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Moxnes and Jensen (2009) present a study of decision making under conditions of uncertainty using a computerised simulation of alcohol pharmacokinetics. In their article, they conclude that their findings challenge the 'folk wisdom' that advises against drinking on an empty stomach. We contend that this is a problematic conclusion for three reasons: (1) the study and findings presented in their paper are simply not sufficient to allow one to, even tentatively, draw such a conclusion; (2) the conclusion is contrary to basic pharmacological knowledge concerning alcohol absorption, metabolism and the implications for peak blood alcohol concentration; and (3) the implications for understanding the process of decision making while alcohol intoxicated are not considered in the study. The Moxnes and Jensen (2009) study did not involve alcohol administration and is therefore an examination of decision making in situations of uncertainty rather than a specific exploration of drinking-related decision making. Recent formulations of the effects of alcohol on cognitive processing would lead to different conclusions than those presented by Moxnes and Jensen (2009). We conclude by suggesting our understanding of the implications of the study. [ABSTRACT FROM AUTHOR]

Background: Changes in patterns of drug use and population needs necessitate the adoption of new technologies. Despite high failure rates in adopting new technologies acquired in training, little is known about the process that can support successful change. This study explores the impact that staff and service characteristics have on the process of training adoption in Irish opiate substitution therapy services, with a specific focus on the concept of organizational readiness to change., Methods: A cross-sectional survey was conducted on a convenience sample of 132 staff members across 12 services in Ireland. The relationship between staff demographics, their perceptions of organizational readiness to change, burnout, and a four-stage process of training adoption were considered., Results: Discipline, job tenure, and educational levels are important predictors of engagement in the adoption process. Staff in services with higher institutional needs, greater pressures for change, and poorer resources were less likely to be exposed to, or adopt, training. Having lower levels of stress and more influence with peers was associated with better adoption of training., Conclusions: Planners and service managers need to carefully consider the composition or dynamics of services when initiating change. Organizational readiness to change and staff characteristics as measured by instruments used in this study are important determinants of the process of innovation or training adoption and provide a good basis for developing further understanding of how treatment services work. This article expands on results from previous studies conducted in the United States to a European context., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article., (Copyright © 2022 International Nurses Society on Addictions.)

Mental ill health among higher education students is a well-established problem; therefore, it is imperative to implement preventative approaches to support wellbeing. Blended and fully online education programmes widens access for mature or returning students; however, the psychological wellbeing of this sub-group of students is under-researched. Finally, evaluating wellbeing interventions that meet the needs of university students as well as accessible for online students is required. The aim of this study was to evaluate a brief, online and mindfulness-based intervention to assist the self-management of wellbeing and stress for both online and on-campus higher education students. The total sample included 427 participants (96% psychology students) at Monash University, Australia ( n =283) and King's College London ( n =144), with 152 participants completing the whole study. Participants were allocated to a brief, self-guided, online and mindfulness-based intervention (over the course of one study period; n =297), or to a wait-list control group ( n =148). Baseline and end of semester questionnaires included the 14-item Warwick-Edinburgh Mental Wellbeing Scale, 10-item Perceived Stress Scale and the 15-item Mindful Attention Awareness Scale. Regression modelling revealed the intervention condition accounted for up to 12% of the variability in change in student wellbeing, stress and mindfulness between the start and end of semester (when controlling for baseline). These findings support the implementation of a brief, online and asynchronous mindfulness-based intervention for supporting student mental health and psychological wellbeing. An on-going challenge in practice includes engaging and maintaining student engagement in wellbeing initiatives., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chung, Mundy, Hunt, Coxon, Dyer and McKenzie.)

Supporting students to develop transferable skills and gain employment is a vital function of Universities in the era of the Fourth Industrial Revolution. A key area is work readiness, which has steadily grown in importance over the last 2 decades as tertiary institutions increasingly aim to produce graduates who perceive and are perceived as work ready . However, a large majority of graduates report a lack of skills and confidence needed for the effective transition from study to work. This may be particularly problematic for disciplines that impart both discipline-specific and transferrable skills, such as psychology. The aim of this paper is to addresses the concept of work readiness within Australian psychological training and explores the need to shed light on and integrate work readiness within the pedagogy of psychology within Australia. Specifically, this paper calls for a review of work readiness skills developed in psychological courses to ensure industry needs are met. Beyond such a review, it is suggested that tertiary centres need to facilitate students in capturing and reflecting upon the transferable skills that they develop; and build assessments that allow students to demonstrate transferable skills in a meaningful way. Further, this paper proposes that work readiness skills be routinely mapped onto graduate attributes and course learning outcomes to be readily available by students so as to increase students' potential to articulate their learnt work readiness skills once in the workplace., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schweinsberg, Mundy, Dyer and Garivaldis.)

