Effects of methadone on cognition, mood and craving in detoxifying opiate addicts: a dose-response study

RATIONALE: Methadone is the most widespread pharmacological treatment for opiate dependency but relatively little is known of its effects on cognitive and psychomotor functioning, drug craving and mood. Objective: The present study aimed to assess the acute effects of methadone in patients admitted to an opiate detoxification programme. METHODS: Patients were randomly allocated to one of two groups who received either 50% or 100% of their daily stabilisation dose, and a placebo, in a double-blind, cross-over design. Twenty patients completed the study, all were assessed pre- and post-drug on 2 separate testing days. RESULTS: Performance on a task tapping episodic memory (delayed recall of a prose passage) was significantly impaired following the 100% daily dose of methadone. Methadone treatment had no effect on craving or mood. Patients were unable to distinguish between methadone and placebo treatments. CONCLUSIONS: A single dose of methadone can induce episodic memory impairment in patients who have a history of heroin use averaging more than 10 years. Such impairment can be avoided by giving methadone in divided doses.     

Performance differences between addicts and non-addicts

Methadone addicts and non-addict controls were tested before and after receiving up to 10 mg of methadone on simple visual reaction time tests and on a vigilance type visual attention test. Addicts were faster than controls on pre-drug testing, although there were no pre-drug differences between groups on the attention task. Addicts maintained faster reaction times than controls even when money was offered as an incentive for speed. Additional methadone did not affect addict performance on any of the tasks. Methadone slowed control reaction times in a doserelated fashion. No significant attention decrements were seen after methadone in controls. Visual reaction time differences between addicts and controls cannot be attributed to group differences in motivation or ability to attend. Slowing of reaction time with acute dose of methadone in controls cannot be attributed to the effect of the drug on attention. An hypothesized drug-induced decrease in visual sensitivity with acute dose in controls and a drug-induced increase in visual sensitivity with chronic dose in addicts can account for the presented data.     

An investigation of cigarette smoking behavior and nicotine dependence among Chinese opiate addicts

To explore the characteristics of nicotine dependence among Chinese opiate addicts, a survey was conducted among 357 opiate addicts in Drug Detoxification and Rehabilitation Center from 4 different provinces by using a self-designed questionnaire and Fagerström Test for Nicotine Dependence (FTND). Among the 357 opiate addicts, 355 (99.4%) had the history of cigarette smoking and the mean cigarette smoked per day were 19.1, 34.9, 21.5 and 21.5 sticks during the time of before drug taking, addiction phase, abstinence period and after abstinence respectively. Among 347 smokers with FTND score, 67.2% were severe nicotine dependence (FTND score ≥ 7.0). The lower education degree, injection, poly-drug use and 3 or more relapse were dependently associated with the severe nicotine dependence, and the adjusted odds ratio (OR) were 3.8 (1.5–10.0), 2.3 (1.3–4.0), 3.7 (2.1–6.5) and 1.9 (1.1–3.4) respectively. This study exhibited high rate of cigarette smoking in Chinese opiate addicts and the majority had severe nicotine dependence and suggested that a comprehensive intervention of cigarette smoking should be paid attention to during substance abuse treatment in China.     

