Antagonist-precipitated heroin withdrawal under anaesthetic prior to maintenance naltrexone treatment: determinants of withdrawal severity

This study sought to characterize antagonist-precipitated heroin withdrawal during and immediately following anaesthesia and to identify the determinants of withdrawal severity and duration in 48 dependent heroin users. Objective withdrawal signs decreased significantly with each naloxone bolus administered under anaesthetic. The cost (amount) of the final heroin administration and the number of hours between last heroin use and commencement of anaesthesia were significant, independent predictors of the severity of withdrawal symptomatology. While 83% (40/48) of participants completed withdrawal according to objective criteria and commenced maintenance naltrexone treatment, almost half (22/48) were unable to commence naltrexone on the day of the procedure due to residual withdrawal signs. Fourteen of these 22 participants subsequently commenced naltrexone (median number of days between admission and commencement of naltrexone was 2, range 1 - 6) while eight left treatment prior to initiation of naltrexone. Significantly fewer of those with more severe withdrawal signs during anaesthesia commenced naltrexone (40% vs. 60%). While the severity and duration of withdrawal symptomatology may be moderated by encouraging participants to reduce (or cease) heroin use close to the time of withdrawal, for a substantial proportion of participants in this study, heroin withdrawal by this antagonist-precipitated procedure was neither rapid nor painless. [Ali R, Thomas P, White J, McGregor C, Danz,C, Gowing L, Stegink A, Athanasos P. Antagonist-precipitated heroin withdrawal under anaesthetic prior to maintenance naltrexone treatment: determinants of withdrawal severity. Drug Alcohol Rev 2003;22:425 - 431]     

A randomised, controlled trial of low dose naltrexone for the treatment of opioid dependence

AIM: To investigate the efficacy of low doses of naltrexone in relapse prevention for heroin dependence. DESIGN: Double blind, randomised comparison of three groups-Group 1 taking 50mg per day, Group 2: 0.5mg per day, and Group 3: 0.05 mg per day. PARTICIPANTS: Sixty-six dependent heroin users. INTERVENTIONS: After detoxification followed by 1 week on 50mg per day naltrexone, participants were randomised to trial medication. All were offered counselling and monitored with weekly clinical reviews. Research interviews were conducted at three and 6 months. OUTCOME MEASURES: Retention in treatment and heroin use at 3 and 6 months. Secondary outcome measures were side effects and craving. FINDINGS: Mean days retained in randomised treatment were-Group 1: 58.9 days; Group 2: 46.6 days; and Group 3: 47.8 days. Differences in retention were not significant using survival analysis. However, nine of the first 60 participants, transferred to the 50 mg dose, and one transferred to a lower dose (chi-square = 0.142; P = 0.018). At follow-up, there was no relationship between abstinence from heroin and naltrexone dose, nor between level of heroin use and dose. There were no differences between groups in craving or depression. CONCLUSION: Low doses of naltrexone had no discernible advantage, and participants preferred 50mg per day. Despite preference for blocking doses of naltrexone, outcomes appeared to be independent of naltrexone dose.     

The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice

On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6β-naltrexol). This study examined the interaction between naltrexone and 6β-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, low doses of 6β-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6β-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1-6 days and then withdrawal was precipitated. Naltrexone was more potent than 6β-naltrexol at all the time points. The ED₅₀ of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6β-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6 days.     

Naltrexone maintenance for heroin dependence: uptake, attrition and retention

With naltrexone registered only recently in Australia in 1999, it is important to examine the rate of uptake of naltrexone treatment, early attrition and retention rates during treatment, in order to inform the way naltrexone is used in Australian practice. Of 317 people screened for the study, 97 participants were recruited post-withdrawal from opiates and were inducted to naltrexone after a period of at least 5 days of abstinence. While in treatment, participants received a 50-mg dose of naltrexone daily, with daily dispensing for the first 7 days, and weekly dispensing for the following 11 weeks. For the naltrexone-treated sample as a whole, the rate of uptake of naltrexone treatment was 30%, with 30% retained in treatment for the entire 12-week program. Attrition from treatment was found to be steady throughout the 12 weeks. The authors conclude that further research is required to improve withdrawal and naltrexone induction techniques and to improve medication compliance and treatment retention. [Tucker TK, Ritter AJ, Maher C, Jackson H. Naltrexone maintenance for heroin dependence: uptake, attrition and retention. Drug Alcohol Rev 2004;23:299-309]     

