Targeted disruption of cocaine-activated nucleus accumbens neurons prevents context-specific sensitization.

Learned associations between effects of abused drugs and the drug administration environment are important in drug addiction. Histochemical and electrophysiological studies suggest that these associations are encoded in sparsely distributed nucleus accumbens neurons that are selectively activated by drugs and drug-associated cues. Although correlations have been observed between nucleus accumbens neuronal activity and responsivity to drugs and drug cues, no technique exists for selectively manipulating these activated neurons and establishing their causal role in behavioral effects of drugs and drug cues. Here we describe a new approach, which we term the 'Daun02 inactivation method', that selectively inactivates a minority of neurons previously activated by cocaine in an environment repeatedly paired with cocaine to demonstrate a causal role for these activated neurons in context-specific cocaine-induced psychomotor sensitization in rats. This method provides a new tool for studying the causal roles of selectively activated neurons in behavioral effects of drugs and drug cues and in other learned behaviors.

Context-specific sensitization of cocaine-induced locomotor activity and associated neuronal ensembles in rat nucleus accumbens.

Repeated cocaine administration to rats outside their home cage induces behavioral sensitization that is strongly modulated by the drug administration environment. We hypothesized that stimuli in the drug administration environment activate specific sets of striatal neurons, called neuronal ensembles, for further cocaine-enhanced activation, and that repeated activation of these neuronal ensembles underlies context-specific sensitization. In the present study, we repeatedly administered cocaine or saline to rats on alternate days in two distinct environments outside the home cage, one paired with cocaine and the other with saline. On test day, cocaine challenge injections in the cocaine-paired environment produced strongly enhanced levels of locomotor activity, while cocaine challenge injections in the saline-paired environment did not. The corresponding record of past neuronal activation in nucleus accumbens and caudate-putamen during repeated drug administration was assessed using FosB immunohistochemistry, while acute neuronal activation on test day was assessed using c-fos in situ hybridization. Although only 2% of striatal neurons were FosB labeled, 87% of these FosB-labeled neurons were co-labeled with c-fos when cocaine was injected in the cocaine-paired environment. The degree of co-labeling was significantly less following cocaine or saline challenge injections in the saline-paired environment. Furthermore, the total number of c-fos-labeled neurons was greater with either cocaine or saline challenge injections in the cocaine-paired environment than in the saline-paired environment. These findings demonstrate that the drug administration environment partly determines which striatal neuronal ensembles are activated, and to what extent, following context-specific sensitization to cocaine.

Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid dependent patients.

BACKGROUND: Benzodiazepine abuse is common among methadone- and buprenorphine-maintained patients; however interactions between these drugs under high dose conditions have not been adequately examined under controlled conditions. OBJECTIVE: To investigate the effects of co-administering diazepam with methadone or buprenorphine under high dose conditions. DESIGN: Double-blind, randomly ordered, 2 x 2 cross-over design in which the effects of diazepam dose (0mg versus 40 mg) and opioid dose (100% versus 150% normal dose) were examined over four sessions in methadone- and buprenorphine-maintained patients. PARTICIPANTS: Four methadone- and seven buprenorphine-prescribed patients without concurrent dependence on other substances or significant medical co-morbidity. MEASURES: Physiological (pulse rate, blood pressure, pupil size, respiratory rate and peripheral SpO2), subjective (ARCI, VAS ratings) and performance (reaction time, cancellation task and Digit Symbol Substitution Test, DSST) measures were taken prior to and for 6h post-dosing. RESULTS: High dose diazepam was associated with time-dependent increases in the intensity of subjective drug effects (strength of drug effect, sedation) and decreases in psychological performance (reaction time, DSST) for both methadone and buprenorphine patients. These effects were generally independent of the opioid dose administered. High dose opioid administration (150% normal dose) was associated with reductions in overall SpO2 levels and performance (reaction time, DSST) in the methadone patients, but had virtually no impact on pharmacodynamic responses in the buprenorphine group. CONCLUSION: High dose diazepam significantly alters subjective drug responses and psychological performance in patients maintained on methadone and buprenorphine.

Switching between methadone and morphine for maintenance treatment of opioid dependence: impact on pain sensitivity and mood status.

Methadone maintenance is associated with hyperalgesia and elevated mood disturbance-effects opposite to those induced by acute opioid administration, which may undermine outcomes during substitution therapy. This study examined the impact of switching between methadone and slow-release morphine on pain sensitivity and mood status in 14 methadone maintenance patients using an open-label crossover design. Pain responses were nearly identical for each drug. Patients reporting inadequate withdrawal suppression on methadone showed greater mood stability when transferred to morphine, but overall mood disturbance levels did not differ between drugs. Hyperalgesia and mood disturbance cannot be resolved by changing from methadone to morphine maintenance.

Fluctuations in (R,S)-methadone pharmacokinetics and response among long-term methadone maintenance patients.

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.

Interactions on mixing diazepam with methadone or buprenorphine in maintenance patients.

