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.     

Naltrexone shortened opioid detoxification with buprenorphine.

This double-blind, randomized, placebo-controlled clinical trial evaluated the impact on withdrawal symptoms of (i) combining naltrexone with a 4-day buprenorphine taper for short opioid detoxification (NB Group), compared to (ii) using a 4-day buprenorphine taper alone, followed by naltrexone on day 8 (PB Group). Sublingual buprenorphine was administered on days 1-4 (26 mg total). For the NB Group (n = 32) escalating doses of oral naltrexone were given on days 2-8 (placebo day 1). For the PB Group (n = 28) placebo was given on days 1-7 and naltrexone on day 8. Main outcome measures were Observed Opioid Withdrawal scores (OOW, 0-30) and use of medications to treat opioid withdrawal. Of 32 patients in the NB group, 59% experienced clinically relevant withdrawal (defined as OOW > or = 5) on day 2, but, after day 5, none experienced withdrawal. In the PB group, the number of patients experiencing withdrawal increased over time. The first naltrexone dose induced comparable withdrawal in both groups: peak OOW scores were (mean +/- SD) 5.2 +/- 3.3 on day 2 for the NB group, and 4.0 +/- 3.9 on day 8 for the PB group (NS), though, on day 2, 7 patients dropped out in the NB group and none in the PB group, while only one patient dropped out in the PB group on day 8. Throughout the 8-day study, patients in both groups received similar amount of adjunct medication: 0.64 +/- 0.07 mg (NB group) of clonidine vs 0.73 +/- 0.15 mg (PB group; NS). Only 25% of patients required use of sedatives (up to 20 mg diazepam). Starting naltrexone on day 2 appeared to abolish withdrawal symptoms after day 5 and, thus, to shorten the duration of withdrawal symptoms. Peak withdrawal symptoms after naltrexone were of moderate intensity, suggesting that naltrexone combined with buprenorphine is an acceptable and safe treatment for shortened opioid detoxification and induction of naltrexone maintenance.     

Effect of ultra-rapid opiate detoxification on withdrawal syndrome

The aim of study was determine the effect of ultra-rapid opiate detoxification (UROD) on the presence or absence of withdrawal syndrome in a group of patients with opiate dependency. In this study, withdrawal syndrome of 173 patients with opiate addiction was evaluated before and after UROD using the Objective Opioid Withdrawal Scale. Hence, each patient was observed for 5 minutes before UROD and at different hours afterward to observe any withdrawal sign. The most prevalent withdrawal sign before UROD was anxiety. Restlessness was the most prevalent finding at 1, 3, and 6 hours. After 12 hours, yawning was reported as the most prevalent finding in 39 participants. Anxiety was reported as the most prevalent finding in 61 participants after 24 hours. Patients with opioid dependency who underwent UROD showed the highest rate of withdrawal symptoms at one hour after anesthesia. Most of these symptoms subsided after 24 hours. UROD can be applied for detoxification of patients with opioid dependency with safety.     

Effect of Ultra-Rapid Opiate Detoxification on Withdrawal Syndrome

ABSTRACT

The aim of study was determine the effect of ultra-rapid opiate detoxification (UROD) on the presence or absence of withdrawal syndrome in a group of patients with opiate dependency. In this study, withdrawal syndrome of 173 patients with opiate addiction was evaluated before and after UROD using the Objective Opioid Withdrawal Scale. Hence, each patient was observed for 5 minutes before UROD and at different hours afterward to observe any withdrawal sign. The most prevalent withdrawal sign before UROD was anxiety. Restlessness was the most prevalent finding at 1, 3, and 6 hours. After 12 hours, yawning was reported as the most prevalent finding in 39 participants. Anxiety was reported as the most prevalent finding in 61 participants after 24 hours. Patients with opioid dependency who underwent UROD showed the highest rate of withdrawal symptoms at one hour after anesthesia. Most of these symptoms subsided after 24 hours. UROD can be applied for detoxification of patients with opioid dependency with safety.     

