A comparison of antagonist-precipitated withdrawal under anesthesia to standard inpatient withdrawal as a precursor to maintenance naltrexone treatment in heroin users: outcomes at 6 and 12 months

To compare two methods of heroin withdrawal, 51 heroin users were randomised to undergo a 1 day precipitated withdrawal procedure using naloxone under anaesthetic. About 50 participants were randomised to receive the current standard inpatient withdrawal treatment using clonidine plus symptomatic medication. Following withdrawal, both groups were offered 9 months of naltrexone treatment and supportive counselling. Outcome measures were: commencement of naltrexone, retention in treatment and heroin use at 6 and 12 months. Significantly more of the precipitated withdrawal group completed withdrawal, commenced naltrexone and stayed in treatment for the first 3 months. Overall, there was a significant reduction in both self-reported heroin use and morphine concentration in hair over the 12 month study period, with participants in the precipitated withdrawal group showing significantly lower morphine concentration at 6 months. Being younger and having a lower level of dependence were predictors of abstinence at 6 and 12 months. The advantage of precipitated withdrawal under anesthesia did not persist beyond 3 months with respect to retention in naltrexone treatment or beyond 6 months with respect to heroin use. Long-term follow-up is crucial in assessing the effects of treatment interventions for heroin dependence.     

海洛因依赖者纳曲酮治疗过程中意外催瘾的研究

目的:探讨海洛因依赖者纳曲酮抗复吸治疗中意外催瘾的作用。方法:对49例应用纳曲酮抗复吸治疗的海洛因依赖者随访6个月,了解患者意外催瘾经历,以及意外催瘾对患者偷吸、脱毒后操守率及服用纳曲酮保持率的影响。结果:27例(55.1%)有意外催瘾的经历;与无意外催瘾组比较,在1-4周内,有意外催瘾组的偷吸人数少(P<0.05,P<0.01),2-25周的操守率高(P<0.05);Cox回归分析发现,稽延性戒断症状、患者孤独、沉闷情绪及家庭经济困难是纳曲酮治疗保持率的风险因素。结论:意外催瘾具有厌恶疗法样作用,对应用纳曲酮抗复吸治疗的海洛因依赖者的抗偷吸和抗复吸具有积极意义。     

Emergency management of inadvertent accelerated opiate withdrawal in dependent opiate users

Six opiate-dependent drug users presented to the local emergency department within a 10-day period with symptoms of severe opioid withdrawal immediately following intravenous use of recently acquired street 'heroin'. The withdrawal picture was similar to that described in patients undergoing rapid opioid detoxification, suggesting that the substance injected was contaminated with an opiate antagonist. A number of potential compounds are discussed, including naltrexone and buprenorphine, and recommendations for the medical management of severe opiate withdrawal within an emergency setting are outlined. [Lubman DI, Koutsogiannis Z, Kronborg I. Emergency management of inadvertent accelerated opiate withdrawal in dependent opiate users. Drug Alcohol Rev 2003;2:433 - 436]     

In-patient benzodiazepine withdrawal: comparison of fixed and symptom-triggered taper methods

Fixed and symptom-triggered taper methods during in-patient benzodiazepine withdrawal treatment were compared using a randomized controlled design. Forty-four benzodiazepine users seeking in-patient withdrawal treatment at two substance use treatment clinics in Adelaide, Australia were recruited. Measurements included the Severity of Dependence Scale and the SF-36. A scale comprising six items from the Clinical Institute Withdrawal Assessment Scale--Benzodiazepines (CIWA-B) was used to measure withdrawal symptoms. Participants were randomized to receive a fixed diazepam tapering regime or diazepam only in response to withdrawal symptoms (symptom-triggered group). Results showed that there were no significant differences between treatment groups in terms of withdrawal severity, duration of in-patient treatment, amount of diazepam administered, treatment attrition and benzodiazepine use at follow-up. Both groups showed a reduction in benzodiazepine dosage of 86% over the first 8 days which was maintained at 1 month post-discharge. Although there were improvements in some subscales of the SF-36 between baseline and follow-up, values were significantly below age-matched norms at both time-points. This study showed that benzodiazepine users entering treatment have relatively poor health and that symptom-triggered taper methods incorporating flexible dosing and flexible treatment duration are as effective as fixed dose taper methods for in-patient benzodiazepine withdrawal treatment. [McGregor C, Machin A, White JM. In-patient benzodiazepine withdrawal: comparison of fixed and symptom-triggered taper methods. Drug and Alcohol Rev 2003;22:175 - 180]     

