Early sexual initiation and risky sexual practices among alcohol- and tobacco-using young adults in Taiwan: mediation analysis of preceding-sex use of illicit drugs.

BACKGROUND: As early sexual initiation is increasingly common in East Asia, we examined its relations to risky sexual practices in alcohol- and tobacco-using individuals in Taiwan and evaluated whether the associations were mediated through preceding-sex use of illicit drugs. METHODS: Participants, recruited from alcohol- and tobacco-using adults aged 18 to 50 in Taipei through respondent-driven sampling (N = 1115), completed a computer-assisted self-interview covering questions on substance use and sexual experiences. In a subsample of 916 participants who had had sexual experience (median age 27), we examined the relations of early sexual initiation (< 16 years) to multiple sexual partners, casual sex, group sex, and rare condom use. Causal mediation analyses were conducted to examine whether illicit drug use preceding sex mediated these associations. RESULTS: Around 9.3% reported early sexual initiation and the prevalence of risky sexual practices ranged from 7% (group sex) to 47% (rare condom use). Early initiators had a higher prevalence of regular binge drinking, illicit drug use, and risky sexual practices. In the multivariable analyses, higher odds of multiple sexual partners, casual sex, and group sex were consistently associated with early sexual initiation, gender, and their interaction. Mediation through preceding-sex use of illicit drugs was found between early sexual initiation and the three risky sexual practices, with the proportions mediated ranging from 17 to 19%. CONCLUSIONS: Early sexual initiators were more likely to engage in risky sexual practices and preceding-sex use of illicit drugs partially explained this relationship, calling for more attention to this population's sexual health.

Mis-anaesthetized society: expectancies and recreational use of ketamine in Taiwan.

BACKGROUND: The popularity of ketamine for recreational use has been increasing in Asia, including Taiwan. Still, little known about the pattern of ketamine expectancies and whether such patterns are related to ketamine use. This study aimed to examine whether the positive and negative ketamine expectancies are differentially associated with ketamine-using behavior, and whether such relationship may differ by early-onset use of tobacco or alcohol. METHODS: Participants were recruited using respondent-driven sampling (RDS) among regular tobacco and alcohol users, aged 18 to 50, residing in Taipei from 2007 to 2010. Totally 1115 participants (with an age distribution skewed to the right, median = 26; interquartile range: 22-32) had information on substance use and completed a 12-item ketamine expectancies questionnaire (with 6 positive and 6 negative statements). Using two axes of High and Low expectancies, the four combinations of binary positive and binary negative ketamine expectancies were created. Each participant's drug-using experience was categorized into illicit drug naïve, exclusive ketamine use, polydrug ketamine use, or other illicit drug use. Using the weights in the network output by RDS Analysis Tool, multivariable logistic regression analysis was then conducted. RESULTS: The weighted prevalence was 2.4% for exclusive ketamine use, 9.0% for polydrug ketamine use, and 9.1% for the other illicit drug use. Ketamine users (11.4%) had greater positive expectancies and lower negative expectancies, particularly the combination of High Positive with Low Negative, as compared to the illicit drug-naïve or other illicit drug users. After adjustment for early-onset tobacco (or alcohol) use and sociodemographic characteristics, High Positive, Low Negative, and their combination of High Positive-Low Negative expectancies remained strongly associated with ketamine uses, without evidence of moderation from early-onset use of tobacco or alcohol. CONCLUSIONS: Positive and negative ketamine expectancies were associated in opposite directions with ketamine use, independent of early-onset use of tobacco or alcohol. Our results indicate ketamine expectancies as possible targets for future intervention and prevention of ketamine use, with a less confrontational feedback on decreasing an individual's positive expectancies is essential in preventing young people from the initiation of ketamine use.

Effectiveness of a brief information, motivation and behavioral skills program on stage transitions and lapse for individuals who use ketamine.

