Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal

BACKGROUND: A variety of detoxification methods have been utilized for the treatment of opiate withdrawal syndrome, of which alpha-adrenergic agonists have attracted considerable attention over the last two decades. However, accumulating evidence in rats shows the efficacy of the GABAB receptor agonist, baclofen, in reducing alcohol intake and self-administration of cocaine. OBJECTIVE: To examine the ability of baclofen, in the management of opiate withdrawal. METHOD: A total of 62 opiate addicts randomly assigned to treatment with baclofen or clonidine during a 14-day, double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. Maximum daily doses were 40 mg for baclofen and 0.8 mg for clonidine given three times a day in divided doses. The severity of the opiate withdrawal syndrome was measured on days 0, 1, 2, 3, 4, 7 and 14 using the Short Opiate Withdrawal Scale (SOWS). RESULTS: Baclofen and clonidine were equally effective in treating the physical symptoms of withdrawal syndromes. However, baclofen showed a significant superiority over clonidine in the management of mental symptoms. CONCLUSION: These results suggest that baclofen might be a novel therapeutic agent for opiate withdrawal syndrome. However, a larger study to confirm our results is warranted.     

Baclofen versus clonidine in the treatment of opiates withdrawal, side-effects aspect: a double-blind randomized controlled trial

OBJECTIVE: Baclofen is known for the alleviation of signs and symptoms of spasticity. Reports from our previous study have suggested that it may be at least as effective as clonidine in the management of physical symptoms of opiate withdrawal syndromes and superior to clonidine in the management of mental symptoms. We now report on a randomized double-blind comparison of baclofen vs. clonidine in view of side-effects profile. METHODS: A total of 62 opiates addicts were randomly assigned to treatment with baclofen or clonidine during a 14-day, double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. Maximum daily doses were 40 mg for baclofen and 0.8 mg for clonidine. This trial medication was given three times per day in divided doses. The severity of side-effects was measured in days 0, 1, 2, 3, 4, 7 and 14. RESULTS: There was no significant difference between two treat7ments in terms of retention in treatment (dropout) and overall side-effect. Nevertheless, significantly more problems relating to hypotension were encountered with subjects on clonidine. CONCLUSION: We conclude that, the low incidence of hypotension with baclofen suggests that the drug may be suitable for outpatient ambulatory treatment of withdrawal from opiates.     

New insights and treatments: opiate withdrawal and cocaine addiction

Basic research in the neurosciences has led to a theory of opiate withdrawal involving endogenous opioid peptides and hyperactive norepinephrine neurons. This theory predicts the efficacy of clonidine, a nonopiate agent, in the management of opiate withdrawal. Clonidine, which offers numerous advantages over methadone as a means of opiate detoxification, may be appropriate for use by general practitioners. Clonidine-aided detoxification can be followed immediately by naltrexone maintenance, which facilitates rehabilitation. Cocaine users' reports and clinical and basic studies, when pieced together, provide an outline of the natural history of chronic cocaine abuse. How certain users become addicts is not clear, however. Additional neurochemical research and neurophysiological studies are needed for the development of nonaddictive methods of detoxification (à la clonidine) and prophylaxis (à la naltrexone). In the absence of such studies, cocaine treatment programs use the methods of Alcoholics Anonymous, contingency contracting, and inpatient therapies for addiction.     

Headache in the Use and Withdrawal of Opiates and Other Associated Substances of Abuse

The incidence and character of headache were retrospectively studied in 40 opiate addicts and 40 control subjects. The relationships between headache and use and withdrawal of opiates or other associated substances of abuse were investigated. In the opiate-dependent patients, the effects of opiate intake and withdrawal on headache were also investigated during detoxification treatment. A higher (p less than 0.001) incidence of headache was found in the opiate addicts (60%), particularly those with a longer history of addiction, than in the control subjects. A history of different types of headache (tension type headache, migraine-like headaches), which seemed respectively to be associated with the use of certain types of heroin, cocaine intake, and opiate withdrawal, was reported by the addicts who suffered from headache. Out of the 24 patients who completed the detoxification therapy, a migraine-like headache occurred in 37.5% of the subjects after opiate withdrawal.     

