Rapid detoxification of heroin dependence by buprenorphine

评价丁丙诺啡７－８ｄ递减法治疗海洛因戒断症状（戒毒）的临床疗效．方法：６０例海洛因成瘾者根据依赖程度分为三组，分别给予低、中、高三种剂量丁丙诺啡舌下含服片剂治疗．治疗期间患者戒断症状采用“美国临床研究所麻醉药品评价量表”评价；对海洛因的心理渴求采用“视觉类比量表”自评；丁丙诺啡副作用采用“副反应量表”评价．结果：三组戒毒患者丁丙诺啡平均日消耗量分别为２０，２９和３６ｍｇ．此剂量的丁丙诺啡不仅可有效地控制海洛因戒断症状，且可缩短戒毒时程．结论：丁丙诺啡是一个有希望替代纯阿片受体激动剂的有效、快速戒毒药物．     

Is ecstasy a drug of dependence?

This paper examines the evidence for an MDMA or “ecstasy” dependence syndrome. Animal evidence suggests that MDMA may be a less potent reinforcer than other drugs, but that it does have dependence potential. This suggests that (a) ecstasy dependence might be less likely than dependence upon other drugs; and (b) factors related to the behavioural and psychological aspects of reward and dependence may make a relatively greater contribution for ecstasy than for other drugs, where physically centred (and better understood) features of dependence may be more salient. Human evidence supports this proposition. Some people report problems with their use, but the literature suggests that physical features play a more limited role than psychological ones. Tolerance is apparent, and withdrawal is self-reported, but it is unclear whether these reports distinguish sub-acute effects of ecstasy intoxication from symptoms reflective of neuroadaptive processes underlying a “true” withdrawal syndrome. Studies examining the structure of dependence upon ecstasy suggest it may be different from drugs such as alcohol, methamphetamine and opioids. Consistent with studies of hallucinogens, a two-factor structure has been identified with factors suggestive of “compulsive use” and “escalating use”. Regardless of the nature of any dependence syndrome, however, there is evidence to suggest that a minority of ecstasy users become concerned about their use and seek treatment. Further controlled studies are required to investigate this phenomenon.     

Might expectations explain early self-reported symptoms of nicotine dependence?

We examined youths' expectations about nicotine dependence to determine if these might explain the early appearance of symptoms. A convenience sample of 9th graders (n=460) completed a survey that asked them to imagine they were a novice teen smoker and an inveterate adult smoker and indicate whether they would expect to experience real and bogus symptoms of nicotine dependence. Responses were compared to actual symptom reports from 1375 adolescent novice smokers and 1102 adult smokers. The pattern of symptoms experienced by teen smokers did not match the pattern of symptoms expected by nonsmokers, but matched that of adult smokers almost exactly. The pattern of symptoms expected by novice teen smokers did not match the pattern of symptoms they reported experiencing. We found no evidence that youths' reports of symptoms of nicotine dependence are based on expectations. While youth do share expectations about nicotine dependence, it is not the expectation that they will become dependent; it is the expectation that if they smoke they will be able to quit whenever they want.     

A comparison of the content-, construct- and predictive validity of the cigarette dependence scale and the Fagerström test for nicotine dependence

BACKGROUND: Research showed that the widely used Fagerstrom test for nicotine dependence (FTND) does not cover important aspects of dependence. A new test, the cigarette dependence scale (CDS-12), covers the main elements in DSM-IV and ICD-10 definitions of dependence. We compared the psychometrics of CDS-12, FTND, and CDS-5 and the heaviness of smoking index (HSI), which are short versions of CDS-12 and FTND, respectively. METHODS: Internet survey in 2002-2003. Participants were invited one month after answering the first survey to answer a second survey on smoking status and withdrawal symptoms. RESULTS: Eight hundred two smokers answered both surveys. Cronbach's alpha coefficients were higher for CDS-12 (0.91) and CDS-5 (0.77) than for FTND (0.68) and HSI (0.63). Among 231 smokers who quit smoking at follow-up, higher baseline CDS-12 scores predicted higher withdrawal ratings at follow-up, for all withdrawal symptoms except appetite. FTND and HSI predicted higher craving in quitters, but did not predict the intensity of other withdrawal symptoms. Neither CDS-5, FTND or HSI predicted smoking cessation, but higher CDS-12 scores marginally predicted smoking cessation at follow-up (area under the receiver operating characteristic (ROC) curve = 0.55, 95% confidence interval = 0.51-0.59). CONCLUSIONS: CDS-12 had better content validity and internal consistency than FTND and was a slightly better predictor of withdrawal symptoms. Unexpectedly, higher (not lower) CDS-12 scores predicted subsequent smoking cessation, perhaps because endorsement of some CDS-12 items implies accepting that one is dependent, which in turn could reflect motivation to quit. CDS-12 may represent an alternative to FTND for measuring cigarette dependence.     

