Revisiting the role of hydroxyzine in the management of pediatric pruritus: A Current Thinking

Revisiting the role of hydroxyzine in the management of pediatric pruritus:

A Current Thinking of the Indian Academy of Pediatrics

Authors

1] Dr.V.ANANDAN

Professor & HOD of DVL & Cosmetology

Govt.Stanley Medical College & Hospital

Chennai, Tamilnadu

2] Dr.C.Vijaya Baskar

Professor of DVL

Govt.Madras Medical College & Hospital

Chennai, Tamilnadu

3] Dr.Rajeev Sharma

Senior Consultant Dermatologist

Abstract

Pruritus, or itching, is a widespread symptom in acute and chronic forms. The epidemiology of pruritus is influenced by factors including age, sex, geographical location, and underlying medical conditions. Pediatric pruritus, arising from diverse skin and systemic conditions, significantly impacts children’s well-being, influencing mood, quality of life, sleep, and academic performance. The pathophysiology involves intricate interactions between the nervous system, immune system, and skin cells, leading to the well-known itch-scratch cycle, which is particularly prevalent in chronic pruritus. Accurate diagnosis of pediatric pruritus demands a systematic approach, incorporating medical history, physical examination, skin biopsy, laboratory tests, allergy testing, imaging studies, dermatological tests, scratch tests, medication review, and psychological assessment. Management strategies for pediatric pruritus necessitate a comprehensive approach, adjusted to age-related differences. Treatment options span from topical therapies for mild cases to systemic therapies for severe pruritus. Antihistamines, such as hydroxyzine, are considered first-line treatments for pruritus. The soothing nature of hydroxyzine can benefit children with nocturnal itching affecting their sleep quality. In conclusion, effective management of pediatric pruritus requires a multidisciplinary approach, involving precise diagnosis, severity assessment, and customized treatment strategies.

Keywords: antihistamine, children, hydroxyzine, pruritus

Introduction

Pruritus, commonly known as itching, is a prevalent symptom in various diseases, characterized by an irresistible urge to scratch. (Andrade A et al 2020) It can manifest in acute or chronic forms, with chronic pruritus lasting over six weeks. (Grundmann S et al 2011) Acute and chronic pruritus have prevalence rates of 8.4% and 13.5%, respectively, and the lifetime prevalence of chronic pruritus is 22%. (Godse K et al 2021) The epidemiology of pruritus is diverse, and its prevalence can vary based on factors such as age, gender, geographical location, and the presence of underlying medical conditions. Pruritus can be classified according to its distribution and associated features into three categories: cutaneous, generalized, and localized (Figure 1) (Satoh T et al 2021; Godse K et al 2021).

Figure 1: Classification and causes of pruritus

Pathophysiology of pruritus

The pathophysiology of pruritus involves a nuanced interplay between the nervous system, immune system, and skin cells, constituting a complex web that remains not entirely understood (Golpanian RS et al 2020). Briefly, the sensation of itching is transmitted through nerve fibres in the skin, and scratching is the body’s natural response to relieve the discomfort. There are two types of nerve fibres responsible for nociception. C-fibres are unmyelinated, slower-conducting fibres that have large receptive fields and relay pain intensity, whereas A-delta fibres are lightly myelinated, fast-conducting fibres that have small receptive fields and allow the initial perception of pain (Kendroud S 2023). The transmission mechanism of itch unfolds as a complex sensation transmitted by sensory neurons from the skin to the spinal cord and brain via these nerve nociceptive nerve fibres. Pruriceptors are sensory nerve endings or receptors that are particularly concentrated in the epidermis and dermis and are specifically dedicated to detecting and transmitting signals related to the sensation of itch. Once activated in the presence of specific stimuli (pruritogens), such as histamine, proteases, and cytokines, which are released by cells such as mast cells, keratinocytes, and immune cells, these proprioceptors send signals to the spinal cord, synapsing with second-order neurons that transmit the signal to the brain. The brain processes this signal, generating the unpleasant sensation of itch, prompting the irresistible urge to scratch. (Cevikbas & Lerner 2020; Lerner EA 2018) Skin cells such as keratinocytes and fibroblasts, which actively release pruritogens, can also contribute to the overall development of pruritus (Golpanian RS et al 2020). The multifactorial nature of itch pathophysiology encompasses intricate interactions between the immune system, environmental factors, and the neurobiological basis of pruritus. The exact cause of pruritus remains unknown; however, several pruritogens are suspected to trigger itching, including bile acids, histamine, serotonin, progesterone metabolites, endogenous opioids, lysophosphatidic acid (LPA), and the enzyme autotaxin (ATX) that forms LPA. (Kliegman RM 2019)

