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Drug-Induced Pruritus: a Review

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Drug-Induced Pruritus: a Review Acta Derm Venereol 2009; 89: 236–244 REVIEW ARTICLE Drug-induced Pruritus: A Review Adam REICH1, Sonja STÄNDER2 and Jacek C. SZepietowsKI1,3 1Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, 2Clinical Neurodermatology, Department of Dermatology, University Hospital of Münster, Germany, and 3Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland Pruritus is an unpleasant sensation that leads to scrat- polate to drugs that are prescribed mainly in outpatient ching. In addition to several diseases, the administration clinics, as only inpatients were analysed. In another of drugs may induce pruritus. It is estimated that pru- study on skin reactions due to antibacterial agents used ritus accounts for approximately 5% of all skin adverse in 13,679 patients treated by general practitioners, reactions after drug intake. However, to date there has cutaneous adverse effects were reported in 135 (1%) been no systematic review of the natural course and pos- subjects, and general pruritus accounted for 13.3% of sible underlying mechanisms of drug-induced pruritus. these reactions (4). In a recent analysis of 200 patients For example, no clear distinction has been made between with drug reactions, 12.5% showed pruritus without acute or chronic (lasting more than 6 weeks) forms of skin lesions (5). However, only a few drugs have been pruritus. This review presents a systematic categoriza- analysed more carefully in relation to pruritus, mainly tion of the different forms of drug-induced pruritus, with antimalarials, opioids, and hydroxyethyl starch (see special emphasis on a therapeutic approach to this side- below). Furthermore, analysing the available data on effect. Key words: itch; pruritus; chronic; medication; other drugs, it is sometimes very difficult to distinguish side-effects. between “pure” drug-induced pruritus and symptomatic pruritus accompanying, for example, drug-induced (Accepted January 19, 2009.) urticaria or lichenoid eruptions (1, 6, 7). Acta Derm Venereol 2009; 89: 236–244. The natural course of drug-induced pruritus depends on the drug applied and is not stereotypical. Drug- Adam Reich, Department of Dermatology, Venereology induced pruritus may be acute (lasting only several and Allergology, Wroclaw Medical University, Ul. T. days) or chronic (longer duration for weeks or months). Chalubinskiego 1, PL-50-368 Wroclaw, Poland. E-mail: It may start with the first drug administration or may [email protected] be delayed in time. For instance, in case of liver dys- function, pruritus usually appears several weeks after Pruritus is an unpleasant sensation that leads to intensive the start of the treatment (8–11), although it was also scratching (1). Chronic pruritus (lasting longer than 6 reported after relatively short-term therapy periods (12). weeks) is the most common symptom in dermatology Drug-induced pruritus can be localized or generalized and can occur with or without visible skin lesions. Vari- (1, 6, 13), and may resolve shortly after drug disconti- ous skin and systemic diseases have been characterized nuation (14) or may persist even for several months or to be associated with the presence of pruritus, and dif- years after treatment withdrawal (15–17). ferent mechanisms have been proposed to explain its The pathogenesis of drug-induced pruritus differs origin (1, 2). depending upon the causative agent. Pruritus may be We present herein a detailed literature review in order secondary to drug-induced skin lesions, but a number to analyse the frequency and course of drug-induced of other possible mechanisms of drug-induced pruritus pruritus, describe the most frequent drugs inducing have been postulated, including cholestatic liver injury, acute and chronic pruritus, and present a new systematic xerosis of the skin, deposits of drugs or their metabolites categorization of the different forms of drug-induced in the skin, phototoxicity, or neurological alterations. pruritus, with special emphasis on a therapeutic ap- Often, the underlying mechanism is not known (18). proach to this side-effect. CATEGORIES OF DRUG-INDUCED PRURITUS GENERAL CONSIDERATIONS Summarizing our literature research, for some drugs The prevalence of drug-induced pruritus has not been a clear time-relation has been described and interrup- studied well so far. In one large epidemiological study tion of the drug leads to cessation of pruritus. Pruritus it has been shown that, among hospitalized patients, usually lasts less than 6 weeks in this group, fulfilling pruritus without concomitant skin lesions accounted the definition of acute pruritus. In other drugs, pruritus for approximately 5% of adverse reactions after drug lasts much