Current pharmacotherapies for opioid dependence

Pharmacotherapy of intravenous opioid abusers has taken on increased urgency with the acquired immunodeficiency syndrome (AIDS) epidemic, because in major cities intravenous drug abuse now accounts for half of new AIDS cases. The pharmacotherapy of acute dependence and withdrawal has benefited from the use of clonidine, particularly in combination with antagonist-precipitated withdrawal. However, protracted abstinence and its associated risk of relapse to drug abuse has underscored the need for maintenance pharmacotherapies. Maintenance pharmacotherapies such as methadone and naltrexone are frequently needed to sustain outpatient retention and abstinence from heroin. Methadone is more widely used than is naltrexone, an oral, long acting heroin blocker that can maintain drug abstinence after detoxification. Because of limitations in both of these maintenance agents, two investigational maintenance treatments have been tested: levo-alpha-acetylmethadol (LAAM), a long-acting form of methadone, and buprenorphine, a long-acting mixed opioid agonist-antagonist with properties similar to either methadone or naltrexone, depending on dose. Clinical use, limitations, and outcome with each medication are reviewed.     

全麻下纳曲酮快速阿片类脱毒的初步临床经验

目的··：观察全身麻醉下纳曲酮加洛非西定快速阿片类脱毒（ＲＯＤ）的治疗效果。方法··：２３例接受ＲＯＤ的海洛因依赖者与２０例１０ｄ美沙酮替代递减治疗的海洛因依赖者进行比较。接受ＲＯＤ治疗的患者进行气管插管,硫喷妥钠和氯胺酮静脉复合麻醉。麻醉诱导后,给予纳洛酮２ｍｇ,纳曲酮５０ｍｇ。麻醉结束后患者转入戒毒病房旁的监护病房。ＲＯＤ组在麻醉前及麻醉后２４ｈ,对照组在入院时及入院后ｄ５,进行戒断症状评定。结果··：ＲＯＤ组麻醉后２４ｈ的渴求、焦虑和睡眠障碍分显著低于对照组（Ｐ＜０．０１）,腹泻分高于对照组（Ｐ＜０．０１）,骨骼肌肉疼痛、恶心呕吐及总分与对照组相当（Ｐ＞０．０５）。ＲＯＤ组麻醉后２４ｈ戒断症状总分与海洛因使用量有相关关系（ｒ＝０．４２１,Ｐ＜０．０１）。ＲＯＤ组有７８．２６％的患者接受纳曲酮维持,而对照组只有１０％的患者接受。结论··：ＲＯＤ是一项可选择的脱毒方法     

Use of drug combinations in treatment of opioid withdrawal.

During the last 10 years new approaches for rapid opioid detoxification have included drug combinations such as clonidine and naltrexone to speed and ease the transition from opioid agonist to antagonist maintenance. Other drug combinations include naloxone with midazolam or methohexitone for inpatients, but rapid outpatient methods are more desirable. Clonidine combined with naltrexone enables abrupt opioid withdrawal in 3-5 days in an outpatient/day setting. This approach can be further improved by transition to the partial agonist buprenorphine from either heroin or methadone followed by a 1 day detoxification using naltrexone precipitated withdrawal, ameliorated by clonidine.     

The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats

Rationale

Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to “self-medicate” in order to cope with withdrawal, which promotes escalated alcohol and drug use.

Objectives

The current study aimed to develop a reliable animal model to assess symptoms that occur during spontaneous alcohol and opioid withdrawal.

Methods

Dependence was induced using intermittent alcohol exposure or pulsatile heroin delivery and assessed for the presence of withdrawal symptoms during acute withdrawal by measuring somatic signs, behavior in the forced swim test (FST), and air-puff-induced 22-kHz ultrasonic vocalizations (USVs). Additional animals subjected to 8 weeks of alcohol vapor exposure were evaluated for altered somatic signs, operant alcohol self-administration, and 22-kHz USV production, as well as performance in the elevated plus maze (EPM).

Results

During spontaneous withdrawal from pulsatile heroin or intermittent alcohol vapor, animals displayed increased somatic withdrawal signs, FST immobility, and 22-kHz USV production but did not show any behavioral change in the EPM unless the duration of alcohol exposure was extended to 4 weeks. Following 8 weeks of alcohol vapor exposure, animals displayed somatic withdrawal signs, escalated alcohol self-administration, and increased 22-kHz USVs.

