Dapsone, the sulfone drug that has anchored leprosy treatment since the 1940s, remains the most commonly used drug for the disease, yet its benefits come with a pharmacological price. A review traces how this long-standing medicine, once hailed as a miracle drug, developed resistance problems at low doses, regained effectiveness through combination therapy, and continues to cause well-documented side effects including hemolytic anemia, methemoglobinemia and a potentially fatal hypersensitivity syndrome.
Dapsone was the first drug systematically studied for leprosy and became the gold standard monotherapy for decades after its introduction in the 1940s. Developed initially in the early 1900s for German dye industries, its antimicrobial properties were not recognized until the 1930s. However, reports of antimicrobial resistance gradually increased in the following decades, particularly because dapsone was prescribed at low dosages intended to reduce the risk of dapsone-induced hypersensitivity.
The reintroduction of dapsone at higher doses as part of combination therapy since the 1980s has contributed to a decline in its antimicrobial resistance. According to WHO multi-country surveys, 6.8 percent of new or primary leprosy cases from 2009 to 2015 and 2.5 percent from 2016 to 2019 showed dapsone resistance. Among relapse or secondary cases, 3.9 percent from 2009 to 2015 and 2.2 percent from 2016 to 2019 reported dapsone resistance. At present, dapsone resistance does not directly impact leprosy treatment unless concomitant resistance against rifampicin and clofazimine is present, and clofazimine resistance has rarely been reported.
Dapsone works by binding a bacterial enzyme called 6-hydroxymethyl-7,8-dihydropteroate synthase, or DHPS, which is encoded by the folp1 gene in Mycobacterium leprae. Molecular docking studies have shown that the second loop of DHPS, spanning amino acids 48 to 60, plays a critical role in stabilizing the drug-enzyme interaction.
After oral administration, roughly 86 percent is rapidly absorbed in the intestine, with excretion primarily through urine. Average steady-state blood concentrations at peak and trough reach 2,200 and 1,000 nanograms per milliliter respectively after a 100-milligram oral dose. In mouse foot pad studies, at least 99.4 percent of approximately one million M. leprae bacilli grown in mouse foot pads were killed after just seven days of dapsone treatment at 0.1 g per 100 g of mouse chow.
In red blood cells, N-hydroxy dapsone oxidizes the ferrous iron in oxyhemoglobin to the ferric state, forming methemoglobin, which binds oxygen with high affinity and cannot release it to tissues. Methemoglobin concentrations up to 15 percent have no clinical consequences, but higher levels produce peripheral and central cyanosis at 15 to 30 percent, headache and fatigue at 30 to 45 percent, seizures and coma above 60 percent, and death above 70 percent.
Most cases fall under the DRESS category of drug hypersensitivity, involving systemic symptoms alongside drug-induced skin rashes, with a mortality rate of approximately 10 percent. The worldwide prevalence of DHS varies dramatically by geography, with Indonesia demonstrating a very high prevalence of approximately 10 percent among dapsone users while Brazil, despite being the second-highest reporter of annual new leprosy cases, reports relatively few cases. This variation is now largely explained by the distribution of a human leukocyte antigen variant called HLA-B*13:01, which was shown to be a significant risk factor for DHS and has been repeatedly validated across multiple studies.
The review’s authors conducted their own analysis of HLA-B*13:01 prevalence using data from the Allele Frequency Net Database, finding that Oceania had the highest prevalence at 7.85 percent, followed by South-East Asia at 6.83 percent and South Asia at 1.77 percent. Europe showed the lowest prevalence at 0.1 percent, with a worldwide estimate of 1.1 percent. However, a meta-analysis showed that approximately 15 percent of HLA-B*13:01 non-carriers were still allergic to dapsone, and approximately 15 percent of carriers were non-allergic, suggesting that additional factors, including a specific T-cell receptor repertoire, are required for the syndrome to develop.
Historical patterns suggest that DHS may be dose-dependent. The number of DHS cases decreased after the 1950s, which has been speculated to be due to the reduction of dapsone dosage from 300 milligrams to usually less than 100 milligrams and less frequent than daily dosing to prevent DHS reactions, and cases reemerged after the introduction of multidrug therapy in 1982, when dosages were re-increased to daily 100 milligrams.
No standardized preventative screening tests are currently available in markets where leprosy remains prevalent, although laboratories with PCR facilities may be able to detect HLA-B*13:01 before treatment begins. The review notes that most new leprosy cases are not diagnosed by dermatologists, and general health staff may lack experience with dapsone’s severe side effects, creating dangerous delays between symptom onset and drug cessation. While highly potent drugs such as telacebec (at the preclinical stage) and bedaquiline (in short-term follow-up) have demonstrated promising safety profiles, the authors note that longer-term follow-up in larger populations is essential to confirm these findings, and that it is uncertain whether the mass use of any other new drug might not reveal other hitherto unknown side effects.
Subject of Research: The pharmacology, antimicrobial resistance and adverse effects of the antileprosy drug dapsone
Article Title: Pharmacological and safety profile of the long-standing antileprosy drug dapsone
Article References: Rana, D. R. S. J. B., Hagge, D. A., Shah, M., Aryal, B., Manandhar, S., Singh, A., & Joshi, J. R. (2026). Pharmacological and safety profile of the long-standing antileprosy drug dapsone. Discover Medicine, 3(1), Article 147. https://doi.org/10.1007/s44337-026-00705-6
Image Credits: AI Generated
DOI: 10.1007/s44337-026-00705-6
Keywords: dapsone, leprosy, multidrug therapy, drug resistance, methemoglobinemia, hemolytic anemia, hypersensitivity syndrome, HLA-B*13:01, pharmacokinetics, Mycobacterium leprae, rifampicin, adverse drug reactions
News Source: Ophelia Keating. (November 5, 2026). Dapsone’s Double Edge: How a 1940s Leprosy Drug Still Fights Resistance and Triggers Danger. Scienmag.