Benzodiazepine use by patients in methadone and buprenorphine substitution treatment is common, despite safety concerns regarding these drug interactions. The relative safety of diazepam use by methadone- or buprenorphine-treated patients has not been systematically examined. This study aimed to examine the effect of single diazepam doses, within normal therapeutic range (doses: 0, 10, and 20 mg), upon physiological, subjective, and performance measures in stable methadone and buprenorphine-treated patients. In a double-blind, randomized crossover design, methadone- or buprenorphine-treated patients were administered their normal opioid dose and either placebo, 10-, or 20-mg diazepam, in balanced order over 3 sessions. Eight methadone- and 8 buprenorphine-prescribed patients with no concurrent benzodiazepine dependence or significant comorbidity were recruited from an outpatient addiction clinic in London. Measures were taken at baseline and for 6 hours after dosing, and included physiological responses (pulse rate, blood pressure, pupil size, respiratory rate, and peripheral pO2), subjective drug effects (Addiction Research Center Inventory subscales, visual analog scales of strength of drug effect, drug-liking, and sedation), and performance measures (simple reaction time, cancellation task, digit symbol substitution task, and balance). The 10- and 20-mg diazepam doses resulted in comparable subjective experiences of greater sedation and strength of drug effects in both patient groups, and had minimal impact on physiological parameters. However, diazepam had greater peak effects on performance measures (simple reaction time, digit symbol substitution task, and cancellation time) in methadone-treated than in buprenorphine-treated patients. Diazepam may significantly alter the response to opioid substitution treatment with methadone or buprenorphine.

Feasibility and acceptability of an intranasal diamorphine spray as an alternative to injectable diamorphine for maintenance treatment.

An intranasal (IN) diamorphine spray was investigated as a possible alternative to injectable diamorphine for maintenance treatment. Plasma morphine and 6-monoacetylmorphine (6MAM) concentrations and pharmacodynamic responses were measured for 4 h following intravenous (IV) and IN administration of 40 mg diamorphine in 4 patients prescribed injectable diamorphine. The two routes were primarily differentiated by the significantly greater speed and magnitude of peak plasma morphine and 6MAM concentrations for IV versus IN diamorphine. Beyond this initial peak, mean ratings suggested that withdrawal suppression and positive effects were at least as strong for IN compared to IV administration. All subjects gave favourable appraisals of the IN diamorphine spray, citing advantages including ease of use, the avoidance of needle hazards, and reduced stigma. IN administration may be an alternative or supplementary form of diamorphine maintenance and deserves serious further investigation.

Patient and physician characteristics in relation to clinical decision making in methadone maintenance treatment.

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.

Subjective and physiological responses among racemic-methadone maintenance patients in relation to relative (S)- vs. (R)-methadone exposure.

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.

Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence.

AIMS: To evaluate slow-release oral morphine (SROM) as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. DESIGN: Open-label crossover study. SETTING: Out-patient methadone maintenance programme. PARTICIPANTS: Eighteen methadone maintenance patients. Intervention Participants were transferred from methadone to SROM (once-daily Kapanol trade mark ) for approximately 6 weeks before resuming methadone maintenance. MEASUREMENTS: Patient outcomes were assessed (1) during the transition between medications (dose requirements, withdrawal severity) and (2) after at least 4 weeks on a stable dose of each drug (treatment preference, patient ratings of treatment efficacy and acceptability, drug use, health, depression and sleep). FINDINGS: Transfer from methadone to SROM was associated with relatively mild withdrawal for the first 5 days; the final mean SROM : methadone dose ratio was 4.6 : 1. Compared to methadone, SROM was associated with improved social functioning, weight loss, fewer and less troublesome side-effects, greater drug liking, reduced heroin craving, an enhanced sense of feeling 'normal' and similar outcomes for unsanctioned drug use, depression and health. The majority of subjects preferred SROM (78%) over methadone (22%). CONCLUSIONS: These findings provide justification for further evaluation of SROM as a maintenance pharmacotherapy for opioid dependence.

Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence.

BACKGROUND: Slow-release oral morphine (SROM) has been proposed as an alternative maintenance pharmacotherapy to methadone for treatment of opioid dependence. However, the pharmacodynamics and pharmacokinetics of SROM have not been previously assessed in a methadone maintenance population. METHODS: In 14 methadone maintenance patients reporting adequate (holders, n=7) or inadequate (non-holders, n=7) withdrawal suppression between doses, plasma drug concentrations and indices of opioid effect (withdrawal severity, pupil diameter, and respiratory rate) were determined across a 24 h inter-dosing interval on one occasion at steady-state for methadone and SROM (once-daily Kapanol) using an open-label, crossover design. RESULTS: Opioid effects were of a similar overall magnitude following dosing for each drug and showed an inverse association with plasma drug concentrations, which peaked later for morphine compared to (R)-methadone (6.5 +/- 2.3 h vs. 2.5 +/- 1.4 h, P<0.001). For methadone non-holders, the number of self-reported opioid withdrawal symptoms prior to dosing was less for SROM compared to methadone (3.4 +/- 2.6 vs. 9.0 +/- 3.2, P<0.01); for holders it was approximately equal (4.4 +/- 3.0 vs. 4.0 +/- 3.7, P<0.76). Maintenance doses were more strongly related to plasma drug concentrations for SROM compared to methadone and may thus be more predictive of therapeutic response for the former medication. Twelve of the 14 subjects preferred SROM to methadone (P=0.01). CONCLUSIONS: The pharmacodynamics and pharmacokinetics of SROM support its use as an alternative once-daily agonist option in the treatment of opioid dependence, particularly for patients responding poorly to methadone maintenance treatment.