The burden of pruritus in children and the itch-scratch cycle

Pruritus in children, stemming from various causes including skin and systemic conditions, can significantly impact their well-being. Persistent itching can profoundly impact a child’s overall well-being and emotional state. The presence of itching in children with skin disorders like atopic dermatitis (AD) is linked to notable effects on mood, quality of life, sleep patterns, academic performance, and both social and family interactions. (Kang SY et al 2021) Chronic itching may result in disrupted sleep, heightened irritability, increased anxiety, depression, and impaired academic achievements. Furthermore, it can influence the child’s social interactions, strain family relationships, and elevate the risk of behavioural issues. (Kang SY et al 2021)

The itch-scratch cycle is a phenomenon that occurs in individuals with chronic pruritus. It is a vicious cycle in which itching leads to scratching, which in turn leads to more itching, and so on. Scratching can provide temporary relief from itching, but it can also damage the skin and exacerbate the underlying condition causing the itching. This damage to the skin can then lead to more itching, which leads to more scratching, and the cycle continues. (Sander KM and Akiyama T 2018) The itch-scratch cycle can be particularly problematic in individuals with chronic pruritus, as it can lead to significant skin damage, scarring, and even infection. The cycle can also hurt the quality of life, as it can interfere with sleep, work, and other daily activities. Breaking the itch-scratch cycle is an important goal of treatment for chronic pruritus, and may involve a combination of medications, topical therapies, and behavioral interventions. (Sander KM and Akiyama T 2018)

Diagnosis of pediatric pruritus

Atopic dermatitis, impetigo, insect bites, pruritus, psoriasis, seborrheic dermatitis, and urticaria are among the common skin diseases with itching observed in all age groups, including infancy (0-2 years), preschool (3-5 years), school-age (6-11 years), and adolescence (12-16 years); diaper dermatitis (infancy), popular urticaria (infancy and preschool), acne vulgaris (school and adolescence), xerosis (school and adolescence), and contact dermatitis (preschool, school-age, adolescence) are noted in specific age groups (Kang SY et al 2021). Therefore, an objective assessment of pruritus is essential for differentiating it from other skin diseases with itching (Kang SY et al 2021).

Chronic pruritus in pediatric patients requires a systematic approach for effective management, beginning with the identification of underlying causes, whether dermatologic or non-dermatologic. (Golpanian RS et al 2020) The diagnosis of pruritus, or itching, involves a thorough evaluation by a healthcare professional to identify the underlying cause. The diagnostic process typically includes several steps (Table 1).

Table 1. Steps involved in the diagnosis of pruritus

Diagnostic steps	Description
Medical history	Gather information on the duration, severity, and characteristics of itching, along with associated symptoms. Understanding the patient’s medical history and physical condition is crucial for identifying the root cause of pruritus in children and adolescents. This provides a detailed differential diagnosis, covering skin diseases, systemic conditions, drug reactions, and post-burn states.
Physical examination	Comprehensive assessment of the skin’s appearance and distribution of itching.
Skin biopsy	Obtain a small skin tissue sample for microscopic examination to identify underlying skin conditions.
Laboratory tests	Conduct blood tests to check for markers or systemic conditions associated with pruritus. Complete and differential blood counts play a pivotal role in elucidating hematologic causes, such as polycythemia vera or leukaemia. Additional blood tests may include assessment of levels of creatinine, blood urea nitrogen, liver function markers, iron, fasting glycemia, and thyroid-stimulating hormone.
Allergy testing	Perform patch tests, skin prick tests, or blood tests to identify specific allergens triggering itching. Distinguishing between allergic and non-allergic causes of pruritus is crucial for determining the appropriate treatment strategy—avoiding allergens or addressing other underlying factors.
Imaging studies	Order ultrasound or computed tomography scans to assess underlying structures if systemic diseases are suspected.
Dermatological tests	Conduct skin tests, such as patch tests, to identify allergens or irritants causing itching.
Scratch test	Lightly scratch the skin to observe responses and identify areas of increased sensitivity.
Review of medications	Review current medications to identify drugs known to cause pruritus as a side effect.
Psychological assessment	Explore potential psychological factors such as stress or anxiety contributing to pruritus.