"Induced detoxification treatment" of opiate dependent patients--a new therapy concept

Induced detoxification treatment of opiate addicts by means of naloxone was developed at the intensive care unit of the Department of Psychiatry at the University of Vienna. Two methods were tested 1. Rapid opiate withdrawal by means of a staggered naloxone regimen. 2. Ultrashort opiate detoxification during general anaesthesia using high doses of naloxone. In an open trial 15 patients were treated with staggered doses of naloxone while under tiapride. The various discomforts were satisfactorily reduced, and the detoxification syndrome was limited to 50 hours. In a second open trial 6 patients were administered 10 mg naloxone under general anaesthesia. All naloxone induced withdrawal syndromes can be suppressed by barbiturate anaesthesia. They do not appear even after the effect of the anaesthesia wears off if the patient is kept on a naloxone regimen as long as opiates remain present in the circulatory system. Both methods shorten detoxification treatment and provide smooth transition to a naltrexone maintenance programme.     

清风胶囊治疗海洛因依赖脱毒后稽延性戒断症状的临床研究

目的考察中药制剂清风胶囊治疗稽延性戒断症状的临床疗效。方法将320例脱毒10d以上的海洛因依赖者随机分成安慰剂组及清风胶囊组进行比较,共用药30d。结果用药后,清风胶囊组(n=208)患者的稽延性戒断症状评分值及焦虑症状评分值明显低于给药前,也明显低于安慰剂组(n=112)。清风胶囊能明显改善睡眠,缓解焦虑症状,消除躯体的疼痛,并能降低患者对毒品的渴求。结论清风胶囊对海洛因依赖者脱毒后的稽延性戒断症状及焦虑症状具有显著治疗作用。     

Opiate Detoxification Under General Anesthesia by Large Doses of Naloxone

Abstract

For opiate detoxification 6 volunteer opiate addicts were intravenously administered 10?mg naloxone within one hour while under barbiturate anesthesia.

During administration of naloxone none of the patients demonstrated significant changes in the hemodynamic parameters of heart rate, mean arterial pressure, cardiac index, peripheral resistance or in the oxygen saturation.

After patients awoke from anesthesia, they experienced no or only minimal withdrawal symptoms. Possible explanations for the suppression of withdrawal symptoms are discussed.     

阿片类成瘾者脱毒后感受的质性研究

目的了解阿片类成瘾者经美沙酮维持治疗脱毒后的心理感受。方法采用质性研究中的现象学方法,对14名脱毒者进行访谈。结果采用类属分析法升华出3个主题：美沙酮替代治疗效果显著;孤独无助;避免复吸而采取各种应对方式。结论阿片类成瘾者脱毒后,在社区康复中面临着诸多心理社会问题,需要建立社区康复机制以促进脱毒者的社会回归。     

Self-administration of clonidine, oxazepam, and hydromorphone by patients undergoing methadone detoxification

The extent to which hydromorphone, clonidine, and oxazepam alleviate the symptoms of opioid withdrawal and the extent and pattern of self-administration of these drugs during methadone detoxification were examined within a residential laboratory in three groups of patients dependent on methadone. Six times over the course of detoxification, acute effects of orally administered placebo and a single active drug (hydromorphone HCl, 3 mg, clonidine HCl, 0.3 mg, or oxazepam, 30 mg, all given twice daily) were tested, followed by an opportunity for subjects to self-administer the drug and dose of their choice. Hydromorphone significantly decreased opioid withdrawal symptoms and was more preferred for self-administration than the placebo. Clonidine and oxazepam did not significantly decrease withdrawal symptoms, nor was either drug self-administered significantly more than placebo. Clonidine, however, did induce side effects.     

Passionflower in the treatment of generalized anxiety: a pilot double-blind randomized controlled trial with oxazepam

OBJECTIVE: Passionflower (Passiflora incarnata) is a folk remedy for anxiety. A double-blind randomized trial compared the efficacy of Passiflora incarnata extract with oxazepam in the treatment of generalized anxiety disorder. METHODS: The study was performed on 36 out-patients diagnosed with GAD using DSM IV criteria. Patients were allocated in a random fashion: 18 to the Passiflora extract 45 drops/day plus placebo tablet group, and 18 to oxazepam 30 mg/day plus placebo drops for a 4-week trial. RESULTS: Passiflora extract and oxazepam were effective in the treatment of generalized anxiety disorder. No significant difference was observed between the two protocols at the end of trial. Oxazepam showed a rapid onset of action. On the other hand, significantly more problems relating to impairment of job performance were encountered with subjects on oxazepam. CONCLUSION: The results suggest that Passiflora extract is an effective drug for the management of generalized anxiety disorder, and the low incidence of impairment of job performance with Passiflora extract compared to oxazepam is an advantage. A large-scale trial is justified.     