OBJECTIVE: Chronic ketamine use is a significant public health and social problem in East and South East Asia and may lead to impairments in health and cognitive functioning. The study evaluated effects of an information, motivation and behavior skills (IMB) program on changes in motivational stage and ketamine use. METHODS: Ketamine using individuals residing in the City of Taipei were recruited (N = 395): 279 selected an IMB program consisting of a 1-day workshop of six 50-minute interactive sessions provided in small groups. The remaining 116 participants selected an education-as-usual (EAU) program consisting of a 1-day workshop of six 50-minute didactic lectures provided in a large group format. Motivational stage of change and ketamine knowledge were assessed before and after the interventions. Participants were followed one year later to assess their ketamine use status. RESULTS: No significant difference in knowledge increase between the IMB and EAU groups (p = .59). The proportion of participants who transitioned from the contemplation to preparation motivational stages was greater in the IMB group than in the EAU group (p < .01). A significant difference in the rates of ketamine lapse during a one-year post intervention follow up was observed between the IMB (50%) and EAU (75%) groups (p < .01). CONCLUSIONS: Interventions based on IMB principles may be more effective in supporting motivational stage transition and in prevention of lapses to ketamine use as compared to currently offered standard drug education programs. Policy makers should consider including IMB interventions in their rehabilitation programs addressing ketamine use problems.

Using Social Network as a Recruiting Tool for Research on Substance Use in the Taipei Metropolitan Area: Study Design, Implementation, and Epidemiological Estimates.

BACKGROUND: This study aimed to evaluate the practical utility of respondent-driven sampling (RDS) among regular tobacco and alcohol users in Taipei, Taiwan. METHODS: RDS was implemented from 2007 to 2010 to recruit seed individuals who were 18 to 50 years old, regular tobacco and alcohol users, and currently residing in Taipei. Each respondent was asked to refer up to five friends known to be regular tobacco smokers and alcohol drinkers to participate in the present study. Information pertaining to drug use was collected using an audio computer-assisted self-interview instrument. RDSAT software was used for data analyses. RESULTS: The prevalence estimates of illegal-drug-using behaviors attained equilibrium after three to five recruitment waves. Nearly one-fifth of the participants had ever used illegal drugs, of whom over 60% were polydrug users. The RDS-adjusted prevalences of illegal-drug-using behaviors among early-onset smokers were all two or three times higher than those among late-onset smokers. CONCLUSIONS: Our results provided an empirical basis for the practicality and feasibility of using RDS to estimate illegal drug use prevalence among regular tobacco and alcohol users.

Comparison of adverse obstetric outcomes and maternity hospitalization among heroin-exposed and methadone-treated women in Taiwan.

AIMS: To identify sociodemographic and clinical factors predicting the overall risk of adverse obstetric outcomes and the length of maternal hospital stay among heroin-exposed and methadone-treated women in Taiwan. METHODS: Using the retrospective matched cohort study design, 396 births to women on methadone treatment during pregnancy (the methadone-treated group) and 609 to women who started methadone treatment after childbirth (the heroin-exposed group) were identified in the National Methadone Maintenance Program. Adverse pregnancy outcomes were assessed by still birth, low birth weight and preterm delivery. We used multivariate methods and zero-truncated negative binomial regression to evaluate association estimates. FINDING: Both heroin-exposed and methadone-treated women had 2-4-fold greater risk of adverse pregnancy outcomes. HIV infection increased the overall risk of adverse pregnancy outcome in the methadone-treated group, whereas being unmarried and having treatment history of substance use disorders increased such risk in the heroin-exposed group. Maternal ages at delivery and healthcare facility used had moderate effects on the length of maternal hospital stay; HIV infection significantly increased the length of hospital stay for women in the heroin-exposed group (adjusted relative risk=1.32, 95% CI=1.05-1.68). CONCLUSIONS: Our results showed no appreciable differences in the occurrence of adverse obstetric outcomes and the length of maternity hospitalization between the methadone-treated and the heroin-exposed women; the profile of sociodemographic and clinical predictors was similar as well. Coordination of addiction treatment and prenatal care may help reduce unfavorable obstetric outcomes among female heroin addicts seeking substitution treatment.

Polymorphisms of COMT Val158Met and DAT1 3'-UTR VNTR in illicit drug use and drug-related psychiatric disorders.