The severity of pruritus can be assessed by using scales such as the Children’s Dermatology Life Quality Index and the ItchyQoL questionnaire (Godse K et al 2021; Kang SY et al 2021). The diagnosis of pruritus is often complex and may require collaboration between dermatologists, allergists, and other specialists, depending on the suspected underlying cause. Once the cause is identified, appropriate treatment and management strategies can be implemented.

Management of pediatric pruritus

A comprehensive strategy for managing pruritus in pediatric patients involves assessing the severity of itching using scales such as the Visual Analogue Scale (VAS) and the Dynamic Pruritus Score. Treatment options include topical and systemic therapies, with careful consideration given to age-related differences. (Godse K et al 2020) Symptomatic relief is achieved with bile acid-binding agents (cholestyramine), choleretic agents (ursodeoxycholic acid), opiate antagonists, antihistamines, serotonin reuptake inhibitors (sertraline), and antibiotics. (Kliegman RM 2019) The choice of treatment is tailored to each patient, considering the specific diagnosis, severity of itch, and individual patient preferences. Treatment options range from topical treatments for milder forms of itch to systemic treatments for more widespread and debilitating cases. (Golpanian RS et al 2020) A treatment algorithm for pruritus is illustrated in Figure 2.

Figure 2: Pruritus treatment algorithm

Topical therapies play a significant role, offering viable solutions for the management of topical pruritus. This includes the application of emollients, corticosteroids, and calcineurin inhibitors to address localized symptoms. (Godse K et al 2021) Patient education plays a pivotal role in managing the itch-scratch-itch cycle.

Therapeutic ladders have been proposed for the management of pediatric pruritus, based on the type of systemic pruritus (Gurnani P et al 2021).

Hepatic pruritus
- For mild cases, supportive care and oral antihistamines may suffice, followed by ursodeoxycholic acid and cholestyramine administered for mild-moderate cases. Moderate-severe and severe cases may require the administration of rifampicin, intravenous naloxone or oral naltrexone, inhalational butorphanol, and selective serotonin receptor inhibitors.
Pruritus associated with chronic kidney disease
- For mild cases, supportive care, topical treatments, and oral antihistamines may be used, and treatment with broadband UV-B phototherapy along with more potent topical corticosteroids may be considered if the severity is mild-moderate.
- For moderate-severe and severe cases, gabapentin or pregabalin, high-flux hemodialysis, oral naltrexone, and inhalational butorphanol may be needed.
Lymphoproliferative pruritus
- Handling mild cases of this type of pruritus in children is similar to mild cases of other types of pruritus—starting with supportive care and oral antihistamines.
- Low-dose antidepressants (e.g., mirtazapine) may be administered for children aged 10 years and above in mild-moderate cases, but gabapentin or pregabalin may be added to mirtazapine in moderate-severe cases.
- Severe cases can be treated with narrowband UV-B phototherapy, histone deacetylase inhibitors, and inhalational butorphanol.

Educational training programs and patient education leaflets, as formulated by experts, prove beneficial for both dermatologists and patients. Adjuvant therapies such as acupuncture, hypnosis, and cognitive therapy are reported in the literature, although evidence supporting their efficacy is limited. (Godse K et al 2021)

Antihistamines in pediatric pruritus

Despite not being licensed for pruritus, antihistamines are commonly used in its management, and so far, only H1 receptor antagonists have found a role in the treatment of pruritus and allergic diseases (Weisshar E et al 2019). Antihistamines are typically classified as sedative (first generation) or non-sedative (second generation). The first-line treatment for pruritus involves the use of oral antihistamines such as hydroxyzine, with up-dosing proving effective against pruritus. Modern antihistamines, such as bilastine and fexofenadine, have demonstrated efficacy at higher doses. (Godse K et al 2021; Kang SY et al 2021) Their effectiveness in non-histaminergic pruritus remains limited. (Golpanian RS et al 2020, Satoh T et al 2021) The first-generation antihistamine—hydroxyzine—has demonstrated favourable efficacy outcomes in managing pruritus linked to urticaria, atopic dermatitis, and other pruritic non-inflammatory dermatoses. (Godse K et al., 2021)

