factors that contribute to its appearance are age, seasonal climate and bathing habits, which can favour the alteration of the stratum corneum and the onset of fissures.(AU)

Comparisons of Varying Dosages of Chloral Hydrate-Hydroxyzine with and without Meperidine for Managing Challenging Pediatric Dental Behavior: A Retrospective study of 35 years of Sedation Experiences.

PURPOSE: This retrospective study compares the efficacy and safety of variable dosing of Chloral Hydrate - Hydroxyzine with and without Meperidine (Mep)for managing varying levels of anxiety and uncooperative behavior of young pediatric dental patients over a 35-year period. STUDY DESIGN: Reviews of the sedation logs of 2,610 children, 3-7 years were compared in search of what dosing proves safe and effective for differing levels of challenging behavior. Variable dosing of CH with and without Mep were judged using a pragmatic approach which defined sedation success as optimal, adequate, inadequate, or over-dosage using oneway analysis of variance. Descriptive analyses of behavior and physiologic assessment was included with regard to the extent to which physical restraint occurred to control interfering behavior. Arousal levels requiring stimulation, oxygen desaturation, and adverse reactions were included as indications of safety. RESULTS: Where Mep was used, success rates were consistently higher; need for higher-end dosing of CH was not found beneficial when Mep was included. Significantly less need for physical restraint accompanied the addition of Mep. CONCLUSIONS: There appears to be strong basis for the safety and efficacy of the use of CH-H-Mep in combination at lower dosing than historically used. Addition of Mep was observed to enhance sedations, permit lower CH dosing, lessen or eliminate the need for physical restraint and adverse reactions.

Case report of a phencyclidine false positive due to lamotrigine use with confirmatory testing.

BACKGROUND: Urine toxicology screens are useful in diagnosing patients who present with acute psychosis with a history of substance abuse. Being aware of potential false positive reactants is paramount in diagnostic accuracy. Currently, lamotrigine is not listed among common cross-reactants with phencyclidine (PCP). CASE REPORT: A 49 year old male (98 kg) was brought to the ED by a family member for worsening confusion and agitation. He had a history of Bipolar I, PTSD, schizoaffective disorder, hypertension, and cannabis/opioid abuse. His home medications included paliperidone, duloxetine, lamotrigine, tizanidine, hydroxyzine, and lisinopril. Upon examination, he denied intentional overdose or illicit substances, but largely mumbled incoherently. Blood pressure was 140/90 mmHg, pulse 113. A urine toxicology screen was positive for PCP and cannabinoids. Other labs were unremarkable, co-ingestants negative. By day three, his mental status vacillated but he largely gave unintelligible responses. Given the short half-life of PCP, false positives were investigated. A confirmatory blood test (collected upon admission) for PCP was found to be negative, and a serum lamotrigine level was confirmed to be positive (1.5µg/ml). Once more lucid, the patient admitted to taking large quantities of mirtazapine and tizanidine, making serotonin syndrome the more likely diagnosis. DISCUSSION: There is little in the medical literature describing cross-reactivity of lamotrigine and PCP on urine drug screens. This can be especially difficult to deduce in a known drug abuser who presents psychotic and non-contributory in their work up.

Hydroxyzine Initiation Following Drug Safety Advisories on Cardiac Arrhythmias in the UK and Canada: A Longitudinal Cohort Study.

INTRODUCTION: Regulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories. METHODS: We conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013-March 2016) as well as in a BC advisory cohort (June 2014-May 2017). RESULTS: This study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66-0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors. CONCLUSION: Hydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP.

Do medication prescription patterns follow guidelines in a cohort of women with interstitial cystitis/bladder pain syndrome?

OBJECTIVE: To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current treatment guidelines. METHODS: We sampled female patients with an ICD-9/10 diagnosis of IC/BPS (595.1/N30.10) by querying active users of the Veterans Health Administration. Medical records were reviewed to determine whether patients met IC/BPS diagnostic criteria. A cohort of women with other pelvic pain disorders was identified. Prescription prevalence of typical non-narcotic oral bladder pain medications was compared between the two groups and healthy controls. Prescription prevalence was also compared before and after the diagnosis of IC/BPS was made using Poisson regression. RESULTS: There were 641 women who met criteria for IC/BPS and 197 women with "Other pelvic pain" disorders. Women with IC/BPS were prescribed a pain medication more often than those with "Other pelvic pain" (77% vs. 59%, p < 0.0001). Of the women with IC/BPS, 44% tried three or more pain medications. Of women with a diagnosis of IC/BPS, only 67% were prescribed an American Urological Association-recommended medication. Prescription prevalence increased after diagnosis for both pentosan polysulfate (10%-29%, p < 0.0001) and hydroxyzine (17%-40%, p < 0.0001), but not for amitriptyline or cimetidine. Amitriptyline was prescribed to 223 women with IC/BPS, only 125 of which (56%) had a documented history of depression. CONCLUSIONS: Many women with IC/BPS required multiple bladder prescriptions, highlighting the difficulty in finding an effective treatment for IC/BPS. Pentosan polysulfate and hydroxyzine were preferred IC/BPS medications. Our next step will be to analyze treatment patterns in those patients who did not receive medications.

