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. Design: Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting: Ambulatory. Subjects: Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Methods: Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results: Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1, buprenorphine 136 ± 10. Conclusions: Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.

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). Venous blood was collected for the quantification of plasma (R)-(-)-methadone, LAAM, and nor-LAAM concentrations. The Digit Symbol Substitution Test (DSST) and Trail-Making Test were administered at the time of peak plasma concentration. Ten healthy controls (HCs) also participated. OSPAT scores (obtained for 15 patients) fluctuated significantly across the dosing-interval for both drugs and were lower in patients than HCs at the times of peak concentrations of (R)-(-)-methadone (1 hr: (mean difference; 95% CI) (2.13; 0.18-4.08); 2 hrs: (2.38; 0.48-4.28) postdosing) and LAAM (2 hrs: (1.81; 0.09-3.53), and 4 hrs (1.90: 0.9-3.71) postdosing). Within-participant analysis of the peak-change from baseline for OSPAT scores found that 10 of the 15 patients could be categorized as impaired on methadone and 9 on LAAM. No HCs were impaired. Patients performed worse on the DSST and Trails-A than HCs, but not on Trails-B. Results suggest that some patients receiving opioids long term may exhibit impairment at the time of highest plasma drug concentration. These patients should be made aware that their ability to undertake complex tasks may be affected. (PsycINFO Database Record

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. However for this they need appropriate clinical service and training support. This Commentary discusses strategies to ensure the Discipline is supported by teaching, training and policy organizations, to communicate the full benefits of clinical pharmacology services, put a monetary value on clinical pharmacology services and to grow the clinical pharmacology workforce to support a growing clinical, academic and regulatory need.

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. Cold pressor tolerance values in patients with noncancer, chronic pain, treated with morphine and methadone, were 18.1 +/- 2.6 seconds (mean +/- SEM) and 19.7 +/- 2.3 seconds, respectively; in methadone-maintained subjects it was 18.9 +/- 1.9 seconds, with all values being significantly (P < .05) lower than opioid-naïve subjects (30.7 +/- 3.9 seconds). These results indicate that patients with chronic pain managed with opioids and methadone-maintained subjects are hyperalgesic when assessed by the cold pressor test but not by the electrical stimulation test. None of the groups exhibited allodynia as measured using the von Frey hairs. These results add to the growing body of evidence that chronic opioid exposure increases sensitivity to some types of pain. They also demonstrate that in humans, this hyperalgesia is not associated with allodynia. PERSPECTIVE: This article presents an observational study whereby the pain sensitivity of patients with chronic pain managed with opioids and opioid-maintained patients were compared with opioid-naïve patients. The results suggest that opioid use may contribute to an increase in the sensitivity to certain pain experimental stimuli.

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)). Following a 20 min saline infusion, subjects were administered intravenous remifentanil in seven increasing doses ranging from 0.5 to 3.5 microgkg(-1)min(-1), each for 2 0min. Testing was performed in the last 10 min of each infusion. The testing measures included nociception, as measured by the cold pressor test, withdrawal using the subjective opiate withdrawal scale (SOWS), and subjective opioid effects using the morphine-benzedrine group scale (MBG). Results showed dose-dependent increase in cold pressor tolerance time from baseline of 15.6+/-3.5 (mean+/-SEM)s up to 77.3+/-24.7s during this dosing protocol. During the infusion typical mu-opioid receptor agonist side effects were observed, but with no withdrawal. Methadone-maintained patients demonstrate significant tolerance to remifentanil and may require opioid doses 20-30 higher than required for the treatment of acute pain in opioid-naïve patients.

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.

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. Testing commenced approximately 20 h after the maintenance dose with the next dose given 1h after morphine cessation. Nociceptive stimuli (cold pressor (seconds) and electrical stimulation (volts)) were used to measure pain detection threshold and pain tolerance. Blood samples were analysed by HPLC for plasma morphine and R-(-)-methadone concentrations. Methadone participants were hyperalgesic to cold pressor pain. High plasma morphine concentrations failed to significantly change cold pressor and electrical stimulation pain tolerance for methadone patients, but in controls, morphine significantly (P<0.05) increased mean pain tolerance to cold pressor by 59+/-29% (range -17% to 311%) and electrical stimulation by 19+/-6% (range 0% to 58%). Morphine significantly (P<0.05) decreased respiration rates by 12+/-3% (range -29% to 8%) in methadone subjects. On saline days, rising methadone concentrations significantly (P<0.01) increased cold pressor pain detection threshold by 32+/-6% (range 1-81%) and cold pressor pain tolerance by 23+/-6% (range -32% to 56%). Methadone maintained patients are hyperalgesic and cross-tolerant to the antinociceptive effects of very high plasma morphine concentrations. While even higher morphine doses may achieve some pain relief, this may be at the cost of unacceptable respiratory depression.