Objectives: Alcohol use remains a public health concern with accumulating evidence pointing to alcohol-associated prospective memory (PM) deficits. PM is the cognitive ability to remember to perform an intended action at some point in the future. Following PRISMA guidelines, we searched the evidence base to identify and explore the evidence of a relationship between alcohol use and PM. Methods : We conducted a systematic literature search in Medline, Embase, Pubmed, CINAHL, PsycINFO and Web of Science databases. Studies were included if they met the following criteria: English language publication, healthy adult participants (16 years and over), primary data on the effects of alcohol on PM. Results : Eight peer-reviewed studies were eligible for inclusion, of which five were randomized controlled trials examining the acute effects of a mild dose of alcohol and three were cross-sectional studies assessing the long-term effects of different drinking patterns on PM. Four main findings were supported by the literature: (1) compared with placebo, an acute administration of a mild alcohol dose to healthy social drinkers may lead to poorer PM performance, (2) alcohol consumption over the recommended weekly units can be associated with impaired PM function, (3) other cognitive domains can play a contributing role in alcohol-induced PM impairment, and (4) following future event simulation alcohol-induced PM impairment may be improved. Conclusion : Alcohol consumption potentially impairs PM, even at a low modest dose. Considering the small number of studies and their methodological flaws, additional research is needed to decipher the alcohol-PM relationship and provide further supporting evidence.

Translating innovation, such as contemporary research evidence, into policy and practice is a challenge, not just in substance misuse treatment programs, but across all spheres of healthcare. Organizational readiness to change (ORC) has been described as a fundamental concept, and an important determinant of the process of innovation adoption. The aim of this review was to describe the relationship between staff perceptions of ORC and the process of innovation adoption: exposure, adoption, implementation and integration into practice, in substance misuse treatment programs. This systematic review was conducted in accordance with PRISMA guidelines and fourteen papers were identified as being eligible for inclusion. This review was designed to include all constructs of ORC, but only one tool was used in all of the included papers. Despite this, the heterogeneity of studies in this review made a direct comparison of ORC related variables challenging. None of the included papers clearly related to one stage of the process of innovation adoption, and all of the included papers related to the early stages of the process. Only one paper attempted to measure the sustained integration of an innovation into practice. Overall, the papers were assessed as being low in terms of evidential hierarchy and the quality of the papers was assessed as being on average fair. ORC measurements provide us with a measure of organizational functioning which can be important in terms of predicting how successfully new innovations are adopted. Motivation for change was high in programs where staff identified more program deficits and these staff could also identify more specific needs, but were less likely to have exposure to new innovations. Better program resources and specific staff attributes, increase the likely hood of successful innovation adoption. A good organizational climate is potentially the strongest predictor for the adoption of new practices. It may be beneficial to measure ORC in conjunction with other variables such as program size, location, staff workloads and financial resources. More evidence is required on how to address ORC deficits once they are identified in practice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Prospective memory (PM) is memory for delayed intentions. While deleterious effects of acute doses of alcohol on PM have been documented previously using between-subjects comparisons, the current study adopted a single blind placebo-controlled within-subjects design to explore whether the extent to which alcohol-related impairments in PM are mediated by executive functions (EFs). To this end, 52 male social drinkers with no history of substance-related treatment were tested using two parallel versions of a clinical measure of PM (the Memory for Intentions Test; Raskin et al., 2010), and a battery of EF measures. Testing took place on two occasions, with the order of administration of the alcohol and placebo conditions being fully counterbalanced. Overall, PM was worse under alcohol and participants showed deficits on five of the six subscales making up the clinical test. Hierarchical multiple regression analyses demonstrated that EFs did not predict PM performance decrements overall but did predict performance when time cues were presented and when verbal responses were required. Phonemic fluency was the strongest of the EF predictors; a greater capacity to gain controlled access to information in long-term memory predicted a smaller difference between placebo- and alcohol-related performance on both the time cue and verbal response scales. PM is crucial to compliance with, and response to, both therapy programs and alcohol harm prevention campaigns. The results indicate that individual differences in cognitive function need to be taken into account when designing such interventions in order to increase their effectiveness.