What aspects of treatment matter to the patient in the treatment of cocaine dependence?

Patient views of the helpful aspects of treatment were examined in the NIDA Collaborative Cocaine Treatment Study, a multi-site trial comparing four psychosocial treatments: individual cognitive therapy (CT), individual supportive expressive dynamic therapy (SE), individual drug counseling, and group drug counseling only, for the treatment of cocaine dependence. Factor analysis of the items of Helpful Aspects of Treatment measure suggested a general therapy factor, a group treatment/education factor, and a treatment structure factor. No differences were found among the four treatments on the ratings of helpfulness of these three factors, common factors, or drug intervention components. However, treatment specific cognitive therapy items (e.g. use of the cognitive model) and treatment structure differentiated individual CT from individual SE, and to a lesser extent from individual drug counseling. Ratings of helpfulness were significantly related to retention and alliance but were largely unrelated to changes in drug use or psychiatric outcomes.     

PPARγ dependence of cyclosporine-isoprenaline renovascular interaction: roles of nitric oxide synthase and heme oxygenase

We previously showed that cyclosporine (CSA) impairs renal vasodilations caused by β-adrenoceptor activation. This study investigated whether the peroxisome proliferator-activated receptor gamma (PPARγ) and related nitric oxide synthase (NOS)/heme oxygenase (HO) signaling mediates the CSA-β-adrenoceptor interaction. The vasodilatory response elicited by a bolus injection of isoprenaline (1 μmole) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPARγ antagonist), suggesting the involvement of PPARγ and HO-derived CO in the isoprenaline response. In contrast, the inhibition of NOS activity by N-nitro-l-arginine methyl ester had no effect on isoprenaline responses. CSA (5 μM) significantly attenuated isoprenaline vasodilations, an effect that was abolished in the presence of GW9662 and accentuated by ZnPP. Also, supplementation with the PPARγ agonist pioglitazone or with l-arginine or hemin, substrates for NOS and HO, respectively, eliminated the unfavorable effect of CSA on isoprenaline vasodilations. The protection conferred by pioglitazone against CSA-evoked attenuation of isoprenaline vasodilations was maintained in N-nitro-l-arginine methyl ester-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the HO/CO/PPARγ cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Further, the facilitation of the HO/CO or NOS/NO pathway seems to offset this harmful effect of CSA.     

Pharmacological characteristics of adenosine-induced inhibition of dog ventricular contractility: dependence on the pre-existing level of β-adrenoceptor activation