Buprenorphine and methadone: a comparison of patient completion rates during inpatient detoxification

Buprenorphine and methadone are both effective for the control of the acute signs and symptoms of opiate withdrawal, but it is not known if there are differences between these two medications for other important clinical outcomes. This observational, non-randomized study evaluated completion rates of patients over a 13-month period when buprenorphine replaced methadone as the medication used for short-term inpatient opiate detoxification. Of the 644 patients in the study, the 303 treated with buprenorphine were more likely to complete detoxification than the 341 treated with methadone (89% vs. 78%; P < .001). Improvement in completion rates coincided with the introduction of buprenorphine. We conclude that as compared to methadone, buprenorphine is associated with greater rates of completion of inpatient detoxification.     

Opioid detoxification using high doses of buprenorphine in 24 hours: a randomized, double blind, controlled clinical trial

In recent years, interest in shortening of opioid detoxification has increased with the rising demands to find more cost-effective approaches for treatment of opioid dependence. This study was designed to evaluate the efficacy of administration of high doses of buprenorphine during 24 h in the management of acute opioid withdrawal. A total of 40 treatment-seeking opioid dependents were admitted and randomly assigned to two groups in a double blind, parallel trial. Buprenorphine was administered intramuscularly. Twenty patients received 12 mg buprenorphine in 24 h and the remaining 20 patients treated with conventional doses of buprenorphine tapered down over 5 days. Variables that were assessed included retention in treatment, rates of successful detoxification, the Subjective Opiate Withdrawal Scale (OOWS) scores, the Objective Opiate Withdrawal Scale (SOWS) scores, intensity of craving, drug side effects, and levels of hepatic enzymes (ALT and AST). There was no significant difference between the two groups on most variables. The main difference was in the time that maximal withdrawal symptoms occurred, which in the experimental protocol group appeared early while in the conventional protocol group appeared later during the detoxification period. Moreover, the experimental protocol was not only tolerated well but also accompanied with significantly less elevation in the ALT levels compared to the conventional treatment. However, patients in this group used more indomethacin and trazodone for symptom palliation. This study suggests that administration of high doses of buprenorphine in 24 h may be a reasonable approach for shortening of opioid detoxification. However, a larger study to confirm our results is warranted.     

Tramadol versus buprenorphine for the treatment of opiate withdrawal: a retrospective cohort control study

Various drugs have been used for the treatment of opioid withdrawal, e.g., methadone, buprenorphine, and clonidine. Tramadol is a centrally acting synthetic analgesic agent with opiate activity due to low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to mu opioid receptors. As a consequence, there may be a role for the use of tramadol in the treatment of opiate withdrawal. We attempt to assess the efficacy of tramadol in treating moderate heroin withdrawal through a retrospective cohort control study, conducted in a detoxification unit in a community teaching hospital. Out of 100 heroin abusers admitted for detoxification during the review period, 64 patients who were treated either with buprenorphine or tramadol, were included in this study, with 20 participants in the buprenorphine group and 44 in the tramadol group. Both groups were matched for age, sex, and self-reported average quantity of heroin used per day. In the tramadol group, the average CINA maximum was 9.0, and in the buprenorphine group it was 11.2 (P = 0.07). The use of oral clonidine per patient in the tramadol group was 1.6 tablets, and in the buprenorphine group 0.1 tablets (P = 0.002). The length of stay was 3.7 days in the tramadol group and 4.1 days in the buprenorphine group (P = 0.5). Four participants in the tramadol group received three or more doses of buprenorphine because their symptoms were not controlled, and were considered as treatment failures. These preliminary data suggest that tramadol may be comparable to buprenorphine in the management of mild to moderately severe heroin withdrawal. These findings, if reproduced in larger studies with stronger research designs, have potentially great implications for the management of opioid withdrawal in both the inpatient and outpatient setting.     