Aims: Four experiments were conducted to assess the acute impact of context and exposure to responsible drinking messages (RDMs) on attentional allocation and drinking behaviour of younger drinkers and to explore the utility of lab-based methods for the evaluation of such materials., Methods: A simulated bar environment was used to examine the impact of context, RDM posters, and brief online responsible drinking advice on actual drinking behaviour. Experiments one (n = 50) and two (n = 35) comprised female non-problem drinkers, whilst Experiments three (n = 80) and 4 (n = 60) included a mixed-gender sample of non-problem drinkers, recruited from an undergraduate student cohort. The Alcohol Use Disorders Identification Test (AUDIT) was used to assess drinking patterns. Alcohol intake was assessed through the use of a taste preference task., Results: Drinking in a simulated bar was significantly greater than in a laboratory setting in the first two studies, but not in the third. There was a significant increase in alcohol consumption as a result of being exposed to RDM posters. Provision of brief online RDM reduced the negative impact of these posters somewhat; however the lowest drinking rates were associated with being exposed to neither posters nor brief advice. Data from the final experiment demonstrated a low level of visual engagement with RDMs, and that exposure to posters was associated with increased drinking., Conclusions: Poster materials promoting responsible drinking were associated with increased consumption amongst undergraduate students, suggesting that poster campaigns to reduce alcohol harms may be having the opposite effect to that intended. Findings suggest that further research is required to refine appropriate methodologies for assessing drinking behaviour in simulated drinking environments, to ensure that future public health campaigns of this kind are having their intended effect., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Aims: To examine the literature regarding clinical pharmacokinetics, direct effects and adverse clinical outcomes associated with methamphetamine use., Methods: Relevant literature was identified through a PubMed search. Additional literature was obtained from relevant books and monographs., Findings and Conclusions: The mean elimination half-life for methamphetamine is approximately 10 hours, with considerable inter-individual variability in pharmacokinetics. Direct effects at low-to-moderate methamphetamine doses (5-30 mg) include arousal, positive mood, cardiac stimulation and acute improvement in cognitive domains such as attention and psychomotor coordination. At higher doses used typically by illicit users (> or =50 mg), methamphetamine can produce psychosis. Its hypertensive effect can produce a number of acute and chronic cardiovascular complications. Repeated use may induce neurotoxicity, associated with prolonged psychiatric symptoms, cognitive impairment and an increased risk of developing Parkinson's disease. Abrupt cessation of repeated methamphetamine use leads to a withdrawal syndrome consisting of depressed mood, anxiety and sleep disturbance. Acute withdrawal lasts typically for 7-10 days, and residual symptoms associated with neurotoxicity may persist for several months.

Introduction and Aims: As an antidepressant with sedative and anxiolytic properties, mirtazapine may be an appropriate pharmacotherapy for methamphetamine withdrawal. This study sought to examine whether mirtazapine improves retention and alleviates methamphetamine withdrawal symptoms in an out-patient setting., Design and Methods: An out-patient double-blind, randomised placebo-controlled trial of mirtazapine for the treatment of methamphetamine withdrawal was conducted (15 mg nocte for 2 days, 30 mg nocte for 12 days). Both groups were offered narrative therapy counselling. Measures recorded on days 0, 3, 7, 14 and 35 included: treatment retention, Amphetamine Cessation Symptoms Assessment, the Athens Insomnia Scale, the Brief Symptom Inventory, the Depression-Anxiety-Stress Scale (DASS), Severity of Dependence scale and the Opiate Treatment Index Drug Use subscale., Results: Thirty-one participants were recruited (18 placebo, 13 mirtazapine) and 52% completed the 2-week medication phase. No significant differences between the mirtazapine and placebo groups in retention, or any symptom measure were observed, except greater DASS-anxiety and longer sleep duration were measured at baseline among the mirtazapine group., Discussion and Conclusions: Results suggest that mirtazapine does not facilitate retention or recruitment in out-patient methamphetamine withdrawal treatment, although recruitment may have been insufficient to identify a significant treatment effect. The potential role of narrative therapy for methamphetamine dependent patients deserves further exploration.