To investigate the involvement of COMT Val158Met and DAT1 3'-UTR VNTR genotypes in the pathogenesis of illicit drug use and drug-induced psychotic disorders (DIP), 187 substance users and 386 normal controls were recruited from Northern Taiwan. Substance users and normal controls significantly differed in allele frequencies of COMT Val158Met (p = 0.039) but not in allele frequencies of DAT1 3'-UTR VNTR (p = 0.879). However, neither allele frequencies of COMT Val158Met nor allele frequencies of DAT1 3'-UTR VNTR were associated with DIP. The findings should be confirmed in further studies of a larger sample size and a more homogenous patient group.

A double-blind, randomized comparison study of efficacy and safety of intramuscular olanzapine and intramuscular haloperidol in patients with schizophrenia and acute agitated behavior.

Studies of intramuscular (IM) olanzapine in Asian and Taiwanese populations are limited. This study examined the efficacy and safety of IM olanzapine in Taiwanese patients with schizophrenia and acute agitated behavior.This was a multicenter, double-blind, randomized, parallel study comparing the efficacy and safety of 10 mg/d IM olanzapine (n = 25) against 7.5 mg/d haloperidol (n = 24). The primary objective was to assess the change of agitation from baseline to 2 hours after the first IM injection on the Positive and Negative Symptom Scale-Excited Component Scale.The changes of Positive and Negative Symptom Scale-Excited Component Scale score from baseline to 2 hours after the first IM injection did not show statistically significant difference between study groups (olanzapine -9.0 ± 5.7, haloperidol -7.9 ± 4.0, P = 0.254). Both groups reported insomnia as the most common treatment-emergent adverse event, and no serious adverse event was reported.Intramuscular olanzapine and IM haloperidol are similarly effective antipsychotic agents in treating agitated symptoms in Taiwanese patients with schizophrenia. Both IM olanzapine and IM haloperidol were proven to be safe and well tolerated, which also provided alternative options in the treatment of patients with schizophrenia with agitation.

Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort.

Abstract Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram (p=0.021), and the Treatment Emergent Symptom Scale (TESS) total score (p=0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone (p=0.035), and showed a lower plasma R-methadone/methadone dose ratio (p=0.007) in urine opiate test negative patients, as well as a greater QTc change (p=0.008) and higher total scores of TESS (p=0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.

Health care service utilization and associated factors among heroin users in northern Taiwan.

Due to the needs of medical care, the probability of using health care service from heroin users is high. This cross-sectional study investigated the frequency and correlates of health service utilization among heroin users. From June to September 2006, 124 heroin users (110 males and 14 females, mean age: 34.2 ± 8.3 years) who entered two psychiatric hospitals (N = 83) and a detention center (N = 41) in northern Taiwan received a face-to-face interview. Therefore, socio-demographic characteristics, patterns of drug use, psychiatric comorbidities, blood-borne infectious diseases and health service utilization were recorded. The behaviors of health service utilization were classified into the frequency of out-patient department visit and hospitalization, as well as the purchase of over-the-counter drugs. During 12 months prior to interview, 79.8% of the participants attended health care service at least once. The rate of having any event in out-patients service visit, hospitalization, and over-the-counter drugs were 66.1%, 29.8% and 25.8% respectively. The frequency of health service utilization was associated with numerous factors. Among these factors, patients who were recruited from hospital and having a mood disorder were conjoint predictors of out-patient department visit, hospitalization and purchase of over-the-counter drugs. According to the results of this study, social education and routine screening for mood disorders can help heroin users to obtain adequate health care service. The findings of this study are useful references for targeting the heroin users for whom a successful intervention represents the greatest cost benefit.

Latent tuberculosis among injection drug users in a methadone maintenance treatment program, Taipei, Taiwan: TSPOT.TB versus tuberculin skin test.