The pharmacokinetics of methadone in healthy subjects and opiate users

Aims There is some evidence that monitoring methadone plasma concentration may be of benefit in dosage adjustment during methadone maintenance therapy for heroin (opiate) dependence. However, the kinetics of oral methadone are incompletely characterized. We attempted to describe the latter using a population approach combining intensive 57 h sampling data from healthy subjects with less intensive sparse 24 h data from opiate users. Methods Single oral doses of rac-methadone were given to 13 drug-naive healthy subjects (7 men and 6 women) and 17 opiate users beginning methadone maintenance therapy (13 men and 4 women). Plasma methadone concentrations were measured by h.p.l.c. Kinetic analysis was performed using the P-Pharm software. Results Comparison of kinetic models incorporating mono- or biexponential disposition functions indicated that the latter best represented the data. The improvement was statistically significant for the data from healthy subjects whether the full 57 h or truncated 24 h profiles were used (P<0.031 and P<0.024, respectively), while it was of borderline significance for the more variable data from opiate users (P=0.057) or for pooled (healthy subjects and opiate users) data (P=0.066). The population mean oral clearance of methadone was 6.9±1.5 s.d. l h⁻¹ (5.3±1.2 s.d. l h⁻¹ using 0–24 h data) in the healthy subjects. The results of separate analyses of the data from opiate users and healthy subjects were in contrast with those obtained from pooled data analysis. The former indicated a significantly lower clearance for opiate users (3.2±0.3 s.d. l h⁻¹, P<0.001); 95% CI for the difference=−3 to −6 l h⁻¹ and no difference in the population mean values of V /F (212±27 s.d. l and 239±121 s.d. l, P=0.15), while according to the latter analysis addiction was a covariate for V /F but not for oral clearance. A slower absorption of methadone in opiate users was indicated from the analysis of both pooled and separate data. The median elimination half-life of methadone in healthy subjects was 33–46 h depending on the method used to calculate this parameter. Conclusions Estimates of the long terminal elimination half-life of methadone (33–46 h in healthy subjects and, possibly, longer in opiate users) indicated that accurate measurement of this parameter requires a duration of sampling longer than that used in this study. Our analysis also suggested that parameters describing plasma concentrations of methadone after a single oral dose in healthy subjects may not be used for predicting and adjusting dosage in opiate users receiving methadone maintenance therapy unless coupled with feedback concentration monitoring techniques (for example Bayesian forecasting).     

Pharmacokinetics of methadone during maintenance treatment: Adaptive changes during the induction phase

Summary Deuterated methadone (M-d₃0) and GC-MS were used to study the pharmacokinetics of methadone (M) during the induction stage of methadone maintenance treatment (MMT). A pulse dose of M-d₃ was given on Days 1 and 25 of two dosage regimens, one with a continuous 30 mg dose (n=6), and the other with 30 mg for 10 days, followed by 60 mg as the maintenance dose (n=6). Plasma and urinary levels of M and M-d₃ were measured throughout and plasma half-lives, oral bioavailabilities and volumes of distribution were calculated from the data of Days 1–2 and 24–26. The oral bioavailability of a methadone solution was found to be between 81 and 95%; elimination half-life in the -phase varied between 19 and 58 h; the volume of distribution was 4.1±0.65 l/kg; and total body clearance of M was 54–195 ml/min and its renal clearance 3.4–34 ml/min. A consistent finding was a lower urinary pH and increased renal clearance during the first days of MMT as compared with after one month. In 4/12 of the patients dispositional tolerance was developed to methadone during the first month of treatment. The shorter elimination half-lives in those patients probably caused unacceptably high fluctuation in the body content of M during the 24 h dosage interval, and may have interfered therefore, with its therapeutic effectiveness     

丁丙诺啡舌下含片与美沙酮用于海洛因依赖门诊稽延期治疗的对照研究

目的观察丁丙诺啡舌下含片与美沙酮用于海洛因依赖者稽延期治疗的价值。方法对完成脱毒治疗患者,依先后次序交叉纳入观察组与对照组,分别给予丁丙诺啡舌下含片和美沙酮治疗6个月,观察操守时间,并于人组前后做焦虑量表评分。结果丁丙诺啡舌下含片组比美沙酮组的操守时间长（P〈0．01）,焦虑评分低（P〈0．05）。结论丁丙诺啡舌下含片于海洛因依赖门诊稽延期治疗能更好地缓解焦虑情绪并延长操守时间。     

Accelerated lofexidine treatment regimen compared with conventional lofexidine and methadone treatment for in-patient opiate detoxification