As many of the harms associated with drug use may be due to intoxication, particularly where the individual is driving, operating machinery or involved in other tasks requiring high level psycho-motor functioning, it follows that having a valid, reliable convenient measure of recent drug use and, if possible, intoxication, will be important in reducing drug-related harm. Oral fluid testing is the latest technology offering promise in this area. As with any such technology, it has advantages and disadvantages. In this Harm Reduction Digest, Dyer and Wilkinson describe the technology, its strengths and limitations and provide examples of where it is currently being employed in practice. This is a must read paper for those of us interested in reducing drug-related harm.

Knowledge of how methadone disposition may fluctuate during the course of maintenance treatment is presently limited. This study investigated long-term fluctuations in methadone pharmacokinetics in five methadone maintenance patients who participated in two 24-hour testing sessions separated by at least one year. Results indicated substantial fluctuations between sessions in dose-corrected average steady-state plasma (R)-methadone concentrations (Cav), ranging from a 51% decrease to a 466% increase. These fluctuations were not consistently associated with changes in methadone dose or self-reported withdrawal status. The plasma (S)-:(R)-methadone Cav ratio increased significantly (12%, P = 0.04) between the sessions, suggesting a different pattern of long-term change in the pharmacokinetics of each enantiomer over time. The pronounced and variable fluctuations in methadone disposition evident in these patients highlight the need for an individualized approach to patient dosing and monitoring.

Delivery of methadone maintenance treatment (MMT) varies considerably between service providers, but the reasons for this are unclear. This two-phase study involved a controlled investigation of factors that influence clinical decision making by methadone-prescribing physicians in regard to three decision-making scenarios: (1) individuals seeking induction into MMT and existing patients seeking (2) replacement and (2) takeaway methadone doses. In phase 1, physicians (n = 17) rated the diagnostic merit of 87 patient factors for each scenario. Ratings suggested that decisions are influenced by a range of subjective and "nonmedical" patient factors (e.g., contact with drug subculture, appearance, employment status, social support, having children), in addition to more conventional information sources regarding patients' medical and treatment status (e.g., being pregnant, urinalysis evidence of opioid and poly drug use, signs of opioid withdrawal). Phase 2 (n = 296) investigated relationships between physician characteristics and responses to randomized-controlled case vignettes (decisions and confidence ratings) in which the amount and type of diagnostic and nondiagnostic patient information was controlled. Vignette responses were significantly related to physician characteristics (e.g., professional orientation, location, and experience) independent of the patient information provided. Delivery of MMT may vary due to the diversity of patient factors that influence decisions and variability between physicians in the way such information is used to form judgments. Training programs for methadone prescribers should account for these sources of potential variability in treatment management.

Aims: To investigate the possibility that (S)-methadone influences therapeutic and adverse responses to rac-methadone maintenance treatment, by examining how subjective and physiological responses among rac-methadone maintenance patients vary in relation to relative exposure to (S)- vs. (R)-methadone., Methods: Mood states (Profile of Mood States), opioid withdrawal (Methadone Symptoms Checklist), physiological responses (pupil diameter, heart rate, respiration rate, blood pressure), and plasma concentrations (CP) of (R)- and (S)-methadone were measured concurrently 11-12 times over a 24-h interdosing interval in 55 methadone maintenance patients. Average steady-state plasma concentrations (C(av)) and pharmacodynamic responses were calculated using area under the curve (AUC). Linear regression was used to determine whether variability in pharmacodynamic responses was accounted for by (S)-methadone C(av) controlling for (R)-methadone C(av) and rac-methadone dose. Ratios of (S)-:(R)-methadone using AUC(CP) and trough values were correlated with pharmacodynamic responses for all subjects and separately for those with daily rac-methadone doses > or = 100 mg., Results: (S)-methadone C(av) accounted for significant variability in pharmacodynamic responses beyond that accounted for by (R)-methadone C(av) and rac-methadone dose, showing positive associations (partial r) with the intensity of negative mood states such as Tension (0.28), Fatigue (0.31), Confusion (0.32), and opioid withdrawal scores (0.30); an opposite pattern of relationships was evident for (R)-methadone. The plasma (S)-:(R)-methadone AUC(CP) ratio (mean +/- SD 1.05 +/- 0.21, range 0.65-1.51) was not significantly related to pharmacodynamic responses for the subjects as a whole but showed significant positive associations (r) with the intensity of negative mood states such as Total Mood Disturbance (0.61), Tension (0.69), Fatigue (0.65), Confusion (0.64), Depression (0.49) and heart rate (0.59) for the > or = 100-mg dose range., Conclusions: These findings agree with previous evidence that (S)-methadone is associated with a significant and potentially adverse profile of responses distinct from that of (R)-methadone. Individual variability in relative (S)- vs. (R)-methadone exposure may be associated with variability in response to rac-methadone maintenance treatment.

