Emmanuel Streel

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.

Ultra-rapid opiate detoxification: from clinical applications to basic science

Rapid or ultra‐rapid opiate detoxification has become increasingly popular in both private and public addiction centres. These techniques seem to facilitate the transfer of opiate‐dependent patients from opiate agonist to opiate antagonist. Despite the probable complex neuropharmacological aspects involved in these procedures, their development over nearly three decades is notable for the almost complete absence of clinically relevant animal studies. This paper discusses the historical background of this occurrence, and reviews the small number of animal studies that have been conducted. Many discussions and arguments about the techniques seem to underscore their true purpose, which is not “simply to detoxify” opiate‐addicted patients but to initiate long‐term management with naltrexone. For this reason, it may be better to conceptualize these techniques not as “rapid detoxification” but as “rapid antagonist induction”.

Interference with withdrawal signs of naloxone-induced opiate withdrawal under anesthesia is anesthetic-specific in opiate-dependent rats.

We hypothesized that interference of opiate antagonist-precipitated withdrawal signs under anesthesia is anesthetic-specific. Three groups of morphine-dependent rats were compared in different experimental conditions using a protocol of rapid withdrawal induction by an antagonist under anesthesia. We observed that ketamine and midazolam have different effects on the expression of withdrawal. This brings specific insights into the pharmacological basis of therapy with induction of opiate antagonist.

Current Issues in the Use of Opioid Antagonists (Naltrexone for Opiate Abuse: A Re-Educational Tool as Well as an Effective Drug)

The increasing availability in the past decade of largely unlicensed but clinically effective implant and depot preparations of naltrexone has greatly reduced the compliance problems that limited oral naltrexones usefulness in opioid dependence. This chapter describes the evolution of these preparations, reviews the growing literature and discusses the new clinical issues and problems that their effectiveness can create. We describe a new phenomenon, ‘pseudo-breakthrough’, as well as clinical examples of true opioid breakthrough and show that blood naltrexone levels well above the conventional effective minimum (around 2 ng/ml) may occasionally fail to block opioids. The history of naltrexones alleged hepatotoxicity is explained and demolished. Durable and effective opiate blockade makes psycho-social components of treatment easier to deliver and facilitates lasting cognitive and behavioural changes. Other topics covered include tissue reactions, other side effects, opioid receptor up-regulation and the conceptual and practical similarities between using naltrexone for opioid abuse and disulfiram for alcohol abuse. Finally, we stress the urgent need to use and improve the various rapid, humane and effective techniques of naltrexone induction. Otherwise, the generally low true completion rates of conventional opioid withdrawal techniques will prevent many suitable patients from initiating naltrexone treatment and thus benefiting from its new formulations.

Original strategies of screening, evaluation, and care of adolescent substance abuse

This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism in Mannheim, Germany, in October 2004. The aim of this symposium was to discuss new and interesting strategies of screening, evaluation and care of adolescent substance abuse developed in various countries. Our speakers have had to explain these strategies and to detail and focus on the more original tools of diagnosis or way of care used in their country. This symposium described two ways for screening and assessment (one developed in France [MR, LK] and the other in Switzerland [LC]) and made the point about questionnaires and biomarkers for alcohol problems in adolescents (JPA). The symposium was concluded by the presentation of a cannabis clinic (ES, JP).

Long-acting naltrexone has long-acting benefits and 100% induction rates are not difficult to achieve

Jarvis et al.’s comprehensive review of Vivitrol (extendedrelease-naltrexone/XR-NTX) [1] included three important clinical issues worth expanding. First, their discussion of low ‘rates of induction’ onto XR-NTX, defined as the percentage of those offered XR-NTX who received their first injection, ignores evidence from studies of implanted NTX that intention-to-treat induction rates of 100% have been routinely and safely achieved for many thousands of patients with relatively simple techniques [2–4], including one that requires no nursing or medical presence. To describe induction procedures lasting 7–8 days as ‘rapid’ suggests unfamiliarity with these methods, which eliminate what is perhaps the biggest obstacle to wider use of XR-NTX. Carreño et al.’s definition of ‘rapid’ induction techniques (those that, inter alia, enable patients to have taken full therapeutic doses of NTX within 24 hours) [5] has not been disputed. Secondly, quantifying ‘opioid use’ by ‘the percentage of urine samples negative for opioids’ is arguably an inappropriate sole measure of opioid intake in patients receiving adequate doses of XR-NTX because (unlike patients on agonist maintenance) NTX patients usually develop no agonist effects from even large doses of opiates [6,7]. Continued use of opiates despite complete blockade is an interesting and challenging phenomenon [7–11], but compatible with complete abstinence from opiates at the neuropharmacological level. Even persistent opiate use (usually intravenous) during the first weeks of parenteral NTX treatment sometimes disappears eventually. Habit and curiosity often drive early use. That curiosity may reflect hopes that the blockade can be over-ridden, or is waning, but it often reflects understandable needs for reassurance that NTX really does block opiates, thus reinforcing initially fragile beliefs in the possibility of remaining opiate-free for long enough for new opiate-free habits to become both automatic and effortless [12]. This leads to the third issue. They note, correctly, that other forms of XR-NTX can provide opiate blockade for as much as 7months, but the crucial clinical relevance of this advantage is obscured by their claim that ‘the effects of XRNTX have been shownnot to persist once discontinued’. On both theoretical and empirical grounds, that claim is questionable except for very short-term treatment. Patients who persist with XRor implanted NTX are, by definition, ‘good compliers’ and thus more likely to do well when NTX is discontinued [13]. Furthermore, being unable to experience agonist effects for several months, rather than having to decide every month to continue treatment (or not), makes it more likely that patients will adapt to opiate-free habits even if their motivation was initially poor. We have previously noted the many (largely unrecognized) similarities between disulfiram in alcohol dependence and NTX in opiate dependence. In the remarkably successful Out-patient Long-term Intensive Therapy for Alcoholics (OLITA) alcoholism programme, patients took supervised disulfiram for an average of about 3 years but 75% were still abstaining after 9 years [14]. In a British audit of long-acting NTX implants, 52% of patients who had one implant (and 100% of those who had two) remained opiate-free at 24 months, long after opiate-blockade had disappeared [15].