Opiate withdrawal in the fetal rat: a behavioral profile

Offspring of women exposed to opiate drugs such as heroin and methadone during pregnancy have a high incidence of morbidity and mortality. Infants also show opiate withdrawal. In this study, we examined the behavioral effects of precipitated withdrawal in morphine-dependent fetal rats at gestational day (GD) 20. The dam was implanted on GD 14 with a pellet containing 75.0 mg of morphine. On GD 20, the dam underwent chemoyelotomy at L1/L2. The uterine horns were externalized and four subject fetuses were selected for behavioral observation, two from each uterine horn. The fetus was then injected subcutaneously with either saline or naltrexone (1.0 mg/kg) and the behaviors of the fetus recorded every 15 sec for 20 min. The results show that naltrexone injected fetuses that had been chronically exposed to morphine demonstrated increased limb and mouth movements, face wiping, and body curls, and spent less time quiet as compared with control fetuses. These results indicate that a morphine withdrawal-like syndrome occurs in the fetal rat.     

Naltrexone for heroin dependence treatment in St. Petersburg, Russia

Naltrexone may be more effective for treating opioid (heroin) dependence in Russia than in the U.S. because patients are mostly young and living with their parents, who can control medication compliance. In this pilot study we randomized 52 consenting patients who completed detoxification in St. Petersburg to a double blind, 6-month course of biweekly drug counseling and naltrexone, or counseling and placebo naltrexone. Significant differences in retention and relapse favoring naltrexone were seen beginning at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in treatment and had not relapsed as compared to 4 of 25 placebo patients (16%; p<0.05). Since heroin dependence is the main way HIV is being spread in Russia, naltrexone is likely to improve treatment outcome and help reduce the spread of HIV if it can be made more widely available.     

The association between naltrexone compliance and daily supervision

Most studies investigating the efficacy of naltrexone maintenance as a treatment for illicit heroin use have reported poor patient compliance in taking naltrexone. A number of studies have, however, reported better compliance when patients receive family therapy, or when patients resided in a supportive family environment. These studies suggest that patient outcomes on naltrexone maintenance may be better if there is ongoing family support to continue naltrexone use. The current study investigated 6-month outcome status in 300 illicit heroin users who commenced naltrexone maintenance in a community-based out-patient treatment programme. The study aimed to assess the relationship between vigilance of naltrexone supervision by salient others over the first 6 weeks of treatment and patient status at 6 months. Supervision of naltrexone at week 6 was a predictor of a patient's status at 6 months, with those receiving less supervision of 3-4 days more likely to have returned to heroin use or be assessed as 'heroin use undetermined'. In contrast, patients who still received naltrexone supervision for 6 or 7 days per week at week 6 were more likely to be taking naltrexone or were naltrexone- and heroin-free at 6 months. It is argued that since relapse to heroin use is a common occurrence, vigilant supervision of naltrexone dosing in a supportive environment may improve patient retention and reduce relapse. It is suggested that poor outcomes reported in many previous studies may reflect use of inadequate supportive frameworks that encourage naltrexone compliance.     