Although methadone maintenance is designed to stabilize opioid-dependent patients, some experience significant withdrawal in the latter part of the 24-hour interdosing interval. This study was designed to determine the mood changes that maybe associated with such withdrawal. Eighteen methadone patients, nine of whom experienced significant withdrawal, were tested over a single interdosing interval. During this time, 13 blood samples were collected to measure plasma racemic methadone concentrations, and the Profile of Mood States (POMS) was administered on 11 of these occasions. The POMS was also administered on 11 occasions over 24 hours to 10 drug-free healthy controls. In comparison with controls, methadone patients showed increased anger, depression, tension, confusion, and fatigue, as well as decreased vigor. For all scales, maximal differences from controls occurred at times of trough methadone concentration and minimal differences around the time of peak concentration. Changes in mood over the interdosing interval were more exaggerated in the nine patients who experienced significant withdrawal compared with those who did not. The composite Total Mood Disturbance (TMD) scores were calculated for each subject at each time point. The sigmoid Emax model was used to relate plasma concentrations to these data and to calculate the slope factor (N). This model could be fitted for 14 of the 18 patients with a mean +/- SEM slope factor of 2.2 +/- 0.5. TMD score was also shown to be inversely related to the rate of decline in methadone concentration from peak to trough. These results show that significant mood changes occur in response to changes in methadone concentration, and these are more pronounced in those who experience withdrawal. The concentration-effect relationships suggest that relatively small changes in plasma concentration will result in significant mood change. Differences in the degree of mood change between those who do and do not experience significant withdrawal may be explained by variation in the rate of decline in plasma concentration from peak to trough.

Aims: To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population., Methods: Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha1-acid glycoprotein concentrations were quantified by radial immunoassay., Results: (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCtau&#95;¿u¿ss (167%) was significantly (P < 0. 001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCtauss, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%., Conclusions: Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.

Objective: To determine plasma racemic methadone concentration-effect relationships for subjective and objective responses and whether pharmacokinetic and/or pharmacodynamic factors influence withdrawal severity., Methods: Eighteen patients enrolled in a public methadone maintenance program, nine of whom experienced significant withdrawal, received constant doses of methadone once daily for at least 2 months. During an interdosing interval, 13 blood samples were collected to measure plasma racemic methadone concentrations (patients); subjective (withdrawal severity, direct opioid effects, and pain threshold) and objective (pupil diameter and respiratory rate) opioid effects were quantified on 11 occasions (all participants). The sigmoid Emax model was used to relate plasma concentrations and effects and to calculate the slope factor (N). The rate of decline in plasma concentration during each hour from the peak to the trough concentration was calculated., Results: There was an inverse relationship between plasma concentrations and withdrawal severity and pupil diameter, as well as a direct relationship with subjective opioid effects and pain threshold. The mean N values were 5.4+/-0.9 for withdrawal severity, 5.1+/-1.1 for subjective opioid effects, 1.2+/-0.1 for pupil diameter, and 2.8+/-0.7 for pain threshold. Withdrawal severity correlated with the maximum rate of decrease in plasma concentration (P < .01). There were no differences between those who reported significant withdrawal and those who did not with respect to mean area under the plasma concentration versus time curve and predose plasma concentration, but maximal rate of decline was greater in the former group (74.5 versus 42.1 ng/mL/h)., Conclusions: In this group of long-term methadone-maintained recipients, opioid responses were strongly correlated with changes in plasma racemic methadone concentrations. For the subjective responses, notably withdrawal, small changes in plasma concentrations translate into relatively large changes in effect; therefore, clinically important withdrawal is a consequence of more rapid decline in methadone concentration.

