Abstract Introduction and aims Pruritus is a debilitating symptom across dermatological and systemic diseases, and conventional therapies often provide incomplete relief. The µ-opioid receptor pathway is a key regulator of itch. A range of µ-pathway-modulating agents are used off-label for refractory pruritus. This review aimed to systematically evaluate the efficacy, safety, and real-world use of µ-opioid pathway modulators for pruritus of dermatological and systemic origin. Methods We conducted a systematic review following PRISMA guidelines (PROSPERO CRD420251207101), with a comprehensive search of four databases. Results were narratively synthesized owing to heterogeneity. Results Of 3274 records identified, 69 studies met inclusion criteria: 14 randomized controlled trials (RCTs) (n = 795) and 55 nonrandomized studies (n = 351). Five RCTs evaluated dermatological conditions (atopic dermatitis, prurigo nodularis, chronic urticaria, and lichen planopilaris), while 9 RCTs evaluated systemic pruritus, predominantly cholestatic pruritus and uraemic pruritus. RCTs (1980–2023) assessed oral or topical naltrexone, intravenous naloxone, nalmefene and nalbuphine extended release. Most RCTs demonstrated clinically meaningful reductions in pruritus severity, measured using validated itch scales visual analogue scale, numeric rating scale (NRS) or worst itch NRS, with the strongest evidence observed in atopic dermatitis, cholestatic pruritus, and uraemic pruritus. Nonrandomized studies (1979–2024) included 199 dermatological and 152 systemic cases, reporting improvement across conditions such as Hailey–Hailey disease, Darier disease, psoriasis, dermatomyositis, chronic pruritus, postburn pruritus, systemic sclerosis and cholestatic disease. Adverse events were mostly mild and tolerated. Conclusions µ-Opioid pathway modulators demonstrate promising efficacy with acceptable short-term safety across a broad spectrum of pruritic conditions. Evidence from randomized trials is strongest for naltrexone and nalmefene in cholestatic pruritus, naltrexone in atopic dermatitis and chronic urticaria, and nalbuphine in uraemic pruritus. In addition, signals of benefit from nonrandomized and real-world studies suggest potential utility across a wider range of dermatological and systemic conditions. Larger, high-quality RCTs are needed to define optimal dosing and support further clinical translation.
Ahmed et al. (Tue,) studied this question.