Hydroxyzine

Hydroxyzine is an H1 receptor antagonist, competitively inhibiting histamine action. This mechanism plays a crucial role in mitigating the inflammatory response linked to allergic reactions, ultimately reducing pruritus. According to the European guidelines on chronic pruritus, hydroxyzine is recommended as the initial treatment for pruritus arising from various causes due to its antipruritic, anxiolytic, and sedative properties (Weisshaar E et al 2021). Hydroxyzine was first approved for use in the United States in 1957 and remains extensively utilized to this day, marking over seven decades of continuous usage. (NIDDKD 2017) Hydroxyzine is approved in 22 Member States of the EU (Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Luxembourg, Malta, Netherlands, Poland, Portugal, Slovakia, Spain, Sweden, and United Kingdom) plus Norway and Iceland. Approved uses vary between countries and include treatment of anxiety disorders, relief from pruritus, premedication before surgery, and treatment of sleep disorders. (European Medicines Agency 2015) In 2010, the Central Drug Standard Control Organization (CDSCO) in India approved the utilization of hydroxyzine in the treatment of pruritus. (CDSCO)
It comes in various generic formulations and is sold under the brand names Atarax and Vistaril, in the form of tablets or capsules ranging from 10, 25, 50, and 100 mg. Hydroxyzine is available in the form of oral suspension, syrup, and liquid injection. (NIDDKD 2017) According to the Nelson Textbook of Pediatrics, the recommended dose of hydroxyzine for pruritis is 0.5-1 mg/kg administered every 6 hours via intravenous or oral route, with a maximum daily dosage of 600 mg. (Kliegman RM 2019)

Evidence on efficacy

A real-world multicenter study evaluating the efficacy of hydroxyzine in patients with chronic pruritus due to dermatological causes in India (N=400) showed that there was a significant improvement in baseline DLQI and 5-D itch scores at 2 and 12 weeks after treatment with the drug, with almost half of the study population terminating the study early due to symptom relief. (Thomas J et al. 2019)

Comparison of hydroxyzine with other treatment options

Alternative treatment options for pruritus in young children include topical antihistamines administered through creams or lotions, offering targeted relief for pruritic skin conditions while minimizing systemic exposure and potential central nervous system effects. (Gober H J et al 2022) Additionally, topical corticosteroids are commonly employed to alleviate itching and inflammation associated with dermatologic conditions such as atopic dermatitis in pediatric patients. Studies of newer, nonsedating antihistamines have shown variable effectiveness in controlling pruritus in AD, although they may be useful in a small subset of patients with AD and concomitant urticaria. (Kliegman RM 2019) Emollients and moisturizers, when used regularly, can help maintain skin hydration, reducing pruritus in children with dry or eczematous skin. It is crucial to identify and address potential triggers of pruritus, such as allergens or irritants, to manage the underlying cause of the itching effectively. Lastly, behavioural interventions such as habit reversal training may prove beneficial in managing pruritic behaviours in children, especially in cases where scratching exacerbates the condition. This comprehensive approach aims to provide relief while considering the specific needs and sensitivities of young children. (Gober H J et al 2022)

An Indian expert consensus highlighted the superior efficacy of hydroxyzine compared to neuroleptics such as thiothixene, chlorpromazine, and thioridazine in reducing histamine-induced pruritus, emphasizing hydroxyzine’s specific effectiveness in addressing pruritus associated with histamine release. (Rajagopalan M et al 2017) A randomized, double-blind study comparing the safety and efficacy of hydroxyzine, the tricyclic antidepressant doxepin, and the second-generation antihistamine cetirizine in patients with pruritus due to sulfur mustard (N=75) showed that all three drugs were equally effective in reducing pruritus scores in the patients and controlling the symptoms of chronic pruritus, but hydroxyzine was more effective than cetirizine, though not significantly, in reducing the mean pruritus scores (-20.6 with hydroxyzine vs -13.4 with cetirizine; p=0.057) (Shohrati M et al. 2007). In another study comparing the efficacy of hydroxyzine against Avena sativa and diluted vinegar in hemodialysis patients with uremic pruritus (N=23), a type of pruritus associated with chronic kidney disease, significant improvements were seen with all three drugs in the pruritus and VAS scores, and the authors suggested that Avena sativa and diluted vinegar could be used together with hydroxyzine to achieve synergistic effects (Nakhaee S et al. 2015).
It is noteworthy that there have been no clinical studies on the use of hydroxyzine in pediatric patients with pruritus in India. Given the potential variability in treatment practices and the need for region-specific evidence, there is a pressing need for research studies in India to further investigate the safety and efficacy of hydroxyzine in managing pruritus among pediatric populations.