Detoxification of nonopiate drugs in the chronic pain setting and clonidine opiate detoxification.

Although the pain physician is most familiar with the treatment of the opiate withdrawal syndrome, other drugs are abused by the chronic pain patient. The pain physician should then be familiar with the withdrawal syndromes associated with other drug groups. The withdrawal syndromes associated with hypnosedatives, psychotomimetics, nicotine, stimulants, ergot alkaloids, beta adrenergic blocking agents, antidepressants, muscle relaxants, and alpha-adrenergic agonists are described. Drug detoxification protocols for these drugs are reviewed. Additionally, the rationale for clonidine opiate detoxification is discussed, and current clonidine detoxification protocols are reviewed.     

A clinical trial of buprenorphine: comparison with methadone in the detoxification of heroin addicts

The efficacy of buprenorphine and methadone was compared in the outpatient detoxification of heroin addicts. Forty-five patients were randomized to receive either sublingual buprenorphine or oral methadone under double-dummy and double-blind conditions to study the pharmacology of buprenorphine in a 90-day detoxification protocol. The patients were administered either 2 mg buprenorphine or 30 mg methadone for 3 weeks followed by 4 weeks of dose reductions and 6 weeks of placebo medication. No significant between-group differences were seen on measures of treatment retention, drug use, or symptom report. During the hydromorphone challenge, methadone attenuated opioid effects to a greater extent than did buprenorphine on both physiologic (pupil constriction) and self-report measures. However, this did not result in greater abuse of illicit opioid drugs by subjects taking buprenorphine. The results of this clinical trial indicated that buprenorphine was acceptable to patients and as effective as methadone in the detoxification treatment of heroin addicts.     

Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence

BACKGROUND: Buprenorphine is a partial mu-opiate agonist and kappa-opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence. METHODS: Two hundred outpatients currently dependent on both cocaine and opiates were randomly assigned to double-blind groups receiving a sublingual solution of buprenorphine (2, 8, or 16 mg daily, or 16 mg on alternate days, or placebo), plus weekly individual drug abuse counseling, for 13 weeks. The chief outcome measures were urine concentrations of opiate and cocaine metabolites (quantitative) and proportion of urine samples positive for opiates or cocaine (qualitative). Group differences were assessed by use of mixed regression modeling. RESULTS: The target dose of buprenorphine was achieved in 179 subjects. Subjects receiving 8 or 16 mg buprenorphine daily showed statistically significant decreases in urine morphine levels (P =.0135 for 8 mg and P <.001 for 16 mg) or benzoylecgonine concentrations (P =.0277 for 8 mg and P =.006 for 16 mg) during the maintenance phase of the study. For the 16-mg group, mean benzoylecgonine concentrations fell from 3715 ng/mL during baseline to 186 ng/mL during the withdrawal phase; mean morphine concentrations fell from 3311 ng/mL during baseline to 263 ng/mL during withdrawal. For the 8-mg group, mean benzoylecgonine concentrations fell from 6761 ng/mL during baseline to 676 ng/mL during withdrawal; mean morphine concentrations fell from 3890 ng/mL during baseline to 661 ng/mL during withdrawal. Qualitative urinalysis showed a similar pattern of results. Subjects receiving the highest dose showed concomitant decreases in both urine morphine and benzoylecgonine concentrations. There were no significant group differences in treatment retention or adverse events. CONCLUSIONS: A sublingual buprenorphine solution at 16 mg daily is well tolerated and effective in reducing concomitant opiate and cocaine use. The therapeutic effect on cocaine use appears independent of that on opiate use.     

Total neurochemical lesion of noradrenergic neurons of the locus ceruleus does not alter either naloxone-precipitated or spontaneous opiate withdrawal nor does it influence ability of clonidine to reverse opiate withdrawal.

