Drug-induced pruritus
DOI:
https://doi.org/10.2478/amb-2026-0047Keywords:
itch, pruritus, medications, drugs, ADRAbstract
Abstract. Drug-induced pruritus is a common problem in daily medical practice. Many drugs can cause pruritus after systemic or topical administration, but often the exact mechanism underlying the pathogenesis of itching caused by drugs remains unclear. Therefore, the diagnosis and treatment of drug-induced pruritus are challenging. In the present review, the current knowledge of the most common medications inducing itch with or without skin rash and their underlying mechanisms is summarized. Opioids can cause pruritus, especially if they are administered intrathecally. Some antineoplastic agents can frequently cause intense pruritus due to immune-related cutaneous reactions (immune checkpoint inhibitors) or via triggering hypersensitivity reactions (taxanes) in cancer patients. Recently, it was found that MAS-related G protein-coupled receptor X2 (MRGPRX2), expressed on mast cells in humans, is responsible for drug-induced non-histaminergic pruritus and pseudoallergic reactions.
References
Reich A, Ständer S, Szepietowski JC. Drug-induced pruritus: a review. Acta Derm Venereol, 2009, 89(3):236-244.
Bagatin E, Costa CS. Antihistamines reduce isotretinoin-induced pruritus. Int J Dermatol, 2024, 63(7):839-840.
Sibaud V. Dermatologic Reactions to Immune Checkpoint Inhibitors: Skin Toxicities and Immunotherapy. Am J Clin Dermatol, 2018, 19(3):345-361.
Eshaq AM, Flanagan TW, Ba Abbad AA, et al. Immune Checkpoint Inhibitor‑Associated Cutaneous Adverse Events: Mechanisms of Occurrence. Int J Mol Sci, 2024, 26(1):88.
Beuers U, Wolters F, Oude Elferink RPJ. Mechanisms of pruritus in cholestasis: understanding and treating the itch. Nat Rev Gastroenterol Hepatol, 2023, 20(1):26-36.
Kremer AE, Mettang T, Weisshaar E. Non-dermatological Challenges of Chronic Itch. Acta Derm Venereol, 2020, 100(2):adv00025.
Yosipovitch G, Misery L, Proksch E, et al. Skin Barrier Damage and Itch: Review of Mechanisms, Topical Management and Future Directions, Acta Derm Venereol, 2019, 99(13):1201‑1209.
Di Bartolomeo L, Irrera N, Campo GM, et al. Drug-Induced Photosensitivity: Clinical Types of Phototoxicity and Photoallergy and Pathogenetic Mechanisms. Front Allergy, 2022, 3:876695.
Butler DC, Berger T, Elmariah S, et al. Chronic Pruritus: A Review. JAMA, 2024, 331(24):2114-2124.
Papier A, Strowd LC. Atopic dermatitis: a review of topical nonsteroid therapy. Drugs Context, 2018, 7:212521.
Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp Dermatol, 2010, 35(1):2-6.
Benson JL, Campbell HE, Phillips CN. Opioid-induced pruritus. Consult Pharm, 2015, 30(4):221-7.
Kim BS, Inan S, Ständer S, et al. Role of kappa-opioid and mu‑opioid receptors in pruritus: Peripheral and central itch circuits. Exp Dermatol, 2022, 31(12):1900-1907.
Thomas DA, Williams GM, Iwata K, et al. The medullary dorsal horn. A site of action of morphine in producing facial scratching in monkeys. Anesthesiology, 1993, 79(3):548-54.
Wang Z, Jiang C, Yao H, et al. Central opioid receptors mediate morphine‑induced itch and chronic itch via disinhibition. Brain, 2021, 144(2):665-681.
Okutani H, Lo Vecchio S, Arendt-Nielsen L. Mechanisms and treatment of opioid‑induced pruritus: Peripheral and central pathways. Eur J Pain, 2024, 28(2):214-230.
Togashi Y, Umeuchi H, Okano K, et al. Antipruritic activity of the kappa-opioid receptor agonist, TRK-820. Eur J Pharmacol, 2002, 435(2-3):259-64.
Charuluxananan S, Kyokong O, Somboonviboon W, et al. Nalbuphine versus ondansetron for prevention of intrathecal morphine‑induced pruritus after cesarean delivery. Anesth Analg, 2003, 96(6):1789-1793.
Tubog TD, Harenberg JL, Buszta K, et al. Use of Nalbuphine for Treatment of Neuraxial Opioid‑Induced Pruritus: A Systematic Review and Meta-Analysis. AANA J, 2019, 87(3):222230.