Conclusions

These paradigms provide consistent methods to evaluate the behavioral ramifications, and neurobiological substrates, of alcohol and opioid dependence during spontaneous withdrawal. As immobility in the FST and percent open-arm time in the EPM were dissociable, with 22-kHz USVs paralleling immobility in the FST, assessment of air-puff-induced 22-kHz USVs could provide an ethologically valid alternative to the FST.     

Stress reinstates heroin-seeking in drug-free animals: An effect mimicking heroin,not withdrawal

Exposure to 10 min of footshock stress (1 mA; 0.5 s on, with a mean off period of 40 s) reinstated heroin-seeking behavior in heroin-experienced, drug-free rats after many sessions of extinction and up to 6 weeks after last exposure to heroin. In reinstating the behavior, the footshock mimicked the effect of a non-contingent priming infusion of heroin (50 µg/kg). By contrast, the aversive state of acute opioid withdrawal induced by injection of the opioid receptor antagonist naltrexone (5 mg/kg, SC), following an acute injection of morphine (10 mg/kg, SC), had no effect on heroin-seeking behavior. In a second experiment it was shown in drug naive animals that these parameters of footshock increased dopamine overflow in the nucleus accumbens, a terminal region of the mesolimbic dopamine system implicated in the reinforcing effects of drugs. Similarly, dopamine overflow was increased by an injection of 10 mg/kg morphine, SC, an effect that was reversed by an injection of 5 mg/kg naltrexone given 40 min after to induce the withdrawal condition. A possible interpretation of the present results is that stressors can reinstate drug-taking behavior by activating neural systems in common with those activated by heroin.     

The relationship of conduct disorder to attempted suicide and drug use history among methadone maintenance patients

In order to examine the effects of a diagnosis of childhood conduct disorder (CD) on history of attempted suicide and drug use, unconfounded by early onset heroin use, 181 methadone maintenance patients who commenced heroin use after the age of 15 were interviewed. CD was diagnosed in 54% of patients. Compared to other patients, CD patients were younger and less educated. The onset of drug use, injecting drug use and heroin use occurred, on average, 2 years earlier than in other patients, and they had broader histories of injecting polydrug use. CD patients were more likely to have attempted suicide and to have been hospitalized after an attempt, and to have attempted suicide while enrolled in their current treatment. The current study indicates that a history of CD increases the risk of attempted suicide over and above the higher risks associated with injecting drug use per se. [Darke S, Ross J, Lynskey M. The relationship of conduct disorder to attempted suicide and drug use history among methadone maintenance patients. Drug Alcohol Rev 2003;22:21 - 25]     

Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor.

Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.     

Effects of training and withdrawal periods on heroin seeking induced by conditioned cue in an animal of model of relapse

Rationale  A high incidence of relapse can be triggered by exposure to conditioned cues previously associated with heroin. Extended access to drug and withdrawal are thought to affect the motivation for drug seeking. Objectives  The present study evaluated how different periods of training to self-administer heroin and different periods of withdrawal affected drug seeking. Materials and methods  Following 1 to 14 days of heroin self-administration, rats were left in the home environment for 1 or 14 days. Subsequently, rats were evaluated for extinction of nose poke during the first hour after being returned to the training apparatus. One hour later, a conditioned stimulus was presented to initiate cue-induced reinstatement. Results  Extending the training period from 1 to 14 days caused an escalation of reinstatement of drug seeking induced by conditioned cues. Increasing the withdrawal period from 1 to 14 days produced a similar increase in reinstatement of drug seeking induced by cues. Reinstatement of drug seeking induced by cues was augmented by pretreatment with naltrexone (1, 5 mg/kg) 24 h prior to reinstatement on day 1, but not at 14 days of withdrawal from heroin self-administration. Conclusions  These experiments demonstrate that increasing the duration of either heroin self-administration or the withdrawal periods from heroin self-administration augments the reinstatement induced by cues that were associated previously with heroin reinforcement. Additionally, we provide one of the first demonstrations that opiate withdrawal induces heroin seeking, as assessed in the reinstatement model.     

