Schmittner John, Schroeder Jennifer R, Epstein David H, Krantz Mori J, Eid Nicole C, Preston Kenzie L
Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Pharmacotherapy. 2009 May;29(5):495-502. doi: 10.1592/phco.29.5.495.
To determine the electrocardiographic effects of coadministration of lofexidine and methadone.
Prospective, double-blind study.
Outpatient drug treatment research clinic.
Fourteen adults (mean +/- SD age 34.9 +/- 5.3 yrs) with physical dependence on opioids.
Participants were stabilized on methadone maintenance therapy, reaching a target dose of 80 mg/day. After 3 weeks of methadone stabilization, participants received lofexidine 0.4 mg or placebo once/day, each for 1 week, administered at the same time as methadone. From weeks 3-8, all subjects received lofexidine, with the dose escalated each week in 0.2-mg increments so that by week 8, participants were receiving lofexidine 1.6 mg/day. Electrocardiograms (ECGs) were obtained at baseline (before methadone), after stabilization with methadone, and after lofexidine coadministration during peak plasma lofexidine levels.
Prespecified outcome measures of mean and maximal changes in heart rate, and PR, QRS, and QTc intervals were obtained after stabilization with methadone and after lofexidine 0.4 mg coadministration. Repeated-measures regression showed no significant changes in heart rate or PR, QRS, or QTc interval after methadone stabilization, but a significant decrease in heart rate (mean +/- SD -8.0 +/- 7.3 beats/min, p=0.0006) after starting lofexidine. When data were analyzed by using maximal ECG response, again, no significant changes were noted during methadone induction compared with baseline, but significant changes did occur in all four ECG parameters when lofexidine was coadministered: decreased heart rate (mean +/- SD -9.6 +/- 5.8 beats/min, p<0.0001) and increased PR interval (+11.1 +/- 19.8 msec, p=0.026), QRS interval (+3.7 +/- 4.3 msec, p=0.002), and QTc interval (+21.9 +/- 40.8 msec, p=0.018). In three female participants, the change in QTc interval from baseline was clinically significant (> 40 msec).
Our preliminary data suggest that coadministration of lofexidine and methadone induces QTc interval prolongation. This drug combination should be prescribed cautiously, with ECG monitoring. Furthermore, because the participants with the largest changes in QTc interval in our study were female, women may be at highest risk.
确定洛非西定与美沙酮联合使用时的心电图效应。
前瞻性、双盲研究。
门诊药物治疗研究诊所。
14名对阿片类药物产生身体依赖的成年人（平均年龄±标准差34.9±5.3岁）。
参与者接受美沙酮维持治疗并达到稳定状态，目标剂量为80毫克/天。在美沙酮稳定治疗3周后，参与者每天一次接受0.4毫克洛非西定或安慰剂，各持续1周，与美沙酮同时给药。从第3周到第8周，所有受试者均接受洛非西定，剂量每周以0.2毫克的增量递增，至第8周时，参与者接受1.6毫克/天的洛非西定。在基线（美沙酮治疗前）、美沙酮稳定治疗后以及洛非西定联合给药且血浆洛非西定水平达到峰值后获取心电图（ECG）。
在美沙酮稳定治疗后以及联合给予0.4毫克洛非西定后，获得心率、PR间期、QRS间期和QTc间期的预设平均和最大变化的结果测量指标。重复测量回归分析显示，美沙酮稳定治疗后心率、PR间期、QRS间期或QTc间期无显著变化，但开始使用洛非西定后心率显著降低（平均±标准差 -8.0±7.3次/分钟，p = 0.0006）。当使用最大心电图反应分析数据时，同样，与基线相比，美沙酮诱导期间未观察到显著变化，但联合使用洛非西定时，所有四个心电图参数均发生了显著变化：心率降低（平均±标准差 -9.6±5.8次/分钟，p<0.0001），PR间期增加（+11.1±19.8毫秒，p = 0.026），QRS间期增加（+3.7±4.3毫秒，p = 0.002），QTc间期增加（+21.9±40.8毫秒，p = 0.018）。在三名女性参与者中，QTc间期相对于基线的变化具有临床意义（>40毫秒）。
我们的初步数据表明，洛非西定与美沙酮联合使用会导致QTc间期延长。这种药物组合应谨慎处方，并进行心电图监测。此外，由于我们研究中QTc间期变化最大的参与者为女性，女性可能风险最高。