Buprenorphine and Methadone

Abstract

Buprenorphine and methadone are both effective for the control of the acute signs and symptoms of opiate withdrawal, but it is not known if there are differences between these two medications for other important clinical outcomes. This observational, non-randomized study evaluated completion rates of patients over a 13-month period when buprenorphine replaced methadone as the medication used for short-term inpatient opiate detoxification. Of the 644 patients in the study, the 303 treated with buprenorphine were more likely to complete detoxification than the 341 treated with methadone (vs% 89. 78%; P< .001). Improvement in completion rates coincided with the introduction of buprenorphine. We conclude that as compared to methadone, buprenorphine is associated with greater rates of completion of inpatient detoxification     

A randomized double-blind study of neuroelectric therapy in opiate and cocaine detoxification

Prior research on the use of transcranial neuroelectric stimulation suggested that the application of low-amperage, low-frequency alternating current via surface electrodes placed in the mastoid region could relieve the physiological signs and subjective symptoms of withdrawal and craving during opiate detoxification. These effects were reported without gradual tapering of the opiate or the addition of other medications. To test the efficacy of one particular form of neuroelectric therapy (NET), a double-blind, randomized, placebo-controlled study was conducted comparing active NET and placebo NET in the treatment of withdrawal and stabilization of 18 opiate-dependent and 25 cocaine-dependent subjects. Scores on scales for measuring substance withdrawal and craving for each abused substance, as well as the multiple dimensions of mood, were compared for degree of difference across the 10 days of treatment. There was an overall completion rate of 88%, with both cocaine and opiate groups reporting a comfortable detoxification and substantial improvement over the course of a 12-day hospitalization. There was no significant difference between the active or placebo groups, suggesting that placebo was as effective as active NET in reducing drug withdrawal or craving during cocaine and opiate detoxification. However, all placebo patients received 0.2 mA of current, which may have provided a degree of active current. Suggestions are offered for future research.     

Opioid detoxification with buprenorphine,clonidine, or methadone in hospitalized heroin-dependent patients with HIV infection

With the growing role of intravenous drug use in the transmission of HIV infection, HIV-infected patients frequently present with comorbid opioid dependence. Yet, few empirical evaluations of the efficacy and consequences of opioid detoxification medications in medically ill HIV-infected patients have been reported. In a randomized, double-blind clinical trial, we evaluated the impact of three medications on the signs and symptoms of withdrawal and on the pain severity in heroin-dependent HIV-infected patients (N=55) hospitalized for medical reasons on an inpatient AIDS service. Patients received a 3-day pharmacologic taper with intramuscular buprenorphine (n=21), oral clonidine (n=16), or oral methadone (n=18), followed by a clonidine transdermal patch on the fourth day. Observed and self-reported measures of opioid withdrawal and pain were taken 1-3 times daily for up to 4 days. Opiate administration used as medically indicated for pain was also recorded. Observer- and subject-rated opiate withdrawal scores decreased significantly following the first dose of medication and overall during treatment. Among all 55 subjects, self-reported and observer-reported pain decreased after treatment (on average observer-rated opioid withdrawal scale (OOWS) scores declined 5.6 units and short opioid withdrawal scale (SOWS) declined 4.8 units, P<0.001, for both) with no indication of increased pain during medication taper. There were no significant differences of pain decline and other measures of withdrawal between the three treatment groups. During the intervention period, supplemental opiates were administered as medically indicated for pain to 45% of the patients; only 34% of men versus 62% of women received morphine (P<0.05). These findings suggest buprenorphine, clonidine, and methadone regimens each decrease opioid withdrawal in medically ill HIV-infected patients.     

A pharmacological modulation of opiate withdrawal using an up-/down-regulation of the noradrenergic system in opiate-dependent rats