longer due to the underlying mechanisms. intake (3). However, these data are difficult to extra- For example, in hydroxyethyl starch (HES)-induced Acta Derm Venereol 89 © 2009 The Authors. doi: 10.2340/00015555-0650 Journal Compilation © 2009 Acta Dermato-Venereologica. ISSN 0001-5555 Drug-induced pruritus 237 pruritus, neuronal storage of the substance evokes may suffer from generalized itching (64, 65, 139). pruritus, which slowly relieves after degradation of Chloroquine-induced pruritus is the most common the substance. This can be grouped as chronic pruri- adverse drug reaction experienced by Black Africans, tus, since it lasts for more than 6 weeks. In addition, and negatively affects compliance with antimalarial many drugs are described to induce chronic pruritus by therapy (62). It has been shown that more than 10% unknown mechanisms. In this group of drug-induced of pregnant women avoided malaria chemoprophylaxis pruritus, therapy is very difficult, including the decision with chloroquine due to the fear of pruritus (67). An- to interrupt or change the drug prescription. According other study on antenatal patients documented that the to our experience, interruption for at least 6 weeks is frequency of pruritus with chloroquine was the only necessary to prove that chronic pruritus is due to the factor that correlated with the continuation of the use accused drug. In sum, several groups of drug-induced of this drug for malaria (140). pruritus can be defined, as summarized in Table I. Pruritus was also reported after other antimalarials, The most important groups of drugs that might be such as amodiaquine, halofantrine and hydroxychloro- responsible for pruritus are listed in Table II. However, quine, although less commonly and with lower intensity these data must be considered with some caution, as it is (68–71). Frequently, aquagenic or post-wetness type almost impossible to mention all drugs that could evoke of pruritus without visible skin lesions was observed, itching. Pruritus is most often mentioned as a complica- usually located in the lower extremities and back (71). tion after systemic drugs. However, pruritus may also It appeared approximately 1–3 weeks after initiation accompany local skin or mucous membrane reaction of treatment and developed mainly after hot showers, after topical application of different medicines, e.g. beginning within minutes of water contact, persisting at ciprofloxacin (132) or calcineurin inhibitors (133). a high intensity for several minutes, and then remaining at low intensity for several hours (71). The pathogenesis of chloroquine-induced pruritus ACUTE PRURITUS remains unclear. Genetic background seems to be a Pruritus induced by chloroquine and other antimalarials strong predisposing factor, as this symptom is observed mainly in Black Africans. Chloroquine has been shown Chloroquine, a widely used anti-malarial agent, may to release histamine, and antihistamic drugs have been produce pruritus of unknown mechanism in up to 60– demonstrated to be effective in a subgroup of patients 70% of Black Africans (61–64). This type of pruritus (61, 62, 72). Severity of pruritus also correlated with has been considered as severe in almost 60% of pruritic the antecedent malaria parasite density in the blood subjects (62–64). Interestingly, chloroquine-induced (61). Furthermore, there was a reduced frequency of the pruritus is uncommon in Caucasian or Asian people sickle cell trait among itchers relative to non-itchers, (65, 66). In the study by Bussaratid et al. (65) among while glucose-6-phosphate dehydrogenase deficiency Thailand’s population only 1.9% of over 1000 malaria was more common among pruritics than non-pruritics patients experienced pruritus due to chloroquine (141). In addition, it was suggested that subjects with therapy. Regarding Black Africans, pruritus appeared pruritus may present slower metabolism of chloroquine, mainly in young patients (< 40 years of age) and the leading to higher plasma concentrations of chloroquine, majority of patients experienced the onset of itching although the overall pharmacokinetic patterns were within the first 24 h after chloroquine ingestion (64). comparable in both pruritic and non-pruritic patients Pruritus lasted longer than 48 h after the last dose of (73, 74). Another possibility is mediation of pruritus chloroquine in nearly half of the patients (64). The in malaria individuals by endogenous opioid peptides longest duration for chloroquine-induced pruritus via μ-opioid receptors (62, 75). Based on these data, was 7 days (139). Chloroquine-induced pruritus may it seems that chloroquine-induced pruritus should be be limited to the hands and feet, while other subjects considered as a multifactorial phenomenon. Table I. Drug-induced pruritus (without
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