Buprenorphine Maintenance Subjects Are Hyperalgesic and Have No Antinociceptive Response to a Very High Morphine Dose.

Objective: Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown.

Impaired psychomotor function and plasma methadone and levo-alpha-acetylmethadol (LAAM) concentrations in opioid-substitution patients.

Tolerance to the psychomotor impairing effects of opioid drugs is expected to develop with repeated dosing, but may be incomplete. The relationship between plasma opioid concentration and psychomotor function in opioid-dependent patients was examined to determine whether impairment was more likely at the time of highest plasma drug concentration. Sixteen patients participating in a cross-over trial comparing methadone and LAAM completed a tracking task (OSPAT) 11 times over the dosing-interval for methadone (24-hrs) and LAAM (48-hrs).

Achieving the World Health Organization's vision for clinical pharmacology.

Clinical pharmacology is a medical specialty whose practitioners teach, undertake research, frame policy, give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. It involves a combination of several activities: drug discovery and development, training safe prescribers, providing objective and evidence-based therapeutic information to ethics, regulatory and pricing bodies, supporting patient care in an increasingly subspecialized arena where co-morbidities, polypharmacy, altered pharmacokinetics and drug interactions are common and developing and contributing to medicines policies for Governments. Clinical pharmacologists must advocate drug quality and they must also advocate for sustainability of the Discipline.

Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients.

Unlabelled: This observational study aimed to determine whether pain sensitivity in patients with noncancer chronic pain, taking either methadone or morphine, is similar to patients maintained on methadone for dependence therapy, compared with a control group. Nociceptive thresholds were measured on a single occasion with von Frey hairs, electrical stimulation, and cold pressor tests. In all subjects receiving methadone or morphine, nociceptive testing occurred just before a scheduled dose.

Antinociceptive effects of high-dose remifentanil in male methadone-maintained patients.

The treatment of acute pain in patients maintained on methadone is difficult due to increased pain sensitivity (hyperalgesia) and cross-tolerance to other opioids. This study aimed to investigate whether remifentanil elicits antinociception in methadone-maintained subjects in a dose-dependent manner. Eight chronic methadone-maintained subjects attended the testing session approximately 20 h after their normal methadone dose (range 50-110 mgday(-1)).

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.

Methadone maintenance patients are cross-tolerant to the antinociceptive effects of very high plasma morphine concentrations.

Opioid dependent patients require higher than normal doses of opioid analgesics. However, this regimen has not been formally tested. This study utilised a double-blind placebo-controlled design to examine antinociceptive responses to saline and pseudo-steady-state plasma morphine concentrations (173+/-11 (mean+/-SEM), range 106-305 ng/ml) in 18 methadone participants in three stable, once daily methadone dose ranges 11-45 mg (n=6), 46-80 mg (n=6), 81-115 mg (n=6) and 10 controls.

Within- and between- subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects.

Aims: To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state.

Methods: Six non-holder subjects were studied on three occasions at 7-16 day intervals; doses (20-170 mg/day) remained unchanged. Blood samples and pharmacodynamic data were collected 10-12 times over a 24-h inter-dosing interval.

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.

Comparison of tincture of opium and methadone to control opioid withdrawal in a Thai treatment centre.

Aims: To evaluate the effectiveness of oral tincture of opium (TOP) and methadone to control opioid withdrawal in patients in northern Thailand.

Methods: Open label, parallel group study in an inpatient facility compared 15 former heroin users receiving methadone 5-20 mg 12 hourly with 15 former opium smokers receiving TOP (3.33-10 mg morphine equivalents 12 hourly).

Evaluation of levo-alpha-acetylmethdol (LAAM) as an alternative treatment for methadone maintenance patients who regularly experience withdrawal: a pharmacokinetic and pharmacodynamic analysis.

The aim of this study was to determine if substitution of daily methadone with second daily levo-alpha-acetylmethadol (LAAM) would convert non-holders on methadone into holders on LAAM, and to compare plasma concentration-time profiles of (R)-methadone with LAAM and its two metabolites. Sixteen stable methadone maintenance treatment participants (non-holders, n = 8) were randomly allocated to continue methadone for 3 months or switch to LAAM for 3 months, and then crossed over to the alternative drug for 3 months. At steady state, there were two testing sessions (24 h for methadone and 48 h for LAAM), during which opioid withdrawal severity, respiration rate and pupil diameter were measured 10-11 times and venous blood was collected 13-15 times.

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.

Population pharmacokinetics of (R)-, (S)- and rac-methadone in methadone maintenance patients.

Aim: To construct a population pharmacokinetic model for methadone enantiomers in the setting of methadone maintenance treatment for opioid dependence.

Methods: A population pharmacokinetic model was developed using P-Pharm software for rac-, (R)- and (S)-methadone using data (8-13 plasma samples per subject) obtained from 59 methadone maintenance patients during one interdosing interval at steady state. The patients were randomly assigned to either a development (n = 38) or a validation dataset (n = 21).

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.

Tenecteplase for massive pulmonary embolus.

The treatment of massive pulmonary embolus remains controversial. We describe the first report of the successful use of the thrombolytic agent, tenecteplase, in treating a hypotensive elderly patient with a saddle embolus. A brief review of the current literature concerning thrombolysis for massive pulmonary embolus is given.