Affective and somatic aspects of spontaneous and precipitated nicotine withdrawal in C57BL/6J and BALB/cByJ mice

The aversive aspects of nicotine withdrawal are powerful motivational forces contributing to the tobacco smoking habit. We evaluated measures of affective and somatic aspects of nicotine withdrawal in C57BL/6J and BALB/cByJ mice. Nicotine withdrawal was induced by termination of chronic nicotine delivery through osmotic minipumps or precipitated with the nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine or dihydro-beta-erythroidine (DHbetaE). A rate-independent discrete-trial intracranial self-stimulation threshold procedure was used to assess brain reward function. Anxiety-like behavior and sensorimotor gating were assessed in the light-dark box and prepulse inhibition (PPI) tests, respectively. Acoustic startle response and somatic signs of withdrawal were also evaluated. Spontaneous nicotine withdrawal after 14-day exposure to 10-40 mg/kg/day nicotine induced no alterations in anxiety-like behavior, startle reactivity, PPI, or somatic signs in either strain, and no changes in thresholds in C57BL/6J mice. Extended 28-day exposure to 40 mg/kg/day nicotine induced threshold elevations, increased somatic signs, and anxiety-like behavior 24 h post-nicotine in C57BL/6J mice; thresholds returned to baseline levels by day 4 in nicotine-exposed mice. Mecamylamine or DHbetaE administration induced threshold elevations in nicotine-exposed C57BL/6J mice compared with saline-exposed mice. In conclusion, administration of relatively high nicotine doses over prolonged periods of time induces both the affective and somatic aspects of spontaneous nicotine withdrawal in the mouse, while exposure to nicotine for shorter periods of time is sufficient for nAChR antagonist-precipitated nicotine withdrawal. The current study is one of the first to demonstrate reward deficits associated with both spontaneous and nAChR antagonist-precipitated nicotine withdrawal in C57BL/6J mice.     

Naltrexone,smoking behaviour and cigarette withdrawal

In order to examine the role of endogenous opioids in the reinforcing effects of nicotine, a double-blind, placebo-controlled, cross-over design was used to study the effects of the opiate antagonist, naltrexone, on smoking behaviour and cigarette withdrawal in 12 heavy smokers. Although naltrexone (50 mg) appeared to reduce the perceived difficulty of abstaining during 24-h cigarette withdrawal, other withdrawal symptoms were unaffected. Naltrexone also had no effect on a variety of biochemical and behavioural measures of nicotine intake or on subjective satisfaction and enjoyment from the first cigarette smoked after 24-h abstinence. Similarly naltrexone (100 mg) had no effect on smoking behaviour, nicotine intake or satisfaction from smoking during a 48-h period of ad libitum smoking. However, during the ad libitum smoking period naltrexone caused mood changes of the kind that occur during tobacco withdrawal. Since nicotine intake and smoking behaviour were unaffected, the mood changes are unlikely to have been mediated by blockade or any other form of opioid interaction with nicotinic mechanisms. These findings provide evidence against the notion that the endogenous opioids are involved in mediating the reinforcing properties of nicotine in smokers under normal conditions.     

海洛因依赖者自然戒断后免疫学动态变化

目的 :研究海洛因依赖者自然戒断后 3个月内不同时点的免疫系统及相关激素水平的变化。方法 :2 5例海洛因依赖者在戒断后 4 8h、30d、6 0d、90d测查IL - 1β、IL - 6和sIL - 2R ,IgA、IgG和IgM ,补体C3、C4以及COR和PRL水平的变化 ,并与 15例正常受试者进行比较。结果 :与正常对照组比较 ,海洛因依赖者的IL - 1β在自然戒断后 4 8h较低 ,此后各时点与正常对照组比较无显著性差异 ;IL - 6在自然戒断后各时点均保持在较低水平 ;sIL - 2R则在自然戒断后各时点均保持在较高水平 ;IgA ,IgM在自然戒断后各时点均保持在较低水平 ,补体C3、C4在自然戒断后 4 8h检测值较低 ,90d恢复至正常 ;COR在自然戒断后 6 0d内各时点检测值均较高 ,PRL在戒断 4 8h内检测值较低 ,COR和PRL在戒断 90d后恢复至正常水平。结论 :海洛因依赖者免疫系统及内分泌系统会发生某些改变 ,自然戒断后 ,有些改变会很快恢复正常 ,但有些则会持续超过 3个月。     

The effect of clonidine on the naltrexone-induced withdrawal response in morphine-treated guinea-pigs