Reassessing naltrexone maintenance as a treatment for illicit heroin users

Most studies investigating the efficacy of naltrexone maintenance as a treatment for illicit heroin users have reported poor outcomes. Many of these studies, however, classify patients who periodically return to heroin use while receiving naltrexone maintenance as treatment failures. This study investigated 6-month outcome status in 100 illicit heroin users who commenced naltrexone maintenance in a community-based out-patient treatment programme. The study aimed to assess patient status at 6 months using contrasting outcome criteria. In the first analysis periodic heroin use was not considered to constitute treatment failure (hence naltrexone was continued and they remained under observation). In the second analysis, return to heroin use was considered to represent treatment failure. Using the first approach, we found that 60% of patients were still on naltrexone maintenance at 6 months, with only a small number (28%) having returned to heroin use. In contrast, when return to heroin use for 7 or more consecutive days was regarded as a treatment failure, only 31% of patients were "retained in treatment" with the majority (62%) having returned to heroin use. It is argued that since periods of heroin use are commonly associated with attempting to manage heroin dependence, the analysis that allowed periodic heroin use during treatment, and produced positive outcome data, represented a more valid assessment of naltrexone maintenance as a treatment for illicit heroin users. It is suggested that this outcome criterion should therefore be employed in future research. Poor outcomes reported in many previous studies may be an artefact of using inappropriate outcome criteria to assess illicit heroin use.     

Acute dependence on, but not tolerance to, heroin and morphine as measured by respiratory effects in rhesus monkeys

Acute dependence on and tolerance to heroin and morphine were assessed in rhesus monkeys using measures of respiration. Respiratory frequency (f) and minute volume (V(e)) were measured in monkeys breathing air or 5% CO(2) in air using a pressure-displacement plethysmograph. Cumulative doses of naltrexone (0.0001-1.0 mg/kg, i.m) did not alter these parameters in untreated monkeys. Twenty-four hours after a cumulative dose of heroin (1 mg/kg, i.m.), naltrexone produced an increase in both f and V(e) when monkeys were breathing air or 5% CO(2). Following 1 to 3 days of treatment with heroin (0.5 mg/kg/day, i.m.) or morphine (16 mg/kg/day, i.m.), naltrexone produced an increase in f and V(e) that was related to the dose of naltrexone and the number of days of agonist administration. Two days following termination of heroin administration, naltrexone-induced respiratory stimulation declined and had disappeared completely by the fifth day. In tolerance studies, heroin (0.032-0.5 mg/kg, i.m.) and morphine (1-16 mg/kg, i. m.) were injected cumulatively each day for three consecutive days. These drugs suppressed f and V(e) to nearly the same extent on day 3 as they had on day 1 of administration. These results suggest that dependence to morphine and heroin can be measured under conditions of acute 1 to 3 day administration conditions in primates using f and V(e) as reliable and quantitative indicators of opioid withdrawal. Under these conditions, tolerance does not occur.     

Effects of ondansetron administration on opioid withdrawal syndrome observed in rats

This study tested whether a 5-HT₃ receptor antagonist could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days. After the four days, half of the rats in each group received naloxone and half received saline. Each animal also received one of four doses of ondansetron (0, 1, 2 and 4 mg/kg i.p.). Administration of ondansetron to rats receiving naloxone after chronic morphine decreased the intensity of withdrawal signs such as increased defecation, jumping and wet-dog shakes, elevated the nociceptive threshold values which were decreased by precipitated withdrawal, but produced no change in urination, rectal temperature or salivation. The effects exhibited by ondansetron administration may be explained through interference of its 5-HT₃ receptor antagonist activity with serotoninergic mechanisms involved in the regulation of these withdrawal symptoms. The use of this drug is thus suggested as a possible treatment of opioid withdrawal signs in heroin addicts.     

Prolonged activation of mesolimbic dopaminergic neurons by morphine withdrawal following clonidine: participation of imidazoline and norepinephrine receptors.