BACKGROUND: Taiwan has a growing HIV/AIDS epidemic that has recently shifted to an increase among injection drug users (IDUs). IDUs co-infected with HIV and tuberculosis (TB) have a high risk of progression from latent tuberculosis infection (LTBI) to active TB. METHODS: This study aimed to determine the prevalence and correlates of LTBI among IDUs by TSPOT.TB and tuberculin skin test (TST), in a large methadone program in Taipei, Taiwan. Consenting participants were interviewed by a trained worker regarding sociodemographics, substance use history, and health factors. RESULTS: Multivariate analysis was used to determine risks associated with each test outcome. Of 287 participants, 165 (58.7%) tested TSPOT.TB-positive and 244 (85.0%) tested TST-positive. The mean age was 44 y, and 7.3% were HIV-infected. Kappa statistics indicated slight concordance between TSPOT.TB and TST. In multivariate analysis, after controlling for potential confounders, TSPOT.TB positivity was significantly associated with age ≥ 50 y (reference, 20-34 y). A history of ever having had contact with a TB-infected person was associated with TST positivity, whereas HIV infection was inversely associated with TSPOT.TB positivity and TST positivity. CONCLUSIONS: This study shows a high prevalence of LTBI in individuals at risk for HIV infection in Taipei, Taiwan. Future TB prevention programs should particularly focus on IDUs.

Risk factors for HIV, viral hepatitis, and syphilis among heroin users in northern Taiwan.

A total of 125 heroin users were recruited from a detention center and two psychiatric hospitals in northern Taiwan during 2006 in order to investigate the prevalence and correlates of blood-borne infections among heroin users. The seroprevalence rates of the human immunodeficiency virus (HIV), hepatitis C virus (HCV), HBV, HDV, and syphilis were 15.2%, 74.4%, 15.2%, 6.4%, and 8%, respectively. Injection risk behaviors were associated with HIV, HCV, and syphilis infections, but not with HBV infections. Meanwhile, HCV and HBV infections were correlated with the duration of heroin use and age of the subjects, respectively. The results of this study suggest that a comprehensive public health program is needed to prevent transmission of these blood-borne infections. The study's limitations are noted.

Prevalences and associated risk factors of HCV/HIV co-infection and HCV mono-infection among injecting drug users in a methadone maintenance treatment program in Taipei, Taiwan.

BACKGROUND: Injecting drug users (IDUs) in Taiwan contributed significantly to an HIV/AIDS epidemic in 2005. In addition, studies that identified risk factors of HCV/HIV co-infection among IDUs were sparse. This study aimed to identify risk factors of HCV/HIV co-infection and HCV mono-infection, as compared with seronegativity, among injecting drug users (IDUs) at a large methadone maintenance treatment program (MMTP) in Taipei, Taiwan. METHODS: Data from enrollment interviews and HCV and HIV testing completed by IDUs upon admission to the Taipei City Hospital MMTP from 2006-2010 were included in this cross-sectional analysis. HCV and HIV testing was repeated among re-enrollees whose HCV or HIV test results were negative at the preceding enrollment. Backward stepwise multinomial logistic regression was used to identify risk factors associated with HCV/HIV co-infection and HCV mono-infection. RESULTS: Of the 1,447 IDUs enrolled, the prevalences of HCV/HIV co-infection, HCV mono-infection, and HIV mono-infection were 13.1%, 78.0%, and 0.4%, respectively. In backward stepwise multinomial regression analysis, after controlling for potential confounders, syringe sharing in the 6 months before MMTP enrollment was significantly positively associated with HCV/HIV co-infection (adjusted odds ratio [AOR]=27.72, 95% confidence interval [CI] 13.30-57.76). Incarceration was also significantly positively associated with HCV/HIV co-infection (AOR=2.01, 95% CI 1.71-2.37) and HCV mono-infection (AOR=1.77, 95% CI 1.52-2.06), whereas smoking amphetamine in the 6 months before MMTP enrollment was significantly inversely associated with HCV/HIV co-infection (AOR=0.44, 95% CI 0.25-0.76) and HCV mono-infection (AOR=0.49, 95% CI 0.32-0.75). HCV seroincidence was 45.25/100 person-years at risk (PYAR; 95% CI 24.74-75.92/100 PYAR) and HIV seroincidence was 0.53/100 PYAR (95% CI 0.06-1.91/100 PYAR) among re-enrolled IDUs who were HCV- or HIV-negative at the preceding enrollment. CONCLUSIONS: IDUs enrolled in Taipei MMTPs had very high prevalences of HCV/HIV co-infection and HCV mono-infection. Interventions such as expansion of syringe exchange programs and education regarding HCV/HIV prevention should be implemented for this high-risk group of drug users.