Benzodiazepine maintenance in opiate substitution treatment: Good or bad? A retrospective primary care case-note review:

Background: Co-prescribing benzodiazepines to patients in opiate substitution treatment is controversial and often alleged to increase mortality. In an inner-London general practice, patients with problematic benzodiazepine co-dependence were allowed benzodiazepine maintenance treatment (BMT) since 1994, providing an opportunity for analysis. Method: 1) Case-note review of all 278 opiate substitution treatment patients, accruing 1289 patient treatment years; 46% had concurrent BMT. 2) National Health Service database search for patients who died after leaving accrued a further 883 years of information; only patients who left the UK were unaccounted for (4%). Three groups were studied: 1) never obtained benzodiazepine prescription (NOB): n=80); 2) briefly/occasionally prescribed benzodiazepines (BOP): n=71; 3) BMT: n=127. Outcomes measured: Treatment retention (months); deaths/100 patient treatment years; deaths after leaving the service/100 years of information. Results: Treatment retention: NOB: 34 months; BOP: 51 months; BMT: 72 months. In-treatment mortality: NOB: 1.79/100 patient treatment years; BOP: 0.33/100 patient treatment years; BMT: 1.31/100 patient treatment years. Deaths after leaving service: NOB: 2.24/100 years of information, BOP: 0.63/100 years of information. However, mortality for previously BMT-patients increased by 450% to 5.90/100 years of information. Discussion: BMT patients had longer treatment retention than NOB or BOP and lower mortality than NOB patients. It is unlikely that patients had access to prescribed benzodiazepines on leaving the service because of restrictions in the national guidelines but co-dependent patients are a high-risk group who may stand to gain most benefit from opiate substitution treatment if combined with benzodiazepine-maintenance.

Towards a comprehension concerning the clinical effects of therapy with rapid opioid detoxification

SIR Ð It is now well over two decades since rapid opioid detoxification (ROD) was first described. Several techniques involving the administration of opiate antagonists during varying levels of sedation or general anaesthesia are currently being used in numerous centres, among which many are state-funded. Much has been written about ROD. Many clinicians were sceptical or hostile as there was no good comparative study and as some organizations unacceptably commercialized and promoted ROD. Spanagel et al. criticized ROD on the basis of an animal study, claiming that naltrexone-induced withdrawal under barbiturate anaesthesia increases the duration and severity of withdrawal symptoms in rats. They used these interesting results to question the pharmacological basis of ROD in man. Our findings regarding the influence of anaesthesia on the expression of withdrawal signs in opiatedependent rats qualify the results of Spanagel et al. We have shown in opiate-dependent rats that the induction of opiate antagonist-precipitated withdrawal under chloral hydrate anaesthesia increases the expression of withdrawal signs. This decrease is observed on awake animals 2 hours after the induction of anaesthesia. Four hours after this induction, some signs can reappear, some of them being potentiated. Our results lead to the conclusions that previous anaesthesia can temporarily overshadow the expression of withdrawal syndrome in opiate-dependent rats, and that only some signs can be delayed and increased in intensity. We explained this phenomenon by a parallel and temporary effect of anaesthesia on arousal and the pain threshold combined with a differentiated effect of ROD on the central nervous system (CNS) and peripheral system. The potential effect of anaesthesia preventing withdrawal signs is consistent with the emerging results of several comparative studies showing significantly higher rates of successful withdrawal and naltrexone induction with ROD compared with conventional withdrawal. As we have stated, the potential interaction between anaesthesia and opioid antagonists on the expression of withdrawal signs would have been underestimated and remains unclear. Further studies are still needed. However, the controversy concerning the possible pharmacological basis of ROD is at the very least far from being closed.