洛非西定与可乐定控制阿片戒断症状的临床效能比较

洛非西宁（路脱菲）是可乐定的同类物，本文首次报告此药对我国海洛因成瘾者的治疗状况，并与可乐定进行了比较。完成１０ｄ治疗者共７４例（洛非西定组３８例，可乐定组３６例）。两组的最高剂量分别为１．６－２．４ｍｇ．ｄ＾－１（洛非西定）和１．２ｍｇ／ｄ（可乐定）。逐日观察戒断症状及副作用的变化。发现，洛非酮定可有效和较全面地控制阿片类戒断症状，具备治疗的时效作用特点。两组比较一般不良反应相近，大多程度较轻，     

中药济泰胶囊与洛非西定治疗阿片类戒断症状临床双盲对照研究

目的··:观察济泰胶囊控制阿片类物质依赖戒断症状的疗效及不良反应。方法··:97例入组病例按双盲对照设计随机分为济泰组(48例)和洛非西定组(49例),观察10d,比较两药的疗效和不良反应。结果··:济泰胶囊能控制阿片类物质依赖的戒断症状,其副作用同洛非西定相似,而对心血管系统的副作用,尤其对血压、脉搏的影响,在治疗前4d,济泰胶囊明显地较洛非西定轻。济泰胶囊的主要不良反应有:口干、眼花、视物模糊及谵妄。结论··:济泰胶囊控制阿片类物质依赖的戒断症状,其疗效明显,比较安全可靠,有一定的临床价值。     

可乐定对吗啡依赖小鼠催促戒断后行为的影响

目的:研究吗啡依赖小鼠在纳洛酮催促戒断时可乐定治疗对稽延性戒断症状相关行为的影响。方獉法獉:采用剂量递增法使小鼠对吗啡产生依赖;每天sc盐酸吗啡3次,共3d,剂量由50mg·kg-1逐步上升到125mg·kg-1。d4sc注射50mg·kg-1吗啡1h后,可乐定治疗组小鼠ig0.6mg·kg-1可乐定,对照组ig等体积的去离子水;sc吗啡2h后各组小鼠均ip5mg·kg-1的纳洛酮进行催促戒断,观察30min内小鼠的跳跃反应和体重变化。在催促戒断后5h和24-30h通过洞板试验、悬尾试验、十字迷宫试验和自发活动试验,观察小鼠的探究行为、抑郁样行为、焦虑行为及活动性。部分小鼠在第一次戒断后10h及次日重新给予吗啡(100-125mg·kg-1)使之再次产生依赖,在d6依d4操作进行二次戒断,但不给予可乐定治疗。结果:在催促戒断试验中,可乐定可以显著降低吗啡依赖小鼠的跳跃次数和体重减轻(P<0.01);催促戒断5h后,可乐定组小鼠在洞板试验中的探洞次数比对照组少(P<0.01);在悬尾试验中的不动时间比对照组长(P<0.01);在十字迷宫试验中进入开臂的时间和次数与对照组比较差异无显著性;在自发活动试验中,前5min自发活动计数低于对照组(P<0.01),但30min内活动量与对照组比较差异无显著性;催促戒断24-30h后,两组之间的各项行为学指标差异均无显著性;在二次戒断实验中,可乐定组小鼠跳跃次数高于对照组(P<0.05),但两组小鼠体重变化差异无显著性。结论:用于拮抗吗啡依赖小鼠急性戒断症状的可乐定对戒断后的抑郁样行为有加重趋势,对焦虑行为没有影响;可乐定上述作用的行为药理学机制可能是抑制逃脱动机。     