It has been suggested that an increase firing rate of noradrenergic neurons of the locus ceruleus is responsible for the opiate withdrawal syndrome. However, lesion studies have indicated that the noradrenergic neurons of the locus ceruleus are not essential for either the expression or suppression by clonidine of opiate withdrawal. The present study was designed to determine the effect of the almost complete 6-hydroxydopamine lesion of noradrenergic neurons (94%) of the locus ceruleus on various components of the opiate withdrawal syndrome and on its protection by clonidine. Morphine dependence was induced by s.c. implantation of morphine pellets (2 x 75 mg base). The following paradigms were used: 1) naloxone-induced conditioned place aversion, 2) naloxone-precipitated acute opiate withdrawal syndrome, 3) nycthemeral locomotor activity as a measure of spontaneous opiate withdrawal. The results showed that quasi-total lesion of noradrenergic neurons of the locus ceruleus did not modify opiate dependence as revealed by naloxone-induced conditioned place aversion and the expression of an acute morphine withdrawal syndrome. Moreover, clonidine prevented the opiate withdrawal syndrome in both lesioned and sham-operated rats, suggesting that the action of clonidine is certainly mediated through postsynaptic alpha(2)-adrenoceptor stimulation. Finally, the nycthemeral locomotor activity during spontaneous morphine withdrawal did not differ between the lesioned and the sham-operated rats.     

Discriminative stimulus effects of morphine withdrawal in the dependent rat: suppression by opiate and nonopiate drugs

Morphine-dependent rats can be trained to discriminate between s.c. injections of saline and 0.1 mg/kg of naltrexone. The discriminative effects of naltrexone, measured by the number of trials completed on the naltrexone-appropriate choice lever in a 20-trial avoidance paradigm, derive from stimuli associated with morphine withdrawal. Opiate and nonopiate drugs were injected s.c. and examined for their ability to block naltrexone-induced discriminative effects and loss of body weight in morphine-dependent rats. Seven opiates blocked dose dependently the discriminative effects of naltrexone and loss of body weight. Potency ranged from fentanyl (330 X morphine) to meperidine (less than 1 X morphine); effects were stereoselective for levorotatory isomers. Loperamide, an opiate that does not readily enter the brain, blocked loss of body weight but not discriminative effects, suggesting that discriminative effects are mediated centrally. Nonopiate behavioral depressants, diazepam, haloperidol and pentobarbital, did not substantially affect either dependent variable, but clonidine (0.01-1.0 mg/kg) blocked discriminative effects of naltrexone partially and weight loss completely. The blockade by morphine (30 mg/kg) of naltrexone-induced discriminative effects and weight loss was surmounted by increasing the dose of naltrexone whereas the blockade by clonidine (0.1 mg/kg) was not. Thus, blockade by opiates of effects of naltrexone appears to be due to a competitive interaction at the mu opioid receptor; clonidine has a different mechanism of action. This discrimination paradigm may afford a specific animal model for studying fundamental processes underlying physical dependence on opiates and for evaluating novel pharmacologic approaches for treating opiate withdrawal in humans.     

Clonidine versus chlordiazepoxide in acute alcohol withdrawal: a preliminary report

The findings presented here are from the first reported comparison and double-blind evaluation of 20 patients randomly assigned to either chlordiazepoxide (n = 10) or clonidine (n = 10) for the treatment of acute alcohol withdrawal syndrome. Analysis of the study data demonstrated more favorable scores on tests of alcohol withdrawal symptoms (AWS), and better control of blood pressure, pulse, and respiratory rate with clonidine than with chlordiazepoxide therapy. In all other comparisons, clonidine was at least as efficacious. Clonidine may 'represent a new and possibly even superior pharmacologic treatment in the management of acute alcohol withdrawal syndrome.     