To determine whether reduced Na+/K+-ATPase activity might be involved in acrylamide (ACR)-induced peripheral axon swelling and degeneration, rubidium (Rb+) transport was measured as an index of enzyme function. x-ray microanalysis was used to quantify elemental Rb uptake and accumulation in internodal myelinated axons, mitochondria, Schwann cells, and myelin of rat tibial nerve cryosections. Results demonstrated impairment of Rb uptake in tibial axons from orally intoxicated (2.8 mM ACR for 34 days), moderately affected rats. In severely affected oral rats (49 days), complete inhibition of Rb transport and frank axon degeneration were evident. However, in moderate-to-severely affected rats exposed to ACR via ip injection (50 mg/kg/day for 11 days), neither structural nor enzymatic changes were present in tibial fibers. These findings in nerve cryosections suggested inhibition of axolemmal Na+ pump activity and degeneration were dependent upon route of ACR administration. This possibility was substantiated by a quantitative longitudinal morphometric study of conventionally fixed tibial nerve. Oral ACR treatment (2.8 mM ACR for 15-49 days) was associated with progressive axon degeneration, which was preceded by atrophy. Axonal swellings were rarely (<1%) observed. In contrast, ip ACR injection (50 mg/kg/day for 5-11 days) produced classic behavioral neurotoxicity but did not alter axon morphology in tibial nerve. Thus, fiber degeneration and decreased Na+ pump activity were consequences of subchronic oral ACR administration. This parallel expression suggests a mechanistic relationship. However, the corresponding general neurotoxicological significance is unclear since, behavioral toxicity induced by ip ACR develops without structural and enzymatic changes in tibial nerve., (Copyright 1998 Academic Press.)

Aim: Not all maintenance patients respond to methadone in the same manner, and many complain of withdrawal symptoms during the 24-hour inter-dosing interval (i.e. the dose does not 'hold'). The persistence of these complaints are a source of concern as they may signal unsanctioned drug use and poor treatment outcome. This study examined the prevalence and profile of symptom complaints in methadone maintenance patients who report that their methadone dose does not 'hold'., Design: In the first phase, a cross-sectional survey of 114 methadone patients examined a range of symptoms including direct opioid effects and withdrawal. Phase 2 involved a comparison of the temporal pattern of symptom complaints between patients who reported the oral dose not 'holding' and those who did not., Setting: Participants in this study were enrolled in the South Australian Public Methadone Maintenance Program., Measurements: In Phase 1, a checklist of 21 commonly reported symptom complaints associated with methadone maintenance treatment was administered. In Phase 2, this checklist was modified to include only those symptoms that changed in the 24-hour inter-dosing interval. The checklist was administered eight times over this period. Further data were collected using the Morphine Benzedrine Group Scale of the Addiction Research Centre Inventory, a measure of positive opioid effect., Findings: In Phase 1, it was found that approximately one-third of the sample reported that the methadone dose was consistently inadequate in preventing withdrawal symptoms for the entire inter-dosing interval. They could not be differentiated by demographic, health, other drug use or treatment characteristics. In Phase 2, despite having a higher oral methadone dose, patients reporting that their daily dose did not 'hold' experienced a smaller degree of opioid effect, and a greater intensity of opioid withdrawal, during the 24-hour period., Conclusion: These data demonstrate that there is a change in pharmacodynamic response over the 24-hour period for all methadone patients, but the degree of change is greater in a subgroup of patients. Charting symptom presentation throughout the inter-dosing interval can aid in identifying those patients who are experiencing difficulties with their treatment regime.

Bilateral midbody hemimandibular osteotomies were performed between premolars 3 and 4 in 18 adult dogs. Hemimandibles were repaired by use of monocortically applied bone plates (n = 6), an interdental fixator composed of an Erich arch bar and acrylic (n = 6), or a type I external skeletal fixator (n = 6). At the immediate postoperative evaluation, hemimandibles stabilized with interdental fixators had an osteotomy gap distance (mean +/- SEM, 1.6 +/- 0.2 mm) that was significantly (P < 0.05) greater than for hemimandibles stabilized with external skeletal fixators (1.2 +/- 0.3 mm). Osteotomy gap distance of hemimandibles stabilized with external skeletal fixators (1.5 +/- 0.2 mm) was significantly (P < 0.05) greater at weeks 4 (1.1 +/- 0.2 mm) and 8 (0.8 +/- 0.3 mm) after surgery than the osteotomy gap distance of hemimandibles stabilized by application of bone plates. By week 16, significant differences in osteotomy gap distance were not detected between groups. Immediately after surgery, mandibular alignment measurements were not significantly different for dogs with bone plates (0.3 +/- 0.1 mm), interdental fixators (0.3 +/- 0.1 mm), and external skeletal fixators (0.9 +/- 0.5 mm). Mandibular alignment scores were not significantly different between treatment groups during the remaining postoperative period. Occlusal measurements were not significantly different between evaluations performed before surgery and 16 weeks after surgery, regardless of treatment group. Radiographic evidence of healing in hemimandibles stabilized with external skeletal fixators was significantly (P < 0.05) less at 4 and 8 weeks, compared with hemimandibles stabilized with bone plates and interdental fixators; however, radiographic evidence of bone healing was not significantly different between fixation groups at 16 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of short-term phenobarbital administration were evaluated in 6 adult mixed-breed dogs that received phenobarbital (5 mg/kg of body weight, PO, q 12 h) for 8 consecutive weeks. Six additional dogs served as untreated controls. At 2-week intervals, endogenous adrenocorticotropic hormone (ACTH) concentration and cortisol concentration before and 2 hours after administration of porcine aqueous ACTH (2.2 IU/kg, IM) were measured. By means of one-way ANOVA, we were not able to detect a significant (P > or = 0.05) difference in endogenous ACTH concentration and cortisol concentration before and after exogenous ACTH administration within groups over time or between groups at any time. To evaluate effects of long-term phenobarbital administration, sera and plasma were collected from 5 epileptic dogs that had received phenobarbital for > 2 years and had serum phenobarbital concentrations > 20 micrograms/dl. Endogenous ACTH concentration and cortisol concentration, before and after administration of ACTH, were within established reference ranges for all 5 dogs. Together, these results suggest that phenobarbital administration alone does not affect endogenous ACTH concentration or response to exogenous ACTH administration in dogs, and that these may be valid screening tests for hyperadrenocorticism in most dogs receiving phenobarbital.