Chronic opioid exposure induces neuroadaptative changes in several brain systems. Amongst others the alpha adrenergic system appears to be extremely sensitive to opioid exposure and has, therefore, been proposed to play a key role in opiate withdrawal symptoms. In order to better understand the influence of the noradrenergic system in opioid withdrawal and be able to develop new therapeutic strategies, we studied the effect of pre-treatment with the alpha2 agonist (clonidine) and alpha2 antagonist (yohimbine) on naloxone-precipitated withdrawal in opiate-dependent rats. As is already known clonidine pre-treatment significantly enhances autonomic and behavioural signs of opioid withdrawal whereas yohimbine significantly attenuates them with dose-related effect. We also tested the effect of clonidine (0.1 mg/kg) during naloxone-precipitated opiate withdrawal in rats pre-treated with yohimbine (5 mg/kg) and we observed that yohimbine pre-treatment potentiates clonidine efficiency in decreasing opiate withdrawal signs. This study supports the possibility of using a noradrenergic antagonist in order to regulate adrenoreceptors chronically exposed to opioids, therefore interfering with the intensity of naloxone-precipitated opiate withdrawal and potentiating later effectiveness of noradrenergic agonists like clonidine. These results may have various applications in clinical opiate detoxification protocols and are discussed through an up-/down- regulation of adrenoreceptors.     

An investigation of withdrawal symptoms shown by opiate addicts during and subsequent to a 21-day in-patient methadone detoxification procedure

Methadone detoxification procedures are widely accepted as a satisfactory way of withdrawing opiate addicts from drugs. There have, however, been comparatively few empirical studies which have examined the development and course of withdrawal symptoms in opiate addicts in response to such detoxification procedures. This study investigates the opiate withdrawal syndrome in a group of 116 opiate addicts during and subsequent to a gradual oral methadone detoxification programme. Withdrawal symptoms peak at the end of the methadone schedule and decline steadily thereafter. Not until 40 days after the beginning of the withdrawal regime have symptom levels returned to normal. It is suggested that this protracted withdrawal response is not entirely satisfactory and alternative clinical and research options are proposed. The results fail to support the accepted view that dose is a major determinant of withdrawal severity. Low dose users did not experience less severe withdrawal symptoms than high dose users. This finding together with those of a previous study suggest that this issue also warrants further research attention.     

洛非西定与可乐定控制阿片戒断症状的临床效能比较

洛非西定(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 -1(可乐定)。逐日观察戒断症状及副作用的变化。发现 ,洛非西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 ,不影响治疗 ,洛非西定组的血压虽也有所降低 ,但降低幅度比可乐定组小 ,从而增加了其安全性与应用范围。     

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]     

Efficacy of buspirone in the treatment of opioid withdrawal

In an attempt to develop a new opiate detoxification approach, the authors assessed the efficacy of buspirone in the treatment of acute heroin withdrawal. Buspirone, a drug interacting with the serotonergic system, was selected because there is evidence that a decrease in serotonergic neurotransmission may be involved in opiate withdrawal symptoms. Twenty-nine hospitalized heroin addicts were randomized to 4 groups: (1) placebo; (2) methadone; (3) buspirone 30 mg daily; (4) buspirone 45 mg daily. The double-blind trial started in all patients with a 5-day methadone stabilization period ending with a 30-mg dose. This was followed from days 6 through 12 by placebo in group 1 and by a methadone taper in group 2. Because of its delayed action, buspirone was started on day 1 in groups 3 and 4 and was continued, after methadone discontinuation, through day 12. On day 13, drugs and placebo were discontinued and patients were observed through day 14. Withdrawal symptoms were assessed with the "Subjective Opiate Withdrawal Scale" (SOWS) and the "Objective Opiate Withdrawal Scale" (OOWS). The SOWS and OOWS scores were significantly higher in the placebo group than in the methadone, buspirone 30 mg, and buspirone 45 mg groups. There were no significant differences in SOWS or OOWS scores when the methadone group was compared with each of the two buspirone groups or when the two buspirone groups were compared with one another. In conclusion, buspirone, a nonopiate drug with no abuse potential, a safe side effect profile and no withdrawal symptoms, at doses of 30 and 45 mg, was as effective as a methadone taper in alleviating the withdrawal symptoms of heroin addicts stabilized for 5 days with, and then withdrawn from, methadone. The use of buspirone could be particularly helpful in outpatient settings where the duration of the methadone taper recommended for detoxification can be lengthy.     

The Clinical Opiate Withdrawal Scale (COWS)

The clinical opiate withdrawal scale (COWS) is a clinician-administered, pen and paper instrument that rates eleven common opiate withdrawal signs or symptoms. The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and AlcoholMD.com.     