脱毒灵胶囊3日疗法用于海洛因依赖脱毒临床观察

目的:评价脱毒灵3日疗法对海洛因依赖的脱毒效果及不良反应.方法:海洛因依赖患者123例,随机分为脱毒灵组62例和洛非西定组61例,脱毒灵疗程3日,洛非西定疗程10日,对脱毒灵与洛非西定做临床观察对照研究.结果:脱毒灵能全面迅速地控制海洛因依赖戒断症状.治疗d 3戒断症状总分减分率脱毒灵组为0.86±0.11,洛非西定组为0.24±0.18;治疗d 10戒断症状总分减分率脱毒灵组为1.00±0.01,洛非西定组为0.86±0.10.所有疗效观察项目脱毒灵组均显著优于洛非西定组.脱毒灵组未观察到不良反应.结论:脱毒灵3日脱毒法疗程短,效果显著可靠,临床使用安全.     

洛非西定抑制吗啡依赖大鼠蓝斑Fos蛋白的表达

目的·· :研究洛非西定控制阿片类戒断症状的分子机理。方法·· :采用连续5dip 吗啡,建立大鼠吗啡依赖模型 ,给予洛非西定干预、纳洛酮促瘾后观察戒断症状 ,并取桥脑蓝斑切片 ,进行Fos蛋白免疫细胞化学实验。结果··:吗啡依赖大鼠经洛非西定干预后 ,由纳洛酮催促的戒断症状明显低于未经洛非西定处理组 ;经洛非西定干预后 ,蓝斑Fos蛋白免疫反应活性明显低于未经洛非西定处理组 ;但较盐水对照组高。结论·· :洛非西定能抑制吗啡依赖大鼠戒断症状以及蓝斑Fos蛋白的表达。     

济泰片联合洛非西定治疗海洛因依赖的临床疗效观察

目的··:探索戒毒疗效好、不造成新的药物成瘾 ,且经济的脱毒方案。方法·· :将60例海洛因依赖者分成A、B两组组 ,A组给予济泰片联合洛非西定脱毒,B组单纯使用小剂量美沙酮脱毒 ,对照观察两组的脱毒疗效。结果·· :在控制戒断症状方面 ,A组与B组比较无显著性差异(P<0.05) ,但A组不良反应轻微。B组有17例停用美沙酮后有索药行为。两药合用 ,济泰片用量减少。结论··:济泰片联合洛非西定组临床疗效可靠 ,且无成瘾性 ,副作用少 ,价格低,值得推广应用     

脱毒灵胶囊用于海洛因依赖脱毒临床观察

目的:初步评价脱毒灵对海洛因依赖的脱毒效果及不良反应。方法:海洛因依赖戒断症状患者82例,按随机化方法,分为脱毒灵组42例和洛非西定组40例;对脱毒灵与洛非西定进行初步临床观察对照研究。结果:脱毒灵能全面迅速地控制海洛因依赖戒断症状。治疗d 5戒断症状总分减分率脱毒灵组为0.99±0.02,洛非西定组为0.36±0.18;治疗d 10戒断症状总分减分率脱毒灵组为1.00±0.01,洛非西定组为0.78±0.13。所有疗效观察项目脱毒灵组均显著优于洛非西定组,大部分项目P<0.001。脱毒灵组几乎未观察到不良反应和依赖性。结论:脱毒灵对海洛因依赖脱毒效果显著可靠,临床使用安全。     

抗阿片戒断症状新药——盐酸洛非西定

洛非西宁是可乐定的同类物，同属于非阿米片类药物，可缓解阿片类依赖的戒断症状，洛非西定控制症状的效能与可乐定相近，但副作用较轻，百降血压及过度镇静等副作用较轻，使其更适于门诊脱毒治疗。     