A retrospective comparison of haloperidol and hydroxyzine combination therapy with haloperidol alone in the treatment of overactive delirium.

BACKGROUND: For the treatment of delirium, antipsychotics such as haloperidol are used as standard treatments. However, haloperidol has a little sedative effect and may not be sufficiently effective in controlling overactive delirium. Hydroxyzine, an antihistamine, may be used in combination with haloperidol to supplement its sedative effect. The aim of this study was to investigate the effect of haloperidol alone or in combination with hydroxyzine on the improvement of overactive delirium retrospectively. METHOD: Delirium was assessed from medical records using the Intensive Care Delirium Screening Checklist (ICDSC). The number of patients and days with an ICDSC score of < 4, indicating an absence of delirium after haloperidol alone or haloperidol and hydroxyzine was surveyed for 6 days. RESULTS: A total of 157 patients were diagnosed with delirium from April 2019 to July 2021, of which 18 patients received haloperidol alone, and 21 patients received the combination of haloperidol and hydroxyzine for overactive delirium. The number of patients with a mean ICDSC score of < 4 on days 1-6 was two patients (11%) in the haloperidol groups and two patients (10%) in the combination of haloperidol and hydroxyzine group (P = 0.999). The days within < 4 of the ICDSC score on days 1-6 were 0.8 (1.3) and 0.8 (1.5), respectively (P = 0.848). CONCLUSION: Haloperidol alone and haloperidol plus hydroxyzine are both effective in the treatment of overactive delirium. However, the concomitant use of hydroxyzine with haloperidol may not improve the efficacy of treatment of overactive delirium compared to haloperidol alone.

Behaviour of 3-11-year-old children during dental treatment requiring multiple visits: a retrospective study.

PURPOSE: To examine children's behaviours during consecutive dental treatments, relative to gender, age, and behaviour guidance techniques. METHODS: A retrospective study of medical records of children treated by four residents in a Department of Paediatric Dentistry, during 2015-2018. Data included: age, gender, behaviour guidance technique (no medication, inhaled sedation, conscious sedation with hydroxyzine or benzodiazepines) and behaviour according to Frankl scale. RESULTS: Of 205 children, 134 were 3-6 yo (Group 1) and 71 were 6.1-11 yo (Group 2). Most presented a positive behavioural profile, with significant difference between groups (p = 0.02), no significant difference between genders (p = 0.72). A significant association between behaviour guidance techniques and behavioural profile was found (p = 0.01). Most children with positive behaviour received inhaled sedation (83%), while most children with negative behaviour received conscious sedation using benzodiazepines (8%). Negative behaviour was observed only in the younger children receiving conscious sedation with benzodiazepines (9%) or hydroxyzine (3%). CONCLUSIONS: Most 3-11 yo patients exhibited positive behaviour during four consecutive dental treatments, with different behaviour guidance techniques. Negative behaviour was more frequent among 3-6 yo children, where sedation was often required to achieve cooperation, and 4.5% could benefit from general anesthesia.

Development and validation of liquid chromatography-tandem mass spectrometry method for the estimation of a potential genotoxic impurity 2-(2-chloroethoxy)ethanol in hydroxyzine.

2-(2-Chloroethoxy)ethanol (CEE) belongs to the so-called cohort of concerns which were classified as highly potent mutagenic carcinogens by the World Health Organization. It is widely used in the synthesis of the essential anti-histamine drug hydroxyzine. In addition, it is used as a primary solvent in dyes, nitrocellulose, paints, inks and resins. Owing to its potential genotoxicity, an efficient liquid chromatography-tandem mass spectrometry method was developed for the quantitative estimation of CEE traces in an active pharmaceutical ingredients and in tablet dosage forms of hydroxyzine-free base. The chromatographic separation was achieved on a C18 column using a gradient elution mode with a binary solvent system (ammonium formate and methanol). Mass detection was performed for CEE using a positive mode with selected ion monitoring technique at m/z value of [M + NH4 ]+ . The developed method was validated as per the International Conference on Harmonizaiton guidelines. The quantitation limit, linearity and recoveries were found to be 0.56 ppm, 0.56-7.49 ppm (r2 > 0.9985) and 93.6-99.3%, respectively. The proposed method was highly compatible and was used effectively to estimate CEE traces in different stages of drug synthesis and in tablet dosage forms of hydroxyzine for routine and stability testing.