Summary Experiments were carried out to characterize the adenosine-induced negative inotropic effect in relation to the extent of -adrenoceptor activation in the isolated dog left ventricular myocardium. Adenosine and R-N⁶-phenylisopropyladenosine inhibited the positive inotropic effect of isoprenaline (10^–7 mol/1 and lower) about 20% of its maximal response, which was antagonized by an A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine in a concentration-dependent manner. The negative inotropic effect of adenosine disappeared and that of R-N⁶-phenylisopro-pyl-adenosine decreased when the isoprenaline concentration was elevated to the level higher than 10^–7 mol/1. Adenosine deaminase (1.5 U/ml) that abolished the negative inotropic effect of adenosine enhanced the effect of R-N⁶-phenylisopropyladenosine, indicating that endogenous adenosine released by high isoprenaline concentration (10^–6 mol/1) modulates the interaction. The maximal response to adenosine and R-N⁶-phenylisopro-pyladenosine determined in the presence of 10^–7 mol/1 isoprenaline was 50% of that of carbachol which elicited the maximal inhibition even in the presence of 10^–6 mol/1 isoprenaline. The negative inotropic effects of R-N⁶-phenylisopropyladenosine and carbachol were additive to the maximal response equivalent to that of carbachol. The difference in the efficiency between the adenosine and muscarinic receptor agonists may be partly ascribed to the difference in densities of the respective receptors in the dog ventricular myocardium. The negative inotropic effect of R-N⁶-phenylisopropyladenosine in the presence of isoprenaline was associated with decrease in cyclic AMP levels elevated previously by isoprenaline. The elevation of cyclic AMP levels caused by isoprenaline (3 × 10^–7 mol/1) was abolished by R-N⁶-phenylisopro-pyladenosine (10^–4 mol/1), while the contractile response was reduced only by 30% with R-N⁶-phenylisopro-pyladenosine. In the absence of -adrenoceptor stimulation R-N⁶-phenylisopropyladenosine elicited a negative inotropic effect without changes in cyclic AMP levels, but this effect was less than 10% of the basal force of contraction. It is concluded that in the dog ventricular myocardium adenosine receptors play a role for the inhibitory regulation of contractility, which is influenced markedly by the pre-existing level of -adrenoceptor activation. Send offprint requests to M. Endoh at the above address     

Inhibition of agmatine on psychological dependence induced by morphine and the possible mechanism

Agmatine is the endogenous ligand of imidazoline receptor, it enhanced morphine analgesia, inhibited tolerance to and physical dependence on morphine. In the present study, the effect of agmatine on the psychological dependence on morphine and the possible mechanism was evaluated.     

GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence?

Chronic use of benzodiazepines for the treatment of anxiety has revealed that these drugs can lead to dependence as indicated by withdrawal symptoms following cessation and tolerance to the drugs effects. Together with their reinforcing properties, this has led to them being labelled as scheduled drugs. Our new knowledge regarding the molecular structure of the benzodiazepine binding site and the growing ability to differentiate GABA(A) receptor subtypes, either by genetic manipulation or subtype selective compounds, have begun to facilitate our understanding of what underlies the mechanism of benzodiazepine dependence. In addition, the involvement of GABA(A) receptors in this phenomenon is leading to a greater understanding of other drugs such as alcohol and opiates.     

The clinical efficacy and abuse potential of combination buprenorphine–naloxone in the treatment of opioid dependence

Background: Opioid dependence is a chronic relapsing condition for which long-term opioid substitution treatment (OST) is effective. However, safety and community acceptance of OST is compromised by diversion of prescribed medication. The development of a formulation combining buprenorphine and naloxone is designed to reduce the likelihood of intravenous misuse, and the therefore the value of the medication if diverted to the black market. Objective: To evaluate the evidence for 4:1 buprenorphine–naloxone as an efficacious OST, and as a deterrent to diversion and intravenous misuse. Methods: The literature on buprenorphine–naloxone in a 4:1 ratio is reviewed. Results/conclusion: The addition of naloxone does not appear to affect the efficacy of buprenorphine as a maintenance drug. While offering some deterrence of injection through precipitated withdrawal, there are many circumstances where injecting of buprenorphine–naloxone is reinforcing rather than aversive. The combination will reduce, but not eliminate, intravenous misuse; clinicians therefore need to monitor patients in OST, and be selective in providing patients with medication to be taken without observation.     

Levels of immunoreactive dynorphin A_(1-13) during development of morphine dependence in rats

目的：研究吗啡依赖大鼠组织内免疫活性强啡肽Ａ１－１３含量的动态变化及其与依赖程度的关系．方法：用纳洛酮催促的戒断症状评分测定吗啡依赖程度，用放射免疫测定组织内强啡肽Ａ１－１３水平．结果：在３－６天给药期内，吗啡可进行性降低脊髓、垂体、血浆内免疫活性强啡肽Ａ１－１３水平，升高海马及下丘脑的强啡肽Ａ１－１３水平，继续给药至１２天，各组织内免疫活性强啡肽Ａ１－１３水平不再有显著性变化．结论：吗啡依赖形成过程中脊髓、垂体及血浆内强啡肽Ａ１－１３呈进行性降低，其趋势与吗啡依赖程度一致     

Orientation of μ-conotoxin PIIIA in a sodium channel vestibule, based on voltage dependence of its binding