The psychopharmacological effects of repeated doses of fluvoxamine,mianserin and placebo in healthy human subjects

Summary The psychopharmacological effects of fluvoxamine, 50 mg twice a day, were compared with those of mianserin, 20 mg twice a day, and placebo, each given for 8 days in a double-blind crossover design to 9 healthy human volunteers.At least one week was left between the 8-day courses of drugs. Testing was carried out before and 3 h after taking the morning dose on Days 1 (predrug), 4, and 8, and comprised EEG, cognitive and psychomotor tasks, and self-ratings of mood and bodily symptoms.Fluvoxamine had no effect on any of the EEG wavebands, but mianserin increased voltages in the slow wavebands as compared with placebo. This effect was particularly pronounced on Days 4 and 8.Mianserin significantly decreased critical flicker fusion frequency and speed of reaction time, and slowed down tapping rate; digit symbol substitution and symbol copying test performances were also impaired by mianserin. These effects were most marked after the first dose and had lessened somewhat later in the week. Symbol copying was the only task impaired by fluvoxamine as compared with placebo.Mianserin caused drowsiness after the first dose but this effect declined by Day 8. By contrast, fluvoxamine induced feelings of anxiety, sweatiness, trembling, nausea, loss of appetite, restlessness, muscle tension, irritability, tiredness, headache, and dizziness; these effects were most evident in the middle of the week and relatively reduced at the end of the week. Mianserin produced a few of these effects but they tended to be maximal on Day 1 or 4 and then to wear off.It was concluded that fluvoxamine is much less likely to produce psychomotor and cognitive impairment on repeated usage than is mianserin, but that some adverse effects, particularly nausea, may be troublesome. Fluvoxamine would seem more appropriate in patients in whom sedation is not required, mianserin in those in whom initial sedation is acceptable.     

Mianserin: Cardiovascular effects in elderly patients

Cardiovascular effects of the tetracyclic antidepressant drug mianserin were examined in a prospective study including ten elderly depressed patients (age 60-77 years). During 1 week on placebo and 5 weeks on mianserin, 60 mg per day, orthostatic blood pressure testing, recording of standard electrocardiogram, 24-h electrocardiographic recording and systolic time intervals were carried out along with frequent monitoring of plasma levels of mianserin (13-57 micrograms/l) and the primary metabolite desmethylmianserin (7-27 micrograms/l). Mianserin caused a significant increase in orthostatic systolic blood pressure drop, and this correlated well with the plasma mianserin levels (rs = 0.70). There were no significant changes in supine blood pressure or in orthostatic changes in heart rate. No cardiac conduction disturbances or arrhythmias were provoked, but mianserin caused changes in systolic time intervals indicating impairment of left ventricular contractility and performance. Like tricyclic antidepressants mianserin should thus be used with caution in patients with latent or overt cardiovascular disease.     

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.     

两种电针戒毒仪对治疗急性脱毒期戒断症状的临床比较

目的:以韩氏戒毒仪为参照,验证JY-I型低频戒毒仪(简称:低频戒毒仪)治疗阿片类成瘾戒断综合征的有效性和安全性。方法:筛查合格的受试者以1∶1的比例按入组顺序随机分配到低频戒毒仪或韩氏戒毒仪组,进行10 d的治疗,并分别在基线、治疗d1、2、3、4、5、7、d11进行疗效评价和戒断症状评分,并以治疗d4作为有效评价时间。结果:d4,在符合方案(PP)人群中,低频戒毒仪组和韩氏戒毒仪组治疗总有效率分别为33.34%和25.00%,两组比较差异无显著性(P=0.2898)。在不同时间点戒断症状的评分中,低频戒毒仪组d2、d5、d7治疗前评分较基线有明显下降,与韩氏戒毒仪组相比在PP人群中差异有显著性(P=0.0193、0.0138、0.0140)。两者不良反应发生率组间统计差异无显著性。结论:低频戒毒仪和韩氏戒毒仪一样,都能够明显控制阿片类成瘾者急性脱毒期戒断症状,并具有良好的治疗效果和安全性能。