可乐定脱毒治疗对吗啡依赖大鼠吗啡条件性位置偏爱效应和镇痛作用的影响

目的:研究给予吗啡依赖大鼠可乐定治疗对吗啡奖赏效应和镇痛作用的影响。方法:采用剂量递增法(5-40mg·kg-1,每天3次,30d)建立吗啡依赖大鼠模型,在自然戒断后7d内给予可乐定(0.1mg·kg-1,每天3次)进行治疗;停用可乐定后训练大鼠吗啡(1mg·kg-1)条件性位置偏爱(CPP),观察CPP的形成速度和维持情况;期间利用热痛甩尾法,观察吗啡(5mg·kg-1)的镇痛作用。结果:CPP训练4d后,经可乐定治疗的大鼠形成了吗啡CPP,而未经可乐定治疗的大鼠没有形成CPP;经过8d训练后,经可乐定治疗及未治疗的大鼠均形成了明显的吗啡CPP;在训练停止后14d,经可乐定治疗大鼠的CPP已消退,而未经可乐定治疗的大鼠CPP没有消退。在镇痛实验中,可乐定治疗及未治疗大鼠应用吗啡前后的甩尾时间组间比较差异不显著。结论:可乐定治疗能改变吗啡依赖大鼠的吗啡奖赏效应,但不影响大鼠对吗啡镇痛作用的耐受。     

参附脱毒胶囊与可乐定控制海洛因依赖戒断症状的随机双盲对照研究

目的·· :客观评价参附脱毒胶囊对海洛因依赖的脱毒效应、不良反应及安全度。方法·· :按照卫生部原药政管理局制定的《抗阿片类戒断症状药物临床试验指导原则》 ,采用随机双盲对照临床研究。纳入病例临床观察指标为《戒断症状评定量表》、《HAMA焦虑评定量表》、《不良反应评定量表》 ;实验室检查指标为血尿常规、肝肾功能、心电图、尿液吗啡定性测定。结果·· :纳入病例92例。随机进入参附脱毒胶囊组33例 ,可乐定组30例 ,安慰剂组29例。参附脱毒胶囊组与可乐定组类似 ,在治疗的d1、d2、d3戒断症状快速减轻 (P<0.05) ,呈现出明显的时效关系。在治疗的d3 ,参附脱毒胶囊控制戒断症状的有效率达57.3 % ,可乐定的有效率为46.7 % ,均明显大于安慰剂的有效率6.9 %(P<0.001)。疗程结束时吗啡尿检呈阴性反应 ,停药后戒断症状无反复。参附脱毒胶囊组的不良反应总分、对血压的影响明显较可乐定为低 (P<0.05)。未发现对肝、肾功能、血尿常规的明显影响。结论··:参附脱毒胶囊控制戒断症状的疗效肯定 ,与可乐定疗效相当。不良反应主要为口干、思睡、头晕 ,多为轻度反应 ,无需处理自行消失。在治疗的初期应给予充分剂量 ,每次1.2-1.6g ,每日3次为宜。d4起可逐日减量     

Clonidine in Opiate Withdrawal: Review and Appraisal of Clinical Findings

Studies in animals and humans have demonstrated that clonidine hydrochloride, an alpha-2-nor-adrenergic agonist, significantly attenuates the opiate withdrawal syndrome. Inpatient and outpatient clinical studies have shown that clonidine is a reasonably safe, specific, and effective agent for detoxifying opiate addicts. Clonidine seems best suited for use as a transitional treatment between opiate dependence and induction onto the opiate antagonist naltrexone. Dosage regimens of clonidine must be individualized according to symptoms and side effects and closely supervised because of varying sensitivity to clonidine's sedative, hypotensive, and withdrawal-suppressing effects. Clonidine is an important new treatment option for selected opiate addicts and may be the treatment of choice when detoxification using methadone is inappropriate, unsuccessful, or unavailable. Lofexidine, a structural analogue of clonidine, may be safer and more effective as an opiate detoxification treatment. It has similar withdrawal-suppressing actions but causes little hypotension and sedation. Although clonidine and lofexidine may be highly effective in helping opiate addicts achieve initial abstinence, a multi-modality aftercare treatment approach including naltrexone and psychotherapy may be necessary to maintain an abstinent state.     