Inan S, Dun NJ, Cowan A. Antipruritic Effect of Nalbuphine, a Kappa Opioid Receptor Agonist, in Mice: A Pan Antipruritic. Molecules, 2021, 26(18):5517.
Moustafa AA, Baaror AS, Abdelazim IA. Comparative study between nalbuphine and ondansetron in prevention of intrathecal morphine‑induced pruritus in women undergoing cesarean section. Anesth Essays Res, 2016, 10(2):238-44.
Sheen MJ, Ho ST, Lee CH, et al. Preoperative gabapentin prevents intrathecal morphine‑induced pruritus after orthopedic surgery. Anesth Analg, 2008, 106(6):1868-72.
Bussaratid V, Walsh DS, Wilairatana P, et al. Frequency of pruritus in Plasmodium vivax malaria patients treated with chloroquine in Thailand. Trop Doct, 2000, 30(4):211-4.
Ballut PC, Siqueira AM, Orlando AC, et al. Prevalence and risk factors associated to pruritus in Plasmodium vivax patients using chloroquine in the Brazilian Amazon. Acta Trop, 2013, 128(3):504-8.
Jiménez-Alonso J, Tercedor J, Reche I. Grupo Lupus Virgen de las Nieves. Antimalarial drugs and pruritus in patients with lupus erythematosus. Acta Derm Venereol, 2000, 80(6):458.
Ademowo OG, Sodeinde O. Certain red cell genetic factors and prevalence of chloroquine-induced pruritus. Afr J Med Med Sci, 2002, 31(4):341-343.
Ajayi AA, Kolawole BA, Udoh SJ. Endogenous opioids, muopiate receptors and chloroquine‑induced pruritus: a double-blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine-induced itching. Int J Dermatol, 2004, 43(12):972‑977.
Onigbogi O, Ajayi AA, Ukponmwan OE. Mechanisms of chloroquine‑induced body‑scratching behavior in rats: evidence of involvement of endogenous opioid peptides. Pharmacol Biochem Behav, 2000, 65(2):333-7.
Zhu J, Yang Y, Du L, et al. A regulatory role of the medial septum in the chloroquine‑induced acute itch through local GABAergic system and GABAergic pathway to the anterior cingulate cortex. Biochem Biophys Res Commun, 2024, 721:150145.
Ostadhadi S, Foroutan A, Haddadi NS, et al. Pharmacological evidence for the involvement of adenosine triphosphate sensitive potassium channels in chloroquine‑induced itch in mice. Pharmacol Rep, 2017, 69(6):1295-1299.
Metze D, Reimann S, Szepfalusi Z, Bohle B, Kraft D, Luger TA. Persistent pruritus after hydroxyethyl starch infusion therapy: a result of long-term storage in cutaneous nerves. Br J Dermatol, 1997, 136(4):553-559.
Ständer S, Richter L, Osada N, Metze D. Hydroxyethyl starch-induced pruritus: clinical characteristics and influence of dose, molecular weight and substitution. Acta Derm Venereol. 2014, 94(3):282-287.
Bork K. Pruritus precipitated by hydroxyethyl starch: a review. Br J Dermatol, 2005, 152(1):3-12.
Ständer S, Bone HG, Machens HG, et al. Hydroxyethyl starch does not cross the blood‑brain or the placental barrier but the perineurium of peripheral nerves in infused animals. Cell Tissue Res, 2002, 310(3):279-287.
Ständer S, Szépfalusi Z, Bohle B, et al. Differential storage of hydroxyethyl starch (HES) in the skin: an immunoelectron-microscopical long-term study. Cell Tissue Res. 2001, 304(2):261‑269.
Kamann S, Flaig MJ, Korting HC. Hydroxyethyl starch-induced itch: relevance of light microscopic analysis of semi-thin sections and electron microscopy. J Dtsch Dermatol Ges, 2007, 5(3):204-208.
Reimann S, Szépfalusi Z, Kraft D, et al. Hydroxyethylstärke Speicherung in der Haut unter besonderer Berücksichtigung des Hydroxyethylstärke-assoziierten Juckreizes [Hydroxyethyl starch accumulation in the skin with special reference to hydroxyethyl starch-associated pruritus]. Dtsch Med Wochenschr, 2000, 125(10):280-285.
Szeimies RM, Stolz W, Wlotzke U, Korting HC, et al. Successful treatment of hydroxyethyl starch‑induced pruritus with topical capsaicin. Br J Dermatol, 1994, 131(3):380-2.