The injecting behaviour and risky needle use of a sample of 193 methadone maintenance clients was investigated. The majority of the sample (n = 116) reported injecting one or more drugs in the month prior to data collection. Compared with non-injectors, the injectors were slightly younger, had been on the methadone program for a shorter period of time, had lower methadone doses and more severe drug and legal problems. The injecting sub-group was examined in more detail by comparing those subjects whose injecting practices conformed to guidelines on minimizing risk of HIV transmission with those who, in the preceding month, made at least one injection contravening these guidelines and thus placed themselves at risk of contracting HIV. A greater proportion of these risky injectors were unemployed. Importantly, risky injectors had lesser knowledge of means of preventing the spread of HIV than safe injectors. It is concluded that the reduction of HIV transmission could be enhanced by improvements in methadone programs, particularly ensuring adequate dosing and high retention rates. Further, there is a need to improve knowledge with regard to what are safe and what are risky injecting practices and needle/syringe cleaning methods.

The disposition of clorazepate, a benzodiazepine anticonvulsant, was determined in dogs after administration of a single oral dose of clorazepate (2 mg/kg of body weight) and after oral administration of clorazepate (2 mg/kg, q 12 h) concurrently with phenobarbital (5 mg/kg, q 12 h) for 44 consecutive days. Serum concentrations of nordiazepam, the active metabolite of clorazepate, were measured. After a single oral dose of clorazepate, maximal nordiazepam concentrations ranged from 569.6 to 1,387.9 ng/ml (mean, 880.2 +/- 248.9 ng/ml) and were detected 16.8 to 131.4 minutes (mean, 85.2 +/- 36 minutes) after dosing. After administration of phenobarbital for 44 consecutive days, maximal nordiazepam concentrations were significantly (P < 0.01) lower, ranging from 209.6 to 698.5 ng/ml (mean, 399.3 +/- 155.6 ng/ml) at 68.4 to 145.8 minutes (mean, 93 +/- 25.8 minutes) after dosing. Mean area under the curve (AUC) on day 1 (mean, 3.37 +/- 0.598 ng.min/ml) was significantly (P < 0.001) greater than AUC on day 44 (1.66 +/- 0.308 ng.min/ml). Oral clearance was significantly (P < 0.01) greater on day 44 (12.44 +/- 2.55 ml/min/kg), compared with that on day 1 (6.16 +/- 1.35 ml/min/kg). Values for area under the first moment curve, oral volume of distribution, mean residence time, and elimination half-life were not significantly altered by concurrent administration of phenobarbital. Administration of phenobarbital altered the disposition of clorazepate such that the amount of nordiazepam in circulation during each dose interval was significantly reduced. Adequate control of seizures in epileptic dogs, therefore, may require higher dosages of clorazepate when it is coadministered with phenobarbital.