The Effects of Pharmacological Treatment of Nightmares: A Systematic Literature Review and Meta-Analysis of Placebo-Controlled, Randomized Clinical Trials.

Nightmares are highly prevalent and distressing for the sufferer, which underlines the need for well-documented treatments. A comprehensive literature review and meta-analysis of the effects of different pharmacological placebo-controlled randomized clinical trials, covering the period up to 1 December 2022, was performed. Searches were conducted in PubMed, Embase, Web of Science, PsychInfo, Cinahl, and Google Scholar, resulting in the identification of 1762 articles, of which 14 met the inclusion criteria: pharmacological intervention of nightmares, based on a placebo-controlled randomized trial published in a European language, reporting outcomes either/or in terms of nightmare frequency, nightmare distress, or nightmare intensity, and reporting sufficient information enabling calculation of effect sizes. Most studies involved the effect of the α1-adrenergic antagonist prazosin in samples of veterans or soldiers suffering from posttraumatic stress disorder. Other medications used were hydroxyzine, clonazepam, cyproheptadine, nabilone, and doxazosin. The vast majority of studies were conducted in the USA. The studies comprised a total of 830 participants. The Clinician-Administered PTSD Scale was the most frequently used outcome measure. The results showed an overall effect size of Hedges' g = 0.50 (0.42 after adjustment for publication bias). The synthetic cannabinoid nabilone (one study) showed the highest effect size (g = 1.86), followed by the histamine H1-antagonist hydroxyzine (one study), and prazosin (10 studies), with effect sizes of g = 1.17 and g = 0.54, respectively. Findings and limitations are discussed, and recommendations for future studies are provided.

Plasma and urine pharmacokinetics of hydroxyzine and cetirizine following repeated oral administrations to exercised horses.

Hydroxyzine and cetirizine are first- and second-generation oral antihistamine drugs, respectively, used to treat allergic reactions in horses. Cetirizine is also a metabolite of hydroxyzine, which may lead to complexities in regulating their use in equine sporting events. The aim of the research was to be able to provide detection times (DT) from pharmacokinetic studies in thoroughbred horses to better inform trainers, and their veterinary surgeons, prescribing these substances for treatment of Thoroughbred racehorses. Six and two horses were given 9 repeated administrations of hydroxyzine HCl (500 mg BID) or cetirizine HCl (190 mg BID), respectively. Plasma and urine hydroxyzine and cetirizine concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A holistic non-linear mixed effects PK model was developed that described both plasma and urine concentrations of hydroxyzine and cetirizine, either from administration of each individually or cetirizine as a metabolite of hydroxyzine. Using the parameters obtained from this PK model in conjunction with methodology developed by Toutain afforded possible screening limits (SL) that can regulate for a DT of 4 days in either plasma or urine. Hydroxyzine and cetirizine concentration prediction intervals for the 80th , 95th and 99th percentiles of a virtual horse population were performed in order to assess the statistical protection of the DT. However, it is down to the individual racing authorities to apply their own risk management.

Selective Serotonin Reuptake Inhibitors and Hydroxyzine in the Treatment of Avoidant/Restrictive Food Intake Disorder in Children and Adolescents: Rationale and Evidence.

Objective: Despite lack of evidence, various pharmacological agents are judiciously used to manage anxiety in avoidant restrictive food intake disorder (ARFID). We aimed to explore the effectiveness of selective serotonin reuptake inhibitors (SSRIs), either alone or in combination with hydroxyzine, in a well-defined cohort of children and adolescents with ARFID receiving treatment in a partial hospitalization program for eating disorders. Methods: We conducted a retrospective chart review of 53 patients with ARFID who were prescribed an SSRI (n = 39) or SSRI with hydroxyzine (n = 14). We investigated changes from admission to discharge in these two medication groups on various outcome measures assessing weight, eating behaviors, mood, anxiety, and fears about food. Results: Participants in the SSRI+hydroxyzine group were significantly older than those in the SSRI only group. The majority of participants in both groups exhibited the fear presentation of ARFID. Repeated-measures analysis of variance yielded a significant main effect for treatment for all outcome measures, indicating that patients in both groups experienced improvements in weight, eating behaviors, mood, anxiety, and fears of food. A significant main effect for medication group emerged on the Children's Depression Inventory, suggesting that the group receiving SSRI+hydroxyzine experienced greater depressive symptomatology than the SSRI-only group. We did not find any significant interactions, indicating that participants in both medication groups experienced similar improvements over the course of treatment. Conclusion: These results provide preliminary evidence that SSRIs and hydroxyzine may be helpful in the treatment of children and adolescents with ARFID. Given that hydroxyzine was prescribed to patients who experienced high pre- and/or postmeal anxiety, it possibly contributed to similar decreases in anxiety and fear of food in a more challenging subset of patients. Randomized, placebo-controlled studies for children and adolescents with ARFID are warranted to better evaluate and understand the efficacy of SSRIs and hydroxyzine in this clinical population.