Lofexidine versus clonidine in rapid opiate detoxification

The aim of the present study is to evaluate lofexidine and clonidine, in an accelerated opiate detoxification procedure (3 days), without anaesthesia. Forty heroin-dependent individuals were detoxified, evaluating withdrawal symptoms, craving levels, mood changes, urine toxicologic screens, and dropout during therapy with either (1) clonidine, oxazepam, baclofen, and ketoprofene, with naloxone and naltrexone for 3 days (20 subjects) or (2) lofexidine, oxazepam, baclofen, and ketoprofene with naloxone and naltrexone for 3 days (20 subjects).Both clonidine and lofexidine rapid detoxifications were found effective. The subjects treated with lofexidine showed significantly lower levels of withdrawal symptoms, fewer mood problems, less sedation and hypotension. No significant differences in craving levels, morphine metabolites in urine, or dropout rate were evidenced between the two groups. The early use of naltrexone during detoxification in combination with either alpha-2-agonist facilitated the acceptance for long-term naltrexone treatment. Lofexidine appeared to be more useful than clonidine in a 3-day accelerated opiate detoxification, not only to counteract withdrawal symptoms, but also in the treatment of dysphoria and mood changes. Because lofexidine does not produce hypotension, safe outpatient treatment, without hospital support, could be possible.     

Double-blind study of lofexidine and clonidine in the detoxification of opiate addicts in hospital

Twenty eight opiate addicted inpatients who had been stabilised on methadone took part in a double-blind randomised trial of clonidine and lofexidine (14 on each treatment) for opiate detoxification; clonidine or lofexidine dosage was titrated according to symptoms. The course of withdrawal symptoms was very similar with both treatments, representing an appreciable suppression of symptoms when compared with experiences of sudden methadone withdrawal, but lofexidine resulted in significantly less hypotension and adverse events. These results suggest that lofexidine is a valuable drug for opiate detoxification and may be more acceptable to patients wishing to withdraw from opiates.     

A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal

CONTEXT: Lofexidine is an alpha-2-adrenergic receptor agonist that is approved in the United Kingdom for the treatment of opioid withdrawal symptoms. Lofexidine has been reported to have more significant effects on decreasing opioid withdrawal symptoms with less hypotension than clonidine. OBJECTIVE: To demonstrate that lofexidine is well tolerated and effective in the alleviation of observationally defined opioid withdrawal symptoms in opioid dependent individuals undergoing medically supervised opioid detoxification as compared to placebo. DESIGN: An inpatient, Phase 3, placebo-controlled, double-blind, randomized multi-site trial with three phases: (1) opioid agonist stabilization phase (days 1-3), (2) detoxification/medication or placebo phase (days 4-8), and (3) post detoxification/medication phase (days 9-11). SUBJECTS: Sixty-eight opioid dependent subjects were enrolled at three sites with 35 randomized to lofexidine and 33 to placebo. MAIN OUTCOME MEASURE: Modified Himmelsbach Opiate Withdrawal Scale (MHOWS) on study day 5 (second opioid detoxification treatment day). RESULTS: Due to significant findings, the study was terminated early. On the study day 5 MHOWS, subjects treated with lofexidine had significantly lower scores (equating to fewer/less severe withdrawal symptoms) than placebo subjects (least squares means 19.5+/-2.1 versus 30.9+/-2.7; p=0.0019). Lofexidine subjects had significantly better retention in treatment than placebo subjects (38.2% versus 15.2%; Log rank test p=0.01). CONCLUSIONS: Lofexidine is well tolerated and more efficacious than placebo for reducing opioid withdrawal symptoms in inpatients undergoing medically supervised opioid detoxification.     