Diazoxide in the treatment of schizophrenia: novel application of potassium channel openers in the treatment of schizophrenia

OBJECTIVE: Schizophrenia is a very common disorder, affecting 1% of the world population. People who develop schizophrenia experience severe suffering and approximately 10% commit suicide. The causes of schizophrenia are still largely unknown. The relative ineffectiveness of dopamine antagonists to treat some symptoms of schizophrenia has promoted many investigators to postulate the involvement of the neuronal system in the pathophysiology of this disease. It has been suggested that the dopamine-coupled adenosine triphosphate (ATP)-sensitive channels may function by hyperpolarizing cells during metabolic stress, a function that may be disrupted in people with schizophrenia. Therefore, application of potassium channel openers/activators may be beneficial in schizophrenia. Diazoxide is a benzothiadiazine derivative related to the thiazide diuretics and a potassium channel opener. The purpose of the present investigation was to assess the efficacy of diazoxide, as an adjuvant agent in the treatment of schizophrenia. METHODS: Forty-two patients who met the DSM IV criteria for chronic schizophrenia completed the study. Patients were randomized to haloperidol 20 mg/day plus diazoxide 200 mg/day (21 subjects) or to haloperidol 20 mg/day plus placebo (21 subjects) in this 8-week double-blind study. RESULTS: Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of haloperidol and diazoxide showed a significant superiority over haloperidol alone in the treatment of positive and general psychopathology symptoms as well as positive and negative syndrome scale (PANSS) total scores. In addition, in the diazoxide group a rapid onset of action on the positive symptoms was observed in week 2, whereas in the placebo group there was no significant effect at week 2. No significant differences were observed between the two protocols on the negative scores. CONCLUSION: The results of this study present a novel application for potassium channel openers/activators in the neuropsychiatric disorders and diazoxide may be an effective adjuvant agent in the management of schizophrenia.     

The Abrupt Cessation of Therapeutically Administered Sodium Oxybate (GHB) Does Not Cause Withdrawal Symptoms

Sodium oxybate (gamma-hydroxybutyrate; GHB) has demonstrated efficacy for the treatment of narcolepsy. However, there are reports of withdrawal following chronic abuse of illicit GHB which involve escalating both doses and dosing frequency. The present trial afforded an opportunity to test the hypothesis that chronic daily therapeutic dosing of sodium oxybate in narcoleptics does not cause withdrawal following abrupt cessation. Fifty-five narcoleptic patients, taking sodium oxybate (dose range 3–9 gm/night) for 7–44 months (mean 21 months), were randomized into a 2-week double-blind period: 29 patients received placebo and 26 continued to receive sodium oxybate. During this 2-week trial period, the following symptoms were reported in patients receiving placebo (N): anxiety (2), dizziness (1), insomnia (1) and somnolence (1). While these symptoms may represent possible symptoms of mild GHB withdrawal, they are also highly consistent with the returning symptoms of narcolepsy. We conclude there is minimal evidence of withdrawal symptoms following abrupt cessation of chronic sodium oxybate dosing in the therapeutic range.     

Opiate and cocaine dependencies. Techniques to help counter the rising tide

Clonidine (Catapres) is a safe and effective agent for detoxification of selected opiate addicts. It seems best suited for transitional treatment between opiate dependency and aftercare with naltrexone (Trexan). The current epidemic of cocaine abuse in the United States is associated with intensified usage patterns and an increased prevalence of adverse medical consequences. Successful treatment of the cocaine abuser may require either hospitalization or structured outpatient treatment in a specialized program.     

中药康复新、福康片和可乐定对阿片类戒断症状的双盲对照研究

目的评价康复新胶囊、福康片、盐酸可乐定对海洛因依赖的脱毒效应、不良反应及安全度。方法海洛因依赖者,按区组随机进入康复新胶囊组33例,可乐定组30例,福康片组28例,安慰剂组29例。3次/d口服给药。在规定时间内按照原卫生部药政管理局制定的《阿片类戒断症状药物临床试验指导原则》评定药物疗效和不良反应;按照汉密顿焦虑量表(HAMA),评定焦虑情绪变化情况。肝肾功能、血常规、心电图、尿吗啡定性检测(TLC)治疗前后各查1次。结果(1)康复新胶囊、福康片和可乐定疗效相当,疗程结束后戒断症状无反复。(2)吸毒史、末次用量、末周平均用量、汉密顿焦虑量表评分以及戒断症状总分与药物的疗效呈高度相关。(3)康复新胶囊不良反应评分介于可乐定组与福康片组之间。结论发现中药戒毒药物疗效明确,可用于治疗较重度戒断症状,无依赖性,不良反应轻。