This open study compares an accelerated 5-day lofexidine regimen with orthodox 10-day lofexidine and methadone regimens in the treatment of opiate withdrawal in 61 polysubstance abusing opiate addicts. Significant differences in levels of withdrawal symptoms were found on days 11, 13–15 and 17–20, symptoms resolving most rapidly in the 5-day lofexidine treatment group, whilst withdrawal responses in the 10-day lofexidine treatment group were intermediate between the 5-day lofexidine and standard methadone treatment conditions. When the two lofexidine regimens were separately compared with methadone the 5-day lofexidine treatment was significantly more effective on day 10, 11 and 13–20, whilst the 10-day lofexidine treatment was not significantly different from methadone. There were no significant differences in rates of completion of detoxification between the three treatments. Both the lofexidine treatment regimens had a similar effect on blood pressure. Five patients experienced side effects which resolved with dose reduction, all remaining in the study. An accelerated 5-day lofexidine regimen may attenuate opiate withdrawal symptoms more rapidly than conventional 10-day lofexidine or methadone treatment schedules without exacerbating hypotensive side effects.     

绵阳市滥用阿片类物质成瘾者艾滋病相关知识、行为及生物学监测分析

目的：了解滥用阿片类物质成瘾者艾滋病相关知识、行为及生物学现状,为开展健康教育和行为干预提供依据。方法：在绵阳市涪城区、游仙区社区内采用滚雪球等方法招募滥用阿片类物质成瘾者319名,在绵阳市强制隔离戒毒中心随机抽取新入所的滥用阿片类物质成瘾者82名,由经过培训的专业人员逐一进行问卷调查,并采血作HIV抗体、HCV抗体和梅毒抗体检测。结果：调查滥用阿片类物质成瘾者401名,艾滋病相关知识总知晓率为92．61％;当前使用的主要毒品为海洛因者占96．01％,静脉注射吸毒占69．33％,最近1个月（或入所前1个月）未与他人共用过针具;最近1次性行为时安全套使用率为62．82％;最近1次与商业性伴发生性行为时安全套使用率为75％;最近1年接受艾滋病预防服务措施覆盖率为97．26％;HIV抗体阳性率为1％,HCV抗体阳性率为66．83％,梅毒抗体阳性率为1．51％。结论：绵阳市滥用阿片类物质成瘾者艾滋病相关知识知晓率较高,HIV抗体阳性率和注射毒品共用针具的比例明显下降,但安全套使用率较低,高危行为依然存在,需要继续加强各项干预措施的落实。     

Insomnia among addicts during supervised withdrawal from opiates: A comparison of oral methadone and electrostimulation

Measures of sleep disturbance were taken among drug-dependent inpatients being withdrawn from opiates using either a conventional oral methadone regime or electrostimulation (ES). Sleep was found to be disturbed in both groups. Subjects receiving ES showed the more marked sleep reduction and higher levels of night time waking during withdrawal: insomnia was most evident during the first 14 days of withdrawal. The degree of sleep disturbance among the methadone subjects was less severe but there were also sleep difficulties in this group. As late as 1 month after admission there was considerable night-to-night variability in sleep times with mean values between 4 h and 6 h in both groups. The ES procedure was unsatisfactory for managing insomnia during opiate withdrawal, but neither can methadone be regarded as fully satisfactory in this respect. An incidental finding to emerge from this study is that those subjects in the ES group who remained in treatment experienced more sleep disturbance than those who dropped out prematurely.     

Pharmacokinetics of methadone during maintenance therapy: Pulse labeling with deuterated methadone in the steady state

Summary A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d₃) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d₀) was substituted by one dose of methadone-d₃ and plasma levels of methadone-d₀ and methadone-d₃ were followed for 48 h using a precise (SD±5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (t_1/2) for both methadone-d₀ and metadone-d₃ were calculated from samples obtained 8–24 h following the dose of methadone-d₃. The t_1/2 of oral methadone-d₃ was shorter (22±2 h) than that of methadone-d₀ (52±20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.     