A single injection of mipafox was administered to both Long-Evans hooded rats and White Leghorn hens in dosages which inhibited the activity of brain neurotoxic esterase 30-50%, 60-80%, or greater than 80% four hr after intoxication. All animals were monitored for clinical evidence of organophosphorus induced delayed neuropathy for 21 days, euthanatized, and regions of the nervous system were histologically evaluated. Only hens manifested clinical signs of neuropathy; however, light and electron microscopic lesions were present in the nervous systems of both species. In rats, these lesions were well developed in only the highest dosage group and confined to the rostral level of the fasciculus gracilis in the medulla oblongata. Swollen axons containing a single vacuole filled with flocculent material were the most prominent lesion in rats. Hens manifested more extensive and varied fiber breakdown in multiple spinal cord tracts, with the intensity of degeneration increasing with increasing dosages of mipafox. Both marked Wallerian-like degeneration and swollen axons filled with aggregates of cellular debris were observed in the nervous systems of hens. This study indicates that both rats and hens are susceptible to OPIDN. However, there are qualitative and quantitative differences in both clinical manifestations and histologic appearances between the two species.

Delayed neuropathy induced by organophosphorus esters has been reported to be more selective for large diameter myelinated fibers, especially in distal portions of long nerves. This concept was re-evaluated in chickens by quantitatively comparing the effects of the organophosphates tri-ortho-tolyl (TOTP) and phenyl saligenin phosphate (PSP) on two separate nerves, the branch of the tibial nerve that supplies the gastrocnemius muscle, and the small cervical nerve that innervates the biventer cervicis muscle. Histograms illustrating the distribution of myelinated fibers within each nerve showed that the biventer nerve is composed of a population of fibers smaller than those within the tibial nerve branch. However, the number of myelinated fibers measured per mm2 of endoneurium was reduced in both nerves 10 and 15 days after organophosphate administration, providing indirect evidence that fiber diameter is not critical in determining susceptibility to organophosphorus-induced delayed neuropathy (OPIDN). More direct evidence was provided by fiber diameter histograms of both biventer nerves and tibial nerve branches taken from hens that received PSP. In comparison to control values, there was a decrease in all fiber sizes in both nerves, indicating that factors other than axonal size are important in determining nerve fiber susceptibility to OPIDN.

The intraneural course of nerve fibres in the equine recurrent laryngeal nerve was investigated by partially ligating the nerve at a proximal site, and 3-8 weeks later, tracing the course and spatial relationships of intact and degenerating fibres along the distal stump. This nerve was chosen because of its great length, the fact that it is a nonbranching motor nerve and because of debate about the course of abductor and adductor nerve fibres in the recurrent laryngeal nerve. Six ponies were used and in each the recurrent nerve was partially ligatured about 20 cm from the larynx, using a fine silk suture. In all there was a clear separation of intact and degenerating fibres just distal to the suture, but they became mixed close to the point of innervation of the laryngeal muscles. The numbers of intact myelinated fibres remained similar along the partially denervated nerve segment. These results suggest that myelinated fibres mix within the recurrent laryngeal nerve and that focal lesions of this nerve should not result in denervation of individual laryngeal muscles.

Transgenic mice (SV-202) that carry the SV40 early region genes under the control of an inverted metallothionein promoter developed islet cell adenomas, hepatocellular carcinomas, and a generalized peripheral neuropathy. Both the islet cell adenomas and the hepatocellular carcinomas developed from the proliferation of T antigen-positive cells. However, T antigen expression was not seen in either the peripheral or central nervous systems. Stimulation of the metallothionein promoter with heavy metals altered the temporal onset of hepatic expression and broadened the distribution of oncogene expression to include exocrine pancreas and renal tubular epithelium. Although solid tumors were not seen in the exocrine pancreas or kidneys of SV-202 mice, all immunopositive tissues developed histologic changes. These results indicate that metallothionein-directed T antigen expression can induce abnormal cellular growth in a variety of tissues, and the distribution of these tissues can be manipulated with heavy metals.

A line of SV40 transgenic mice (SV-202) developed a generalized peripheral neuropathy, islet cell adenomas of the pancreas, and hepatocellular carcinomas. The neuropathy was not directly associated with T-antigen expression in the nervous system. This study was designed to characterize the morphologic appearance and distribution of the neuropathologic lesions in SV-202 mice, and to relate the temporal development of peripheral nerve lesions to transgene-induced tumorigenesis in pancreatic islet cells. SV-202 mice developed an acute axonal degeneration that preferentially affected large diameter myelinated fibers. The onset of the neuropathy is closely correlated with the development of the hyperinsulinemia and hypoglycemia resulting from the islet cell adenomas.