HIV infection risk among injection drug users in a methadone maintenance treatment program, Taipei, Taiwan 2007-2010.

BACKGROUND: Taiwan has a growing HIV/AIDS epidemic that has recently shifted to an increase among injection drug users (IDUs). This study aimed to measure the prevalence and incidence and identify the correlates of HIV infection among IDUs in a large methadone maintenance treatment program (MMTP) in Taipei, Taiwan. METHODS: Data from intake interviews and HIV testing completed by IDUs upon admission to the Taipei City Hospital MMTP in 2007-2010 were included in this analysis. HIV testing was repeated semi-annually among maintained clients who were HIV-negative during MMTP admission. RESULTS: Of 1444 IDUs admitted, 85.9% were male, median age was 40 years, and mean years of injecting was 14.3 (range: 1-64). The prevalence of HIV, HCV, and HIV/HCV co-infection was 13.4%, 91.1%, and 13.2%, respectively. In multivariable analysis, HIV infection was associated with sharing syringes during the 6 months prior to admission (OR = 14.76, 95% CI 10.31-21.13), homelessness (OR = 6.46, 95% CI 1.49-28.00), and lifetime number of MMTP admissions (OR = 1.76, 95% CI 1.30-2.38) and times incarcerated (OR = 1.10, 95% CI 1.03-1.18). HIV seroincidence was 1.15/100 person-years at risk (95% CI .62-8.77/100 PY) among IDUs who were HIV-negative at first admission. CONCLUSIONS: Taiwanese IDUs in MMTP have a high HIV prevalence, which was associated with syringe sharing and other factors related to social marginalization. Our findings highlight the importance of harm reduction programs, including syringe exchange, along with HIV-prevention education.

Factors associated with drug-related psychiatric disorders and suicide attempts among illicit drug users in Taiwan.

Illicit drug users, entering a detention center and two psychiatric hospitals in Northern Taiwan, were interviewed for lifetime drug-use-related psychiatric disorders and suicide attempts. Among 197 participants, 17.3%, 16.8%, and 14.2% had a drug-induced psychotic disorder (DIP), a drug-induced mood disorder (DIM), and a history of suicide attempts, respectively. Continuous use of methamphetamine and joblessness were associated with DIP and DIM, accordingly. Polysubstance use was collectively correlated with DIP and DIM. Female gender and history of having any mood disorder were predictors of suicide. These results provide useful clues for detecting drug-related psychiatric disorders and suicide among illicit drug users. The study's limitations are noted.

UGT2B7 genetic polymorphisms are associated with the withdrawal symptoms in methadone maintenance patients.

AIM: To test whether the genetic polymorphisms within the gene encoding the UGT2B7 gene may have an impact on methadone treatment. MATERIALS & METHODS: Twelve SNPs in UGT2B7 were selected. 366 methadone maintenance treatment patients in Taiwan were recruited and genotyped. RESULTS: In a genotype recessive model, rs6600879, rs6600880, rs4554144, rs11940316, rs7438135, rs7662029, rs7668258, rs7439366, rs4292394 and rs6600893 showed significant associations with severity of withdrawal symptoms (permutation p < 0.002), pupil size (permutation p < 0.048) and tremor (permutation p < 0.008). Haplotypes of GATCAGCCGC and CTCTGATTCT were significantly associated with pupil size score and tremor score (p < 0.034). CONCLUSION: These results suggest that SNPs of the UGT2B7 gene may play important roles in opiate withdrawal symptoms.

Genetic polymorphisms in the opioid receptor mu1 gene are associated with changes in libido and insomnia in methadone maintenance patients.