宁夏吴忠地区盐酸美沙酮维持治疗154例海洛因依赖者的疗效

目的:探讨盐酸美沙酮替代海洛因维持治疗在宁夏地区实施的可行性、有效性。方法:采用问卷调查对受治者盐酸美沙酮维持治疗前后的效果进行评价。结果:宁夏吴忠地区吸食海洛因者人群结构复杂,吸食者平均时间达8.04年以上,多药物滥用增加了治疗依存性危险度。通过开展药物维持门诊试点工作,87.6%的受治者希望回归社会,维持正常人的生活质量;50%的受治者减轻了心理压力,改善了经济状况,能够参加身体其它疾病的治疗;57.1%的受治者与家庭成员关系发生极大改善;32.5%的受治者与家庭成员关系发生改善。结论:盐酸美沙酮维持治疗对海洛因依赖者治疗效果明显。由于该病属易反复发作的慢性脑疾病。需要多学科、多部门合作,给予受治者心理咨询及行为活动干预,才可保证治疗效果。     

Problem drinking in relation to treatment outcome among opiate addicts in methadone maintenance treatment

This study analyzed indicators of alcohol-related problems in opiate addicts before, during, and after leaving methadone maintenance treatment (MMT), in relation to illicit drug use and retention in treatment. The study was based on 204 patients, admitted to MMT for the first time between 1 January 1995 and 31 July 2000, and followed until 31 December 2000. Three measures were used to indicate alcohol use and alcohol-related problems; records of hospital care with an alcohol-related diagnosis, any treatment with alcohol-sensitizing drugs (disulfiram or calcium carbimide) during MMT, and results of the 5-hydroxytryptophol to 5-hydroxyindoleacetic acid ratio (5HTOL/5HIAA) in urine, a sensitive biomarker for recent drinking. Use of illicit drugs was determined by routine urine drug testing. About one third of the patients (n = 69) had a lifetime prevalence of hospital treatment for an alcohol-related diagnosis, 45 of whom had been hospitalized (mean 4.2 stays) prior to the start of MMT. There was a significant association (p<0.05) between the number of alcohol-related diagnoses prior to treatment and a positive 5HTOL/5HIAA test during MMT. The alcohol indicators first became positive on average 1.6 years after admission to treatment, compared with after about 4 months for illicit drugs. Use of cannabis or benzodiazepines was significantly associated with alcohol use. Female methadone patients with indications of alcohol-related problems relapsed more often into illicit drug use than did women without such indications (3.9 vs. 2.5 relapse periods/year; p<0.005), whereas no significant association was found for men. The results of the present study indicate that drinking problems among patients undergoing MMT is associated with an increased risk of relapse into illicit drug use and with discharge from treatment. Concurrent treatment of alcohol-related problems, including systematic monitoring of alcohol use, therefore should be recommended to reduce the risk for relapse into illicit drug use and improve overall treatment outcome in MMT.     

Sustained attention in patients receiving and abstinent following methadone maintenance treatment for opiate dependence: Performance and neuroimaging results

Objective

Impairments in the function of attention exacerbate the course of opiate dependence and may play a role in the relapsing nature of the disorder. This study used clinical measures and positron emission tomography (PET) to assess the functioning of sustained attention in subjects with a history of opiate dependence.

Methods

A test of auditory sustained attention was administered to 10 subjects receiving methadone maintenance treatment, 13 formerly opiate-dependent subjects in protracted abstinence, and 14 healthy Comparison subjects. Simultaneous measurement of regional glucose metabolism was made by [¹⁸F] flourodeoxyglucose PET. Subjects groups were compared on the measures of sustained attention and regional cerebral glucose metabolism.

Results

Healthy Comparison subjects scored significantly better than either methadone-maintained or abstinent former opiate addicts on measures of sustained attention. Formerly opiate-dependent subjects in protracted abstinence scored better than methadone-maintained subjects on sustained attention. Methadone-maintained subjects demonstrated a relative reduction in regional cerebral glucose metabolism in the right supramarginal gyrus, and the thalamus bilaterally. The Comparison subjects without a history of opiate dependence demonstrated a relative increase in regional cerebral glucose metabolism in the right anterior cingulate gyrus, the right medial superior frontal gyrus and the thalamus bilaterally.

