Diplotype-Guided Differences in Alcohol Withdrawal Severity Under Diazepam Therapy
S. Özkan-Kotiloğlu, D. Kaya-Akyüzlü, M. Danışman, M. A. Yıldırım, I. Özgür-İlhan, S. SüzenIntroduction
Benzodiazepines are the first-line treatment for Alcohol Withdrawal Syndrome (AWS), with diazepam (DZP) favoured for its long half-life and effective symptom control. DZP is primarily metabolised by CYP2C19 enzyme, whose activity can vary significantly due to genetic polymorphisms, leading to differences in treatment response among individuals.
Objectives
This study aimed to assess the association between CYP2C19 variants and alcohol withdrawal severity in patients undergoing DZP treatment.
Methods
A total of 97 male patients diagnosed with AWS and receiving oral DZP therapy were recruited. Genotyping for CYP2C19 *2 and CYP2C19 *17 polymorphisms was performed using PCR-RFLP. The Clinical Institute Withdrawal Assessment for Alcohol Scale-Revised (CIWA-Ar) was used to evaluate withdrawal severity after 10-days oral DZP treatment. The impact of different CYP2C19 genotypes and metaboliser phenotypes (EMs: extensive metabolisers: *1/*1 diplotype; IMs: Intermediate metabolisers: *1/*2 or *2/*17 diplotype; PMs: poor metabolisers: *2/*2 diploype; RMs: rapid metabolisers: *1/*17 diplotype; UMs: ultra rapid metabolisers: *17/*17 diplotype) on CIWA-Ar scores was statistically analysed.
Results
A significant association was observed between CYP2C19 *17 genotypes and CIWA-Ar scores in the co-dominant model (CC: median 5.00 [IQR: 2.00 – 10.00]; CT: 5.00 [3.50 – 9.50]; TT: 1.00 [1.00 – 3.50]; p =0.043). Post-hoc analysis under the C-dominant model revealed a statistically significant difference between TT and CC+CT groups ( p =0.013), whereas the T-dominant model showed no significant difference ( p =0.529). No significant association was found between CYP2C19 *2 genotypes and withdrawal scores ( p =0.941). Notably, UMs exhibited significantly lower alcohol withdrawal scores (median 1.00 [IQR: 1.00 – 3.50]) compared to EMs, who had a median score of 6.00 [IQR: 2.25 – 9.75] ( p =0.012).
Conclusions
This study demonstrates that CYP2C19 *17 polymorphism significantly influences DZP’s effectiveness in managing AWS. Individuals with UM profile, experienced milder withdrawal symptoms compared to EMs. These findings suggest that pharmacogenetic profiling of CYP2C19 could give personalised DZP therapy in AWS, potentially improving treatment outcomes.
This study was supported by Scientific and Technological Research Council of Turkey (TUBITAK) under the Grant Number 121C441. The authors thank to TUBITAK for their supports.
Disclosure of Interest
None Declared