Methadone, a synthetic racemic opioid that primarily works as a µ-opioid receptor (OPRM1) agonist, is commonly used for the treatment of heroin addiction. Genetic association studies have reported that the OPRM1 gene is involved in the physiology of heroin and alcohol addiction. Our current study is designed to test the hypothesis that genetic polymorphisms in the OPRM1 gene region are associated with methadone dosage, plasma concentrations, treatment responses, adverse reactions and withdrawal symptoms in a methadone maintenance treatment (MMT) cohort from Taiwan. Fifteen OPRM1 single nucleotide polymorphisms (SNPs) were selected and genotyped using DNA samples from 366 MMT patients. The plasma concentrations of methadone and its metabolite were measured by high performance liquid chromatography. The results obtained using dominant model analysis indicate that the OPRM1 SNPs rs1074287, rs6912029, rs12209447, rs510769, rs3798676, rs7748401, rs495491, rs10457090, rs589046, rs3778152, rs563649, and rs2075572 are significantly associated with change-in-libido side effects (adjusted p<0.042). Using recessive model analysis, these SNPs were also found to be significantly associated with insomnia side effects in this cohort (p<0.009). The significance of the insomnia findings was mainly contributed by a subgroup of patients who had a positive urine morphine test (p<0.022), and by individuals who did not use benzodiazepine hypnotics (p<0.034). Our current data thus suggest that genetic polymorphisms in OPRM1 may influence the change-in-libido and insomnia side effects sometimes found in MMT patients.

Essentiality of HIV testing and education for effective HIV control in the national pilot harm reduction program: the Taiwan experience.

In 2005, a national pilot harm reduction program (PHRP), which mainly included a methadone maintenance treatment program (MMTP) and a needle/syringe exchange program (NSP), was implemented in Taiwan. We conducted this study to evaluate the effectiveness of harm reduction measures on HIV control among injecting drug users (IDUs) between PHRP and nonPHRP. The data on HIV, collected from incumbent Taiwanese authorities, were analyzed for their associations, risk and protective factors with PHRP measures. While the monthly HIV incidences did not show significant differences before and after PHRP in the four areas with PHRP (Taipei City, Taipei County, Taoyuan County and Tainan County), a significant increase in the HIV incidence was found in the 21 areas without PHRP. Hence, the implementation of the PHRP did result in a significant difference in the monthly HIV incidence between areas with and without the PHRP. Mandatory HIV testing was significantly associated with the HIV incidence according to the generalized estimation equations (GEE) model. With adjustments of time period and area with PHRP, and urban area, protective factors associated with HIV incidence were: educational materials, condoms, dilution water, and alcohol sponges/swabs. MMTP contributed to a higher HIV incidence, probably due to the concurrent HIV testing upon admission. Since HIV testing was not required in the NSP, the HIV testing-dependent MMTP may explain the association of the PHRP intervention and an increased HIV incidence. In summary, HIV testing and education were essential for effective HIV control upon implementing the PHRP.

Genetic polymorphisms in CYP3A4 are associated with withdrawal symptoms and adverse reactions in methadone maintenance patients.

AIM: Methadone maintenance therapy is one of the standard treatments for heroin addiction. The isozyme CYP3A4 of the CYP system is one of the metabolic enzymes, as well as CYP2B6, responsible for the metabolism of methadone. The aim of the present study is to evaluate the potential use of genetic polymorphisms in CYP3A4 as biomarkers for the prediction of methadone treatment responses. MATERIALS & METHODS: A total of 366 Han Chinese methadone maintenance treatment patients in Taiwan were recruited in this study. Main clinical assessments included the clinical opioid withdrawal scale (COWS), the treatment emergent symptom scale (TESS) and the plasma concentrations of methadone and its metabolites. Genetic associations of six SNPs in the CYP3A4 gene were calculated using a general linear model. RESULTS: Genotypes and allele types of rs4646440 and rs2242480 were found to be significantly associated with the severity of withdrawal symptoms rated by COWS (p = 0.012, 0.0096, 0.017 and 0.012, respectively) as well as the side effects rated by TESS (p = 0.0089, 0.028, 0.0027 and 0.0085, respectively). The allele types associated with more severe withdrawal symptoms are also associated with more severe side effects and less betel nut (Areca catechu) use (p = 0.009 for rs4646440, p = 0.0063 for rs2242480). Further analyses on specific withdrawal symptoms in COWS showed that the genetic variants in rs4646440 are significantly associated with heart rate (allele type p = 0.0019). CONCLUSION: These results suggested that genetic variants in the CYP3A4 gene may be useful indicators for the severity of side effects and withdrawal symptoms for methadone treatment.