Conclusions

Subjects with a history of opiate dependence have impairments in the functioning of sustained attention, and abnormalities in brain regions identified as important in attention processing. Impairments in attention performance persist in subjects who enjoy prolonged abstinence from opiates.     

Clinical issues in using buprenorphine in the treatment of opiate dependence

This paper looks at the current role of buprenorphine in the treatment of opiate dependence. It suggests that buprenorphine is a useful alternative to methadone and that in at least some cases it may be the preferred option. Buprenorphineis a partial agonist and a partial antagonist with a ceiling of opiate activity probably approximately equal to 30mg methadone. It achieves this at a dose of 10-12mg, although there is considerable individual variation. Because of its ceiling effect it has a good safety profile compared to full agonists such as methadone although some overdose deaths, particularly in conjunction with benzodiazepine abuse, have been reported in France. Induction of buprenorphine may take slightly longer than for methadone and there is a higher dropout rate compared to methadone in the first 2 weeks. This is probably due to the antagonist action of buprenorphine causing more withdrawal symptoms in comparison to methadone. Also, the ceiling effect for buprenorphine means that some clients do not experience sufficient opiate activity to satisfy them. Buprenorphine has a long half-life and dissociates slowly from opiate receptors. Most clients can be dosed second-daily but some find this unacceptable due to mood swings and/or withdrawal symptomson the second day.For these clients daily dosing is required. Transferring from buprenorphine to methadone is straightforward and well tolerated by clients. Transferring from methadone to buprenorphine, however, is more difficult because of the partial antagonist action of buprenorphine. Clients experience withdrawal symptoms that can take up to 2 weeks to settle. Most clients find these symptoms unacceptable when transferring from doses of over 30mg of methadone. The optimum method for transferring from methadone to buprenorphine is still to be determined. Withdrawal from buprenorphine appears to be relatively easier than from methadone. This is presumably due to buprenorphine's partial agonist effect at mureceptors. It is expected that during 2000 buprenorphine will be approved for use in Australia for the treatment of opiate dependence. It may well becomea first-line choice for opiate replacement in heroin dependence. It is also likely to be useful in assisting detoxification fromboth methadone and heroin. [Chadderton A. clinical issues in using buprenorphine in the treatment of opiate dependence. Drug Alcohol Rev 2000;19:329-335]     

Pharmacokinetics of Intravenous Metronidazole in Man

Abstract: Metronidazole (500 mg) was infused over 20 min. to five patients. At the end of the infusion blood samples were drawn at brief intervals. After subsequent metronidazole analysis the curve plotted for the elimination of the drug showed a bi-exponential profile. Mean peak serum concentrations reached 15 μg per ml. At the end of the distribution phase, which was 20 to 30 min. after the infusion, the concentration had fallen to 10 μg per ml. A two-compartment model was used to calculate the kinetic parameters. The elimination half-life ranged from 4.7 to 15.8 hours, the total clearance from 43 to 193 ml per min., and the peripheral distribution volume from 41.5 to 79.1 1. The areas under the serum level curves exhibited a four-fold variation, due to differences in either metabolism or elimination rate.     

Pharmacokinetics of digoxin: Comparison of a two- and a three-compartment model in man

An experiment has been carried out in man designed to compare the fit of a two- and a three-compartment pharmacokinetic model to experimentally determined serum digoxin concentration-time data following rapid intravenous injection of 1.0 mg of the drug. Digoxin was administered to five healthy male volunteers, blood samples were withdrawn repetitively over a period of 72 hr, and samples were assayed using a ¹²⁵ I radioimmunoassay. Appropriate equations describing two- and three-compartment open models were fitted to the experimental data using weighted nonlinear least squares regression analysis. It was demonstrated that the three-compartment fit resulted in a statistically significant reduction in residual error, a marked improvement in the randomness of scatter of the experimental data about the serum digoxin-time curve, and better agreement of the predicted serum concentration-time curve with experimental serum digoxin concentrations. Thus the three-compartment open model is the simplest pharmacokinetic model consistent with the data observed in this experiment.This study was supported in part by Philips Roxane Laboratories, Inc., Columbus, Ohio.     