Top of Form

Hydroxyzine in nocturnal pruritus

Chronic nocturnal itching in children poses significant challenges, with atopic dermatitis and psoriasis being the primary concerns. Poor sleep quality is associated with adverse neurocognitive, behavioural, and physiologic outcomes in children, including poor school performance, attention deficit hyperactivity disorder, short stature, hypertension, obesity, and impaired immune function. (Boozalis E et al 2018). Short-term and intermittent courses of sedating (first-generation) antihistamines can be used in children if they strongly affect the quality of sleep. (Gurnani P et al 2021; Hachem ME 2021) Pruritus is usually worse at night, and sedating antihistamines (hydroxyzine, diphenhydramine) may offer an advantage when used at bedtime given their soporific side effects. According to the Nelson Textbook of Pediatrics, short-term use of a sedative to allow adequate rest may be appropriate in cases of severe nocturnal pruritus. (Kliegman RM 2019) Since hydroxyzine can also bind to muscarinic and alpha-adrenergic receptors, anticholinergic and other adverse effects can occur. The sedative nature of hydroxyzine offers potential benefits for alleviating nighttime discomfort associated with pruritus. This aspect becomes particularly relevant in improving the overall sleep quality of patients. Non-sedating second-generation antihistamines such as cetirizine may serve as alternatives for daytime relief. (Patel & Yosipovitch 2010) Administered orally, hydroxyzine exhibits rapid absorption from the gastrointestinal tract. The onset of sedation typically occurs within 15–30 minutes after administration, providing timely relief for patients experiencing pruritus-related discomfort. (Malamed 2010)

Evidence on safety

A population-based longitudinal study on children who received hydroxyzine (N=24,371) showed that when comparing repeat prescriptions to a single prescription of hydroxyzine, there is an increase in the likelihood of tic disorder (OR=1.55; 95%CI: 1.23–1.96), anxiety (OR=1.34; 95%CI: 1.05–1.70), and disturbance of conduct (OR=1.34; 95%CI: 1.08–1.66) in children up to the age of 10 years. (Gober H J et al 2022). While these results suggest an association between repeat hydroxyzine prescriptions and certain psychiatric outcomes, the study acknowledges the need for further research to establish a causal relationship between hydroxyzine and neurodevelopmental outcomes in early childhood (Gober H J et al 2022). Currently, there is a lack of data regarding the use of hydroxyzine and its prescription patterns in pediatric patients, especially in India. No severe adverse events have been reported. Dizziness is a mild adverse event most commonly reported by patients within 4–6 weeks. (Shohrati M et al. 2007; Thomas J et al. 2019) However, the long-term safety of hydroxyzine in the pediatric population needs additional research. Given the sedative nature of hydroxyzine, driving or operating a machine is indicated as a label warning. However, in a case-control study among drivers involved in injurious road traffic accidents in France (N=142,771), long-term use of the drug had no effect on the risk (adjusted OR: 0.79) of being involved in accidents among drivers without long-term psychiatric disorders who had high exposure levels of hydroxyzine. (Orriols L 2017) As per the American Association of Psychiatric Pharmacists (AAPP), there are no known adverse effects associated with the long-term use of hydroxyzine. It is a safe and effective medication when used as directed. (AAPP 2016) The product information leaflet acknowledges the possibility of eye irritation after short-term use, but no long-term safety data are available (Pfizer 2007) Hydroxyzine use for managing pruritus in patients with liver disease is typically safe and has not been linked to liver test abnormalities or clinically apparent liver injury, which could be because of the low daily dose and limited duration of use. (NIDDKD 2017)

Conclusion

Pruritus significantly impacts a child’s well-being, mood, quality of life, sleep, academic performance, and social interactions. It can be caused by both dermatological conditions and systemic diseases in children. The systematic evaluation of pediatric pruritus involves a thorough history, focused skin examination, and additional laboratory tests. Evaluating the severity through scales such as VAS directs treatment, spanning from overall care to the application of topical and systemic therapies. Antihistamines, such as hydroxyzine, are considered first-line treatments for pruritus. The sedative nature of hydroxyzine can benefit children with nocturnal itching and improve their sleep quality. Effective pruritus management often requires a multidisciplinary approach, involving collaboration among pediatricians, dermatologists, and psychologists. A comprehensive management strategy encompasses patient education, adjuvant therapies, and the application of a therapeutic ladder approach.

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