The alpha2 adrenoceptor (alpha2R) agonist clonidine is used as a treatment for heroin addiction. Substantial evidence indicates that dopaminergic and noradrenergic systems have key roles in opiate dependence and withdrawal but the possible interactions between these two pathways remain unclear. The objective of this study was to establish the effects of clonidine pretreatment on ventral tegmental area dopaminergic (VTA DA) neuronal activity during morphine withdrawal. Responses of VTA DA neurons to withdrawal precipitated by naltrexone were characterized in anesthetized rats using extracellular recordings. As expected, withdrawal produced a marked inhibition of VTA DA neuronal activity. However, pretreatment with clonidine prevented this inhibition induced by withdrawal, and instead produced a long-lasting activation of firing rate (+50%) and burst firing (+19%). In contrast, pretreatment with a more selective alpha2R agonist, UK14304, did not prevent the inhibition of VTA DA neuron activity during withdrawal. We tested whether the high affinity of clonidine for imidazoline-1 receptors (I1Rs) was responsible for the difference between these two alpha2R agonists. In morphine-dependent rats pretreated with rilmenidine (mixed alpha2R/I1R agonist), precipitation of withdrawal elicited a 22% increase of VTA DA impulse activity. The action of clonidine on I1Rs was studied by coadministering clonidine with RX821002, a specific alpha2R antagonist. Pretreatment with RX821002 plus clonidine prevented the inhibition of VTA DA activity during withdrawal but failed to produce excitation. These results indicate that the pharmacological effects of clonidine on VTA DA neurons during morphine withdrawal is related to actions on I1Rs as well as alpha2Rs.     

美沙酮、丁丙诺啡、可乐定、纳曲酮“阶梯式”疗法治疗海洛因依赖脱毒后复吸患者33例

采用美沙酮、丁丙诺啡、可乐定、纳曲酮为主药的“阶梯式戒毒疗法”，治疗３３例戒毒后屡次复吸的海洛因依赖者。成功戒断８例，已操守０．５ａ以上，停服纳曲酮２个月以上；仍在服纳曲酮１６例，已分别服用１－４个月，操守率７２．７％；失败９例，其中服纳曲酮１－２个月后又复吸海洛因４例，治疗中失去联系而脱试３例，服纳曲酮１次后，戒断症状重而中止，改为自然康复２例，失败率２７．３％；配合心理疏导，有显著抗复吸作用，心理依赖降低，戒毒效果良好。     

纳屈酮对吗啡和海洛因产生依赖的影响

本文观察了纳屈酮对吗啡和海洛因在大、小鼠产生依赖的影响。纳屈酮2.0-4.0mg·kg~(-1)或1.8-3.6mg·kg~(-1)po分别可对抗吗啡和海洛因在小鼠产生身体依赖;1.0-3.0mg·kg~(-1)sc可拮抗吗啡致小鼠条件性位置偏爱的形成。当吗啡诱发小鼠条件性位置偏爱形成后,纳屈酮可加速其消退。提示纳屈酮对小鼠吗啡精神依赖的产生和消退有一定影响。参考上述实验结果和人与动物间剂量折算,我们认为小剂量纳屈酮10-15mg·d~(-1)po防止阿片依赖病人戒毒后复吸是可行的。     

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.     

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.     

Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants

BACKGROUND: Non-fatal overdoses represent a significant morbidity for regular heroin users. Naltrexone is an opioid antagonist capable of blocking the effects of heroin, thereby preventing accidental overdose. However, treatment with oral naltrexone is often associated with non-compliance. An alternative is the use of a sustained release preparation of naltrexone. The aim of this study was to assess the change in number of opioid and other drug overdoses in a large cohort of heroin dependent persons (n=361; 218 males) before and after treatment with a sustained release naltrexone implant. A sub-group of this cohort (n=146; 83 males) had previously received treatment with oral naltrexone, which also allowed a comparison of overdoses pre- and post-oral and also post-implant treatments. METHOD: We used a pre-post design, with data prospectively collected via the West Australian Health Services Research Linked Database, and the Emergency Department Information System. Participants were treated under the Australian Therapeutic Goods Administration's special access guidelines. RESULTS: Most (336, 93%) of the cohort was in one or both databases. We identified 21 opioid overdoses involving 20 persons in the 6 months pre-treatment that required emergency department presentation or hospital admission: none were observed in the 6 months post-treatment. This is consistent with the existing pharmacokinetic data on this implant, which indicates maintenance of blood naltrexone levels at or above 2 ng/ml for approximately 6 months. A reduced number of opioid overdoses were also observed 7-12 months post-implant. The study found a significant increase in sedative "overdoses", some of which occurred in the 10 days following implant treatment and were likely associated with opioid withdrawal and/or implant treatment. For those previously treated with oral naltrexone, more opioid overdoses occurred in both the 6-months prior to and after oral compared to the 6-months post-implant treatment. CONCLUSIONS: The findings support the clinical efficacy of this sustained release naltrexone implant in preventing opioid overdose. However, given the high prevalence of poly-substance use among dependent heroin users, programs offering this type of treatment should also focus on preventing, detecting and managing poly-substance use.     