盐酸美沙酮口服液在中国美沙酮维持治疗患者体内药动学特征

目的建立盐酸美沙酮（MTD）人体内血药浓度的测定方法 ,并对口服MTD口服液后的美沙酮维持治疗患者（MMTPs）体内的药动学过程进行研究。方法采用Agilent ZORBAX SB-C₁₈（250mm×4.6 mm,5μm）色谱柱,以乙腈-磷酸盐缓冲液（pH 2.5）=32:68（V/V）为流动相,流速1.50 mL·min^-1,检测波长206 nm,盐酸苯海索为内标,对血浆中的MTD浓度进行检测。8名MMTPs口服MTD口服液80 mg,分别于服药前和服药后1、2、3、4、6、8、12、24 h采集血样,测定血浆中MTD的浓度,并采用3P97药动学软件对试验数据进行处理,计算有关药动学参数。结果在0.10～10.00 mg·L^-1内,MTD与内标峰面积的比值与浓度之间呈良好的线性关系（r=0.999 6）。日内及日间精密度（RSD）和回收率均符合要求。MTD药-时曲线经拟合符合二室模型,主要参数:ρ_max（623.13 4-231.06）μg·L^-1;t_max为（2.764±1.13）h;AUC_0→24h为（9 569.56±3 294.88）μg·h·L^-1;AUC_0→∞为（21 522.61±10 825.36）μg·h·L^*（-1）;t_1/2为（23.95±13.61）h。结论本试验建立的检测人血浆中MTD含量的HPLC法,适用性强,重复性好,操作简单,快速准确,成本低廉,可用于MTD药动学的研究;MTD药动学特征和参数在个体间存在较大差异,临床治疗中应实施个体化治疗方案。     

Accidental and deliberate overdose among opiate addicts in methadone maintenance treatment: are deliberate overdoses systematically different?

The frequency of accidental or deliberate overdose was investigated among 200 opiate addicts in methadone substitution treatment in clinics in Edinburgh and south London. One hundred and three of the participants reported a mean of 3.4 overdoses, with 71 (69%) reporting that their most recent overdose was accidental, 27 (26%) deliberate-the remainder were uncertain. Those whose last overdose was deliberate were more likely to have been prescribed diazepam at that time and were more depressed at the time of interview. Differentiation by self-reported reason for overdose suggests that treatment providers should distinguish between accidental and deliberate overdose in developing overdose prevention strategies.     

Improvement of saccadic functions after dosing with methadone in opioid addicted individuals

In the current experiment, we used the saccadometric test to study the effect of a single therapeutic dose of methadone on the integrity of cortico-subcortical brain functioning. In this prospective study, we used the Saccadometer System (Advanced Clinical Instrumentation, Cambridge, UK). The saccadometric test was performed before and 1.5 hours after methadone dosing. We analyzed the following saccadic parameters: latency, duration, amplitude, average and peak velocity, and processing performance (promptness) as well as a number of different types of saccades (like correct/incorrect, under/overshoot, and left-sided/right-sided). The sample consists of 40 subjects with an average 18 years of opioid addiction. The mean age is 35.3 ± 7 (80% males and 20% females). The mean period of heroin dependence is 15.3 ± 6.3 years. The mean daily dose of methadone in substitution therapy is 90 ± 26.5 mg. After administration of a single therapeutic dose of methadone, there were statistically significant differences in the values of saccade duration and latency when compared to the values before the drug administration. Average duration of saccade was significantly longer [51.40 ± 8.75 ms versus 48.93 ± 6.91 ms, z = 2.53, p = .01] and average latency was significantly longer [198.85 ± 52.57 ms versus 183.05 ± 30.95 ms, z = 2.09 p < .03]. This is the first study to test the therapeutic effect of daily methadone dosing on the integrity of the cortico-subcortical brain functions as measured by the saccadometry. More research is needed to explore the effect of illicit opioid use on the integrity of brain structures and functions, and the protective effect of opioid agonist therapy on reversing the damaging effects of illicit opioid use.