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. All pharmacodynamic data were expressed as the area under the end-point versus time curve. Using analyses of variance with mixed effects, best estimates were made of the ratio of between- to within-subject variation, with corresponding 95% confidence intervals (CI) for within-subject variation at the average value. RESULTS: Subjects were relatively consistent between occasions, whereas there was much greater between-subject variability (P < 0.02) for all measures. Estimates of the ratio of between- to within-subject variation ranged from 2.2-12.8 for pharmacodynamic measures, and 1.3-7.9 for pharmacokinetic parameters. For pain, total mood disturbance, withdrawal, pupil size and respiration rate, 95% CI for within-subject measures ranged < or = 2-fold, while this was greater for subjective direct opioid effects (4.2-fold). For CL/F of the active (R)-methadone, the variance ratio was 4.9 (P < 0.0003), with 95% CI for within-subject measures ranging < or = 2-fold. (S)-methadone CL/F demonstrated greater within-subject variability (3.4-fold), possibly contributing to a smaller (2.7; P < 0.0003) ratio of between- to within-subject variance. CONCLUSIONS: Non-holder methadone maintenance treatment participants appear to respond consistently with respect to pharmacokinetics and pharmacodynamics over a 1-2 month period. Such knowledge may help prescribers to determine whether alternative dosing regimens or treatments might be more appropriate in this population.

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). At 0, 1, 3 and 8 h, blood, withdrawal scores and subjective opioid effects were collected. RESULTS: There was a reciprocal association between withdrawal scores/direct subjective opioid effects and plasma (R)-methadone, but not plasma morphine, concentrations. Withdrawal scores at the time of dosing were higher in the TOP patients (9.1 +/- 3) than in the methadone patients (4.5 +/- 4.6) and in the TOP patients were significantly (P = 0.001) attenuated at 3 and 8 h. CONCLUSIONS: At the doses used, TOP was inferior to methadone in suppressing withdrawal. It could prove to be a cost effective and valuable drug, but only after dose size and frequency are further investigated.

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.

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. Ten age- and gender-matched controls underwent one 48-h test session. Areas under the withdrawal severity score versus time curve (AUC(0-47) hours for LAAM and controls; AUC(0-24) x 2 for methadone) were similar in holders on methadone and LAAM (P = 0.62), but were greater in non-holders when they were taking methadone than LAAM (P < 0.001). Respiratory depression and pupillary constriction were similar for LAAM and methadone. In comparison to (R)-methadone, plasma nor- and dinor-LAAM concentrations fluctuated little over the dosing interval. LAAM converted methadone non-holders into LAAM holders. LAAM may therefore be useful in selected MMT non-holders and improve retention in opioid treatment programs.

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.

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). The model was refined by inclusion of all subjects to construct a final basic model, which was used to construct a covariate model. RESULTS: A population-based two-compartment open model with first-order absorption and lag time was developed and validated for all analytes. The population geometric mean (coefficient of variation) of maximum a posteriori probability Bayesian estimated values for clearance, terminal half-life and volume of distribution at steady-state of the active (R)-enantiomer were 8.7 (42%) l h(-1), 51 (45%) h and 597 (45%) l, respectively. For all analytes, the volume of the central compartment was decreased with increasing plasma alpha(1)-acid glycoprotein concentration and was lower in females, while the delay in absorption was longer at higher doses. No covariates were identified for apparent oral clearance. The apparent oral clearance of (R)-methadone (geometric mean ratio; 95% confidence interval) was 105% (99, 110), that of (S)-methadone (P = 0.19), while (R)-methadone V(c)/F (154%; 151, 157), V(dss) /F (173%; 164, 183), t(1/2beta) (162%; 153, 172) and mean residence time (166%; 156, 176) were significantly greater (P < 0.0001) than for (S)-methadone. The population pharmacokinetic models were able to predict accurately oral clearance values from limited (one or two samples) blood sampling protocols. CONCLUSIONS: The substantial stereoselectivity in methadone disposition reinforces the potential for misinterpretation of racemic methadone disposition data. The marked interindividual variability in (R)-methadone clearance, with no covariates identified, highlights the need for alternative methods to determine an individual's metabolic clearance. The ability to predict (R)-methadone clearance from one to two blood samples at steady state may prove clinically useful if a drug-drug interaction or poor adherence are suspected and guide the prescriber in deciding if a client's request for a dose increase is warranted or whether an alternative opioid would be more appropriate.

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.

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.

Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine.

We have previously shown that methadone maintenance patients are hyperalgesic. Very little is known about the antinociceptive effects of additional opioids in these patients. This study (1) compared the intensity and duration of antinociceptive responses, at two pseudo-steady-state plasma morphine concentrations (C(SS1) and C(SS2)), between four patients on stable, once daily, doses of methadone and four matched control subjects; and (2) determined, in methadone patients, whether the antinociceptive effects of morphine are affected by changes in plasma R(-)-methadone concentration that occur during an inter-dosing interval. Two types of nociceptive stimuli were used: (1) a cold pressor test (CP), (2) electrical stimulation (ES). Morphine was administered intravenously to achieve the two consecutive plasma concentrations. Blood samples were collected, concurrently with nociceptive responses, to determine plasma morphine concentrations. Methadone patients achieved mean C(SS1) and C(SS2) of 16 and 55 ng/ml respectively; those of controls were 11 and 33 ng/ml. Methadone patients were hyperalgesic to pain induced by CP but not ES. Despite significantly greater plasma morphine concentrations, methadone patients experienced minimal antinociception in comparison with controls. Furthermore in methadone patients, the antinociception ceased when the infusion ended. In comparison, the duration of effect in control subjects was 3 h. The fluctuations that occurred in plasma R(-)-methadone concentration during an inter-dosing interval had little effect on patients' responses to morphine. Our findings suggest that methadone patients are cross-tolerant to the antinociceptive effects of morphine, and conventional doses of morphine are likely to be ineffective in managing episodes of acute pain amongst this patient group. Further research is needed to determine whether other drugs are more effective than morphine in managing acute pain in this patient population.