Mutant cycle analysis has been used in previous studies to constrain possible docking orientations for various toxins. As an independent test of the bound orientation of μ-conotoxin PIIIA, a selectively targeted sodium channel pore blocker, we determined the contributions to binding voltage dependence of specific residues on the surface of the toxin. A change in the "apparent valence" (zδ) of the block, which is associated with a change of a specific toxin charge, reflects a change in the charge movement within the transmembrane electric field as the toxin binds. Toxin derivatives with charge-conserving mutations (R12K, R14K, and K17R) showed zδ values similar to those of wild type (0.61 ± 0.01, mean ± S.E.M.). Charge-changing mutations produced a range of responses. Neutralizing substitutions for Arg14 and Lys17 showed the largest reductions in zδ values, to 0.18 ± 0.06 and 0.20 ± 0.06, respectively, whereas unit charge-changing substitutions for Arg12, Ser13, and Arg20 gave intermediate values (0.24 ± 0.07, 0.33 ± 0.04, and 0.32 ± 0.05), which suggests that each of these residues contributes to the dependence of binding on the transmembrane voltage. Two mutations, R2A and G6K, yielded no significant change in zδ. These observations suggest that the toxin binds with Arg2 and Gly6 facing the extracellular solution, and Arg14 and Lys17 positioned most deeply in the pore. In this study, we used molecular dynamics to simulate toxin docking and performed Poisson-Boltzmann calculations to estimate the changes in local electrostatic potential when individual charges were substituted on the toxin's surface. Consideration of two limiting possibilities suggests that most of the charge movement associated with toxin binding reflects sodium redistribution within the narrow part of the pore.     

Pharmacotherapy for treating tobacco dependence: what is the ideal duration of therapy?

Various forms of nicotine replacement therapy and bupropion have been found to be efficacious and well tolerated for treating patients dependent on tobacco. However, the currently recommended duration of treatment with pharmacotherapy may be insufficient for some smokers to achieve sustained abstinence from tobacco. Extending the use of pharmacotherapy beyond the recommended timeframe may be an effective strategy for helping tobacco users achieve abstinence and for preventing relapse to tobacco use, especially among those who are highly dependent and those who are concerned about bodyweight gain following cessation. Several studies have reported on long-term use of various pharmacotherapies. These studies have demonstrated that such long-term use is not harmful. Moreover, compared with continued smoking, long-term use of pharmacotherapy exposes patients to relatively small amounts of nicotine and none of the cancer-causing chemicals found in cigarettes and other tobacco products. However, more research is needed to further clarify questions regarding the ideal duration of therapy. Two questions have yet to be answered: In what populations of smokers is long-term therapy an effective strategy for achieving abstinence and preventing relapse? Does wider availability of nicotine replacement therapy lead to initiation of nicotine addiction by children and others not using tobacco products? Also, as with all medications, additional documentation of the safety of prolonged use of pharmacotherapy is important. The aim of this review is to present the current evidence supporting the notion that long-term therapy for treating tobacco dependence may be appropriately considered for some tobacco users.     

Is the FTND a measure of physical as well as psychological tobacco dependence?

The Fagerström Test for Nicotine Dependence (FTND) has been developed to assess tobacco dependence from a physical perspective and to match treatments to individuals on the basis of the extent of the physical dependence. This study assessed the extent to which the FTND also measures psychological tobacco dependence. In three independently recruited samples of smokers, FTND scores, scores on indices of psychological dependence and smoking cessation were assessed. The results show that the indices of psychological dependence in all three samples explained about 20% of the variance in FTND scores. Furthermore, the FTND and the indices of psychological dependence both predicted quitting activity prospectively with two quitting measures in all three samples. Lastly, when the FTND and the indices of psychological dependence were combined in one model, the psychological dependence measures predicted quitting activity more consistently than the FTND, although the overlap between the two measures of dependence was small.     

Do smokers of specialty and conventional cigarettes differ in their dependence on nicotine?