Brune A, Metze D, Luger TA, et al. Antipruritische Therapie mit dem oralen Opiatrezeptorantagonisten Naltrexon. Offene, nicht placebokontrollierte Anwendung bei 133 Patienten [Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133 patients]. Hautarzt, 2004, 55(12):1130-1136.
Bhardwaj M, Chiu MN, Pilkhwal Sah S. Adverse cutaneous toxicities by PD-1/PD-L1 immune checkpoint inhibitors: pathogenesis, treatment, and surveillance. Cutan Ocul Toxicol, 2022, 41(1):73-90.
Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol. 2020 Nov, 83(5):1255-1268.
Muntyanu A, Netchiporouk E, Gerstein W, et al. Cutaneous Immune‑Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management. J Cutan Med Surg. 2021, 25(1):59-76.
Bayrak Durmaz MS, Unutmaz DG, Demir M, et al. Hypersensitivity Reactions to Taxanes: A Multicenter Study for Outcomes and Safety of Rapid Drug Desensitization. Allergy Asthma Immunol Res. 2024, 16(2):142-153.
Tsao LR, Young FD, Otani IM, et al. Hypersensitivity Reactions to Platinum Agents and Taxanes. Clin Rev Allergy Immunol. 2022, 62(3):432-448.
Villarreal-González RV, González-Díaz S, Vidal-Gutiérrez O, et al. Hypersensitivity Reactions to Taxanes: A Comprehensive and Systematic Review of the Efficacy and Safety of Desensitization. Clin Rev Allergy Immunol, 2023, 65(2):231-250.
Shenoy ES, Macy E, Rowe T, et al. Evaluation and Management of Penicillin Allergy: A Review. JAMA, 2019, 321(2):188199.
Asyraf PA, Kusnadi IF, Stefanus J, et al. Clinical Manifestations and Genetic Influences in Sulfonamide-Induced Hypersensitivity. Drug Healthc Patient Saf, 2022, 14:113-124.
Romano A, Gaeta F, Caruso C, et al. Evaluation and Updated Classification of Acute Hypersensitivity Reactions to Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAID-Exacerbated or -Induced Food Allergy. J Allergy Clin Immunol Pract, 2023, 11(6):1843-1853.e1.
Bianchi L, Hansel K, Biondi F, et al. Delayed hypersensitivity reactions to iodinated contrast media: A diagnostic approach by skin tests. Contact Dermatitis, 2023, 89(5):352-358.
Kelesidis T, Fleisher J, Tsiodras S. Anaphylactoid reaction considered ciprofloxacin related: a case report and literature review. Clin Ther, 2010, 32(3):515-526.
Hamamura-Yasuno E, Matsushita J, Sato S, et al. Determination of key residues in MRGPRX2 to enhance pseudo‑allergic reactions induced by fluoroquinolones. Sci Rep, 2022; 12(1):6650.
Liu R, Hu S, Zhang Y, et al. Mast cell-mediated hypersensitivity to fluoroquinolone is MRGPRX2 dependent. Int Immunopharmacol, 2019, 70:417-427.
McNeil BD. MRGPRX2 and Adverse Drug Reactions. Front Immunol, 2021, 12:676354.
Yegit OO, Gelmez MY, Demir S, et al. Diagnosis of ciprofloxacin hypersensitivity improves by incorporating MRGPRX2 in basophil activation test. Allergy Asthma Proc, 2025, 46(3):247‑256.
Elst J, Maurer M, Sabato V, et al. Novel Insights on MRGPRX2-Mediated Hypersensitivity to Neuromuscular Blocking Agents And Fluoroquinolones. Front Immunol, 2021, 12:668962.
Van Gasse AL, Elst J, Bridts CH, et al. Rocuronium Hypersensitivity: Does Off-Target Occupation of the MRGPRX2 Receptor Play a Role? J Allergy Clin Immunol Pract, 2019, 7(3):998‑1003.
Lyu S, Oliver ET, Dispenza MC, et al. A Skin Testing Strategy for Non‑IgE‑Mediated Reactions Associated With Vancomycin. J Allergy Clin Immunol Pract, 2024, 12(11):3025-3033.e6.
Paus R, Schmelz M, Bíró T, et al. Frontiers in pruritus research: Scratching the brain for more effective itch therapy. J Clin Investig, 2006, 116, 1174-1185.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 G. Bocheva, J. C. Szepietowski, A. Reich (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
You are free to share, copy and redistribute the material in any medium or format under these terms.
Journal Acta Medica Bulgarica 