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.     

Elevated startle during withdrawal from acute morphine: a model of opiate withdrawal and anxiety

Rationale An elevated startle response has been observed in humans and animals during withdrawal from multiple substances of abuse, a phenomenon thought to reflect the anxiogenic effects of withdrawal. Although anxiety is a common symptom of opiate withdrawal, few studies have examined the effects of morphine withdrawal on acoustic startle.Objective To develop a procedure for assessing opiate dependence through measurement of the startle reflex in rats.Methods The effects of opiate withdrawal on startle were evaluated using both spontaneous and naloxone-precipitated withdrawal from an acute dose of morphine. The ability of the treatment drugs clonidine and chlordiazepoxide to block withdrawal-induced increases in startle was also tested.Results Spontaneous withdrawal from an injection of morphine sulfate produced a significant increase in acoustic startle 2 h (3.2 mg/kg) or 4 h (10 mg/kg) after drug administration. Morphine withdrawal (10 mg/kg morphine sulfate) precipitated by the opiate antagonist naloxone (2.5 mg/kg) also produced a significant increase in startle magnitude. This elevation of startle was blocked by both clonidine (35 g/kg) and chlordiazepoxide (10 mg/kg).Conclusions These data demonstrate that both spontaneous and precipitated withdrawal from an acutely administered opiate produce anxiety-like effects on acoustic startle. This paradigm may be useful in the study of anxiety and the early mechanisms of drug dependence.     

Sensitization to morphine withdrawal in guinea-pigs

The aim of this study was to determine whether sensitization occurred to morphine withdrawal. Guinea-pigs were treated twice daily with increasing doses of morphine (10-100 mg/kg s.c.) for 3 days followed by injection of morphine 100 mg/kg on the fourth day. Sixty min after the last morphine injection, animals were withdrawn from morphine with naltrexone, 15 mg/kg s.c., and locomotor activity and all other behaviours scored over 90 min. Animals were then rested for 3 days. This procedure was repeated twice over the next 2 weeks. Control animals were treated with saline for the first two treatment cycles. Guinea-pigs subjected to three cycles of morphine withdrawal showed a significant increase in the total number of withdrawal behaviour counts over the 90-min observation period following the third cycle of withdrawal compared with the first and second withdrawal cycles. However, locomotor activity, a major sign of morphine withdrawal in guinea-pigs, was not significantly increased. Fos-LI was markedly increased in the repeatedly withdrawn animals in several brain regions, including amygdala, dorsal striatum, thalamus, ventral tegmental area, and ventrolateral periaqueductal gray area. It is concluded that sensitization to morphine withdrawal occurs in guinea-pigs.     

川芎嗪对小鼠吗啡戒断症状的抑制作用

目的：研究川芎嗪对小鼠吗啡戒断症状的影响。方法：以剂量递增法形成吗啡依赖模型,用纳洛酮催促戒断。结果：ｓｃ给药,Ｌｉｇ２０ｍｇ／ｋｇ抑制“湿狗”样抖动,打洞,前爪震颤症状：Ｌｉｇ４０ｍｇ／ｋｇ抑制跳跃、“湿狗”样抖动、上睑下垂,前爪震颤、体重下降等症状。结论：Ｌｉｇ能抑制大部分吗啡戒断症状。