Hydroxyzine for lowering patient's anxiety during prehospital morphine analgesia: A prospective randomized double blind study.

STUDY OBJECTIVE: Hydroxyzine is an antihistamine drug used for symptomatic relief of anxiety and tension. We hypothesized that managing the anxiety of patients with severe pain by adding hydroxyzine to a conventional intravenous morphine titration would relieve their pain more effectively. METHODS: This was a randomized, double-blind, controlled group study of prehospital patients with acute pain scored greater than or equal to 6 on a 0-10 verbal numeric rating scale (NRS). Patients'anxiety was measured with the self-reported Face Anxiety Scale (FAS) ranking from 0 to 4. The percentage of patients with pain relief (NRS score ≤ 3) 15 min after the first injection was the primary outcome. RESULTS: One hundred forty patients were enrolled. Fifty-one percent (95% CI 39% to 63%) of hydroxyzine patients versus 52% (95% CI 40% to 64%) of placebo patients reported a pain numeric rating scale score of 3 or lower at 15 min. Ninety-one percent (95% CI 83% to 98%) of patients receiving hydroxyzine reported no more severe anxiety versus 78% (95% CI 68% to 88%) of patients with placebo (p > 0.05). Adverse events were minor, with no difference between groups (6% in hydroxyzine patients and 14% in placebo patients). CONCLUSION: Addition of hydroxyzine to morphine in the prehospital setting did not reduce pain or anxiety in patients with acute severe pain and therefore is not indicated based on our results.

Rationale and design of the multicentric, double-blind, double-placebo, randomized trial APrepitant versus HYdroxyzine in association with cytoreductive treatments for patients with myeloproliferative neoplasia suffering from Persistent Aquagenic Pruritus. Trial acronym: APHYPAP.

BACKGROUND: Aquagenic pruritus (AP), an intense sensation of scratching induced after water contact, is the most troublesome aspect of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). Mostly described in polycythemia vera (PV, ~ 40%), it is also present in essential thrombocythemia (ET) and primary myelofibrosis (PMF) (10%). Even if this symptom can decrease or disappear under cytoreductive treatments, 30% of treated MPN patients still persist with a real impact on the quality of life (QoL). Because its pathophysiology is poorly understood, efficient symptomatic treatments of AP are missing. The neuropeptide substance P (SP) plays a crucial role in the induction of pruritus. Several studies showed the efficacy of aprepitant, an antagonist of SP receptor (NK-1R), in the treatment of chronic pruritus but never evaluated in AP. The objectives of APHYPAP are twofold: a clinical aim with the evaluation of the efficacy of two drugs in the treatment of a persistent AP for MPN patients and a biological aim to find clues to elucidate AP pathophysiology. METHODS/DESIGN: A multicentric, double-blind, double-placebo, randomized study will include 80 patients with MPN (PV or ET or PMF) treated since at least 6 months for their hemopathy but suffering from a persistent AP (VAS intensity ≥6/10). Patients will be randomized between aprepitant (80 mg daily) + placebo to match to hydroxyzine OR hydroxyzine (25 mg daily) + placebo to match to aprepitant for 14 days. At D0, baseline information will be collected and drugs dispense. Outcome measures will be assessed at D15, D30, D45, and D60. The primary study endpoint will be the reduction of pruritus intensity below (or equal) at 3/10 on VAS at D15. Secondary outcome measures will include the number of patients with a reduction or cessation of AP at D15 or D60; evaluation of QoL and AP characteristics at D0, D15, D30, D45, and D60 with MPN-SAF and AP questionnaires, respectively; modification of plasmatic concentrations of cytokines and neuropeptides at D0, D15, D30, and D60; and modification of epidermal innervation density and pruriceptor expression at D0 and D15. DISCUSSION: The APHYPAP trial will examine the efficacy of aprepitant vs hydroxyzine (reference treatment for AP) to treat persistent AP in MPN patients. The primary objective is to demonstrate the superiority of aprepitant vs hydroxyzine to treat persistent AP of MPN patients. The treatment received will be considered efficient if the AP intensity will be reduced at 3/10 or below on VAS after 14 days of treatment. The results of this study may provide a new treatment option for this troublesome symptom and also give us more insights in the pathophysiology understanding of AP. TRIAL REGISTRATION: APHYPAP. NCT03808805 , first posted: January 18, 2019; last update posted: June 10, 2021. EudraCT 2018-090426-66.