Opiate detoxification with lofexidine

Noradrenergic neuronal hyperactivity is the final common pathway responsible for the signs and symptoms of opiate withdrawal in man. We have used this NE hyperactivity hypothesis to explain a large body of preclinical and clinical research and in screening potential antiwithdrawal treatments for clinical use. While the efficacy of clonidine in human opiate withdrawal offered strong support for the LC disinhibition or NE hyperactivity hypothesis on the basis of the known effects of low dose clonidine on the LC and NE activity, it was only one test of the hypothesis. More recently, we have suggested that lofexidine, an imidazoline derivative which is a structurally related analogue of clonidine, may be the ideal non-opiate antiwithdrawal agent for outpatients. We have recent data from 15 male chronic methadone addicts which demonstrates potent antiwithdrawal activity for lofexidine and offers additional support for the NE hyperactivity hypothesis of opiate withdrawal. Lofexidine significantly reduced withdrawal signs and symptoms. Systolic and diastolic blood pressure were not significantly decreased and remained in the normal range. The effects of clonidine and now lofexidine in opiate withdrawal support the NE hyperactivity hypothesis and suggest these medications reverse opiate withdrawal by replacing opiate-mediated inhibition with alpha-2 adrenergic inhibition of NE activity.     

Double-blind randomised controlled trial of lofexidine versus clonidine in the treatment of heroin withdrawal

Lofexidine is an analogue of clonidine, an agonist at the α₂ noradrenergic receptor. Reports from preliminary open studies have suggested that it may be at least as effective as clonidine in the management of opiate withdrawal, and without the same limitation of postural hypotension. We report on a randomised double-blind comparison of lofexidine versus clonidine in the treatment of heroin withdrawal. A total of 80 hospitalized heroin addicts were randomly assigned to treatment with lofexidine or clonidine during in-patient opiate withdrawal. Maximum daily doses were 1.6 mg for lofexidine and 0.6 mg for clonidine. There was marked diurnal variation of withdrawal symptoms with severity being greatest at the daytime reading at 16.00 h and being markedly less at the night-time reading (recorded at 08.00 h). Lofexidine and clonidine were equally effective in treating the withdrawal syndrome. However, significantly more problems relating to hypotension were encountered with subjects on clonidine, with twice as many instances of withholding medication due to hypotension in the clonidine group. Better treatment retention rates were seen in the lofexidine group, although no difference was found in the proportion who had reached minimal symptom severity by the time of their discharge. We conclude that lofexidine and clonidine are equally effective, but with significantly fewer hypotensive problems with lofexidine. Further benefit from lofexidine may be possible with revised dosing regimens. Outpatient studies of lofexidine are now indicated.     

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.     

Randomised double-blind comparison of lofexidine and clonidine in the out-patient treatment of opiate withdrawal

This study compares the clinical response to lofexidine and clonidine in the out-patient treatment of opiate withdrawal in 50 opiate addicts, using a randomised double-blind study design. Patients were taking 40 mg or less methadone daily, or equivalent amounts of other opiates. Fifty-eight percent of those starting treatment completed detoxification, and were opiate free at 4 weeks: more patients completed withdrawal in the lofexidine group, but the difference was not significant. Clonidine produced more hypotensive effects: more home visits were also required by medical staff. There was no other significant difference in side effects. Both drugs can be used successfully in out-patient detoxification, but lofexidine is more economical in regard to staff time.     

Naltrexone and lofexidine combination treatment compared with conventional lofexidine treatment for in-patient opiate detoxification

This study compares a naltrexone/lofexidine combination treatment with a 7-day course of lofexidine alone in the treatment of opiate withdrawal in 22 opiate-dependent patients. Withdrawal symptoms were significantly less severe on days 4-7, and 9-13, in the naltrexone/lofexidine combination group. There were no significant differences in the percentage of patients completing detoxification or in the mean length of stay for the two groups. Both treatments had similar, minimal effects on blood pressure. The naltrexone/lofexidine combination was associated with a more rapid resolution of the opiate withdrawal syndrome than a 7-day lofexidine-only treatment schedule, without substantial increases in withdrawal symptoms or hypotensive side-effects.