Specialty cigarettes, bidis and kreteks, have commonly been viewed by adolescent users as being less harmful than conventional cigarettes. Biochemical studies, however, have shown that the concentration and delivery of nicotine from these tobacco products are not insignificant. The current study tested whether the diagnosis and symptoms for nicotine dependence differed among conventional-only smokers (n = 16 959), specialty-only smokers (n = 313), and poly-tobacco smokers (n = 1288) from the 2002 and 2003 National Surveys on Drug Use and Health. Compared with the specialty-only smokers, the conventional-only and poly-tobacco smokers were more dependent on nicotine, assessed by the Nicotine Dependence Syndrome Scale and a single item from the Fagerstrom Test for Nicotine Dependence. However, after accounting for differences in smoking frequency, the specialty-only smokers had significantly greater odds of being nicotine dependent than the conventional-only smokers. The reversed effect was primarily attributed to the specialty-only smokers who smoked less frequently, but reported a shorter time to their first cigarette. These findings suggest that the nicotine acquired from specialty cigarettes may be sufficient in yielding a sense of urgency to smoke.     

Is "the resistance to negative reinforcement" a feature of alcohol dependence syndrome?]

In 1979, "Alcoholism Diagnosis Committee, the Ministry of Health and Welfare" established the diagnostic criteria for alcohol dependence syndrome, which included "the resistance to negative reinforcement". The author raises a question about this criterion which indicates the condition that "an individual continues to drink despite alcohol-related physical diseases, rejection by his/her family or economic poverty and drinking-related criminal problem." The author defines this condition not as "resistance to negative reinforcement" but as "resistance to punishment." Furthermore, the author can not find the data supporting that "the resistance to negative reinforcement" in the correct sense exists in the individuals with alcohol dependence syndrome. In a theoretical sense, an opposite idea seems to exist. There is an observed fact that can be regarded as a phenomenon that explains the involvement of "negative reinforcement" in enhancement of psychological dependence as in the case of the secondary development of psychological dependence. Consequently, the author would have to say that defining "the resistance to negative reinforcement" as one of common features of alcohol dependence syndrome or one of diagnostic criteria for alcohol dependence syndrome is inappropriate.     

From substance dependence to addiction: impact of a conceptual shift on therapeutic approaches?

Switching from the concept of substance or alcohol dependence to that of addiction has profoundly modified our ways of approaching, treating and organizing the care of this disease. This more complex and subtle approach gives less importance to the substance and its effects and focuses more on the initiation of pathological behavior. It is important to keep in mind that the addictive process associates a substance (more or less addictive), an individual (more or less vulnerable) and an environment (more or less condoning). Today, it is no longer possible to consider that a drug acts on only one receptor or one system. Current understanding of inner regulation mechanisms integrates the interactions between the various stimulated brain pathways. Addiction treatments which should benefit from advances in genetics, neuropsychology and neuroimaging could be increasingly individualized in the years to come. The "addictology" approach has triggered thinking about other therapeutic approaches such as modification of therapeutic objectives toward "risk reductions" or applying this model to behavioral addictions (food, sex, sport, gaming...). This conceptual shift seems to enrich clinical analysis, the therapeutic possibilities and the avenues for research.     

Buprenorphine–naloxone buccal soluble film for the treatment of opioid dependence: current update

Introduction: Opioid dependence is a severe medical disorder with a high psychiatric and somatic comorbidity and mortality rate. The opioid agonist methadone, mixed agonist-antagonist buprenorphine and the combination of buprenorphine with the opioid antagonist naloxone are the first-line maintenance treatments for opioid dependence. Risk of diversion and accidental intoxications, especially in children, are of great concern. To lower these risks, a novel buprenorphine–naloxone film has been developed and introduced in the USA and Australia.

Areas covered: This review evaluates the available preclinical and clinical data on the novel buprenorphine–naloxone film for treatment of opioid dependence. Literature was identified through a comprehensive PubMed search. Data sources also included official FDA information and material made public by the manufacturer.

Expert opinion: Few preclinical and clinical data on safety and efficacy have been published. The pharmacological differences between the novel film and the conventional buprenorphine/naloxone are small. In an experimental study, the new formulation suppressed symptoms of opioid withdrawal. The spectrum of adverse events seems to be similar to that of the conventional sublingual tablet. Recent data show that patients prefer the novel film over the conventional sublingual tablet. Emerging surveillance data indicate a lower risk of accidental poisoning in children compared with the conventional formulation. Further clinical and preclinical data are needed to explore additional possible advantages of the new formulation.