Rapid opioid withdrawal induced by naltrexone is now used as a treatment for heroin addiction. The alpha2-adrenoceptor agonist, clonidine, is currently used in clinical practice to reduce opioid withdrawal in humans. However, few studies have been reported on its effectiveness for this purpose. Guinea-pigs were made dependent and tolerant to morphine using a 3-day chronic morphine regimen (total 410 mg kg(-1) morphine base), and injected with either clonidine (0.1 mg kg(-1), s.c.) or saline, 1 h before induction of withdrawal with naltrexone (15 mg kg(-1), s.c.). Withdrawal behaviours were measured for 90 min and animals were then euthanased and the brains removed. The presence of the immediate early gene protein product, c-Fos, was detected using immunohistochemical techniques. Clonidine reduced the number of head/body shakes, but had no effect on the total withdrawal behaviour score. In the CNS, clonidine increased the number of Fos-LI neurons in the central amygdala. In conclusion, the modest effect of clonidine in the present experiments suggests that the efficacy of clonidine in humans undergoing naltrexone-induced opioid withdrawal requires further investigation.     

Monoaminergic drugs and directly observable signs of LAAM withdrawal in rhesus monkeys

Monoaminergic ligands modified a naltrexone discriminative stimulus in rhesus monkeys dependent on 2 mg/kg per day of the mu opioid L-alpha-acetylmethadol (LAAM). This study examined a role for monoamines in the directly observable and physiologic manifestations of LAAM withdrawal induced by naltrexone in the same monkeys. The effects of saline, clonidine (0.032 mg/kg), haloperidol (0.032 mg/kg), cocaine (1.0 mg/kg), amphetamine (1.0 mg/kg) and imipramine (10.0 mg/kg) were examined in LAAM-dependent monkeys that subsequently received saline or naltrexone (0.0001-1.0 mg/kg). Naltrexone dose-dependently increased respiration, abdominal rigidity and salivation. Clonidine attenuated each of these withdrawal signs, whereas haloperidol increased some (i.e. respiration) and decreased others (i.e. salivation). When administered alone, cocaine and amphetamine increased respiration and also increased the respiratory stimulant effects of naltrexone; cocaine and amphetamine did not attenuate any measure of withdrawal. With the exception of a decrease in naltrexone-induced salivation, imipramine was without effect. These results are strikingly different from results in these same LAAM-dependent monkeys showing that cocaine and amphetamine, but not clonidine, markedly attenuated a naltrexone discriminative stimulus. That monoaminergic ligands differentially alter the directly observable and discriminative stimulus effects of naltrexone in LAAM-dependent monkeys supports the view that monoamines differentially mediate the physical manifestations (norepinephrine) and subjective experience (dopamine) of opioid withdrawal.     

Depot naltrexone: antagonism of the reinforcing, subjective, and physiological effects of heroin

Rationale

Naltrexone is an opioid antagonist that is currently approved as a treatment for opioid and alcohol dependence. Although it is highly effective in completely antagonizing the effects of opioids, medication noncompliance is a difficult obstacle to treatment. Therefore, a sustained-release form of naltrexone may improve treatment outcome.

Objective

The present study was designed to evaluate the time course, safety, and effectiveness of a depot formulation of naltrexone (Depotrex^®).

Materials and methods

Five heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, the effects of a range of heroin doses (0, 6.25, 12.5, and 25 mg, i.v.) were examined. Participants then received 384 mg naltrexone base. The effects of heroin were again evaluated for the next 6 weeks. One dose of heroin was tested per day and the entire dose range was tested each week. Doses were administered in non-systematic order. During a morning sample session, participants received a dose of heroin and $20 and subjective, performance, and physiological effects were measured both before and after drug administration. During an afternoon choice session, participants were given the opportunity to choose the sampled heroin dose and/or amount of money using a modified progressive ratio procedure.

Results

Depot naltrexone antagonized both the reinforcing and subjective effects of heroin for 4–5 weeks. Subjective ratings of withdrawal were reduced after week 2 and throughout the remainder of the study. The effects of heroin on mean trough pupil diameter began to emerge by week 5. There were no clinically significant effects on respiratory or cardiovascular function.

Conclusions

The present results extend our previous findings by showing that the reinforcing effects of heroin were reduced for 4–5 weeks after administration of 384 mg depot naltrexone.