Analyzing phase III studies in hospice/palliative care. a solution that sits between intention-to-treat and per protocol analyses: the palliative-modified ITT analysis.

Intention-to-treat (ITT) analyses are the standard way to evaluate randomized controlled trials (RCTs) to minimize Type I errors related to differential rates of noncompletion from one study arm. People in palliative care often die sooner than predicted as a direct result of disease progression, some of whom will be participating in RCTs and who will, therefore, withdraw or die after randomization for reasons unrelated to the intervention. This proportion of withdrawals is statistically negligible in other clinical disciplines, but commonplace in hospice/palliative care, creating a systematic bias away from the true effect. ITT analyses in hospice/palliative care that deem all withdrawals to be treatment failures or that impute data from deteriorating participants systematically underestimate the benefits of interventions, reducing the power of these studies. Equally unacceptable would be a per protocol analysis that excludes all withdrawals after randomization as this will underestimate toxicity. A modified analytic approach is needed on a continuum between ITT and per protocol analyses. To address data after randomization where there is a high rate of withdrawals because of death or deterioration, criteria need to include being: 1) prespecified in the original protocol; 2) clinically absolutely the result of disease progression; 3) identified by the blinded Independent Data Monitoring Committee as being unrelated to the intervention(s); and 4) accounted for in the study's CONSORT diagram. Such data should not be included in the analysis of the primary outcome. This article aims to define a better way of balancing Type I and Type II errors in hospice/palliative care RCT analyses using the palliative-modified ITT analysis. Arguably, the palliative-modified ITT analysis should be the primary evaluation of hospice/palliative care Phase III studies but, as a minimum, should routinely be the key sensitivity analysis.

Chronic pain in South Australia - population levels that interfere extremely with activities of daily living.

OBJECTIVE: The prevalence of chronic pain in Australia has only been previously estimated for the state of New South Wales. The aim of this study was to focus estimates on pain severe enough to interfere markedly with daily function irrespective of contact with health services in another region, South Australia. METHODS: A whole of population random face-to-face survey method (n=2,973) was used, directly standardised against the whole population for age, gender, country of birth and rurality. Respondents were asked about chronic pain and the degree to which it interfered with daily activities. RESULTS: The prevalence of chronic pain was 17.9%, and pain that interfered extremely with activity 5.0%. Chronic pain was associated with older age, living alone, lower income, not being in full-time work and lower educational levels in bivariate analyses, however in multifactor analyses the only significant associations were not currently working (p<0.001) and lower levels of educational achievement (p=0.042). Pain that interfered extremely with activity in multifactor analysis was associated with work status where the odds ratio for work-related injury compared to those in full time work was 19.3 (95% CI 7.30-51.3; p<0.001). CONCLUSIONS: This study highlights the high levels of pain with extreme effects on day-to-day life (one in 20 people), the complex inter-relationships of the factors (educational achievement, work status) associated with chronic pain and the impacts that these factors have on the people experiencing such disabling pain in the long-term.

A community population survey of prevalence and severity of dyspnea in adults.

Given the progress in the symptomatic treatment of breathlessness, and the physical and psychological morbidity associated with chronic breathlessness, estimates of the size of the population that may benefit from better support become imperative. Prevalence estimates have varied widely (0.9% of clinical encounters to 32%) and have largely relied only on respondents who used clinical services. Whole-of-population approaches may be able to define better the "true" prevalence of chronic breathlessness and quantify exertion limited by breathlessness. The aim of this study was to estimate population levels of chronic breathlessness, severity of limits to exercise, and demographic predictors of the presence of breathlessness. A whole-of-population face-to-face survey method (n=8,396) in South Australia was used, directly standardized for age, gender, country of birth, and rurality. Respondents were asked about breathlessness and levels of exertion causing breathlessness for at least three of the last six months using a modified Medical Research Council dyspnea scale. Univariate and multivariate analyses identify the demographic characteristics of people more likely to experience chronic breathlessness. With a participation rate of 65.3%, 8.9% of respondents had breathlessness that chronically limited exertion. Significant associations with chronic breathlessness in multivariate analysis included female sex (P<0.001), not working full time (P<0.001), low income (P=0.007), and older age (P=0.031). There are significant levels of chronic breathlessness in the community. Given the prevalence, it is feasible to explore the onset of breathlessness, the underlying etiologies and subsequent health service utilization, and health consequences.

Comfort in the last 2 weeks of life: relationship to accessing palliative care services.

INTRODUCTION: Specialised palliative care services (SPCS) aim to address the needs of patients and caregivers confronting life-limiting illnesses but only half of the potential cohort are referred. Randomised controlled trials of SPCS provision can no longer be ethically justified so there is a need to develop new methods to evaluate the net impact of SPCS for the whole community, not just for those who access SPCS. The aim of this study was to assess whether perceived comfort in the last 2 weeks of life was associated with accessing SPCS. METHODS: This study utilised a whole-of-population random survey (n = 4,366) in South Australia. A total of 802 respondents had someone close to them die within the last 5 years due to a terminal illness, and they had the complete data. A subsequent question was asked whether SPCS had been accessed. Perceived comfort levels for those who had used SPCS were compared with those who did not by using stereotype logistic regression, weighted to a standardised population. RESULTS: Higher levels of comfort of the deceased having been assessed 'very comfortable' was associated with the use of SPCS (p = 0.04; odds ratio, 1.78; 95% confidence interval, 1.02-3.08). For people who accessed SPCS, 13.3% were reported as 'very comfortable' compared with 8.0% without SPCS. Almost one half of respondents (48.4%) reported that the deceased was considered 'uncomfortable' or 'very uncomfortable', irrespective of SPCS access. DISCUSSION: While this study provides further incremental evidence of benefit from access to SPCS, there is much that still needs to be done to improve care for the whole community at the end of life.

A randomized, double-blind, multi-site, crossover, placebo-controlled equivalence study of morning versus evening once-daily sustained-release morphine sulfate in people with pain from advanced cancer.

Diurnal variation in pain perception is recognized. The question of whether opioid prescribing should be adjusted to account for diurnal variation can be tested with the advent of once-daily sustained-release morphine. The study recruited 45 people with opioid-responsive pain on stable doses of analgesics and advanced cancer from five regional palliative care programs in Australia. Each participant took one placebo and a 24-hourly dose of sustained-release morphine daily, 12 hours apart-active dose in the morning for one week and in the evening for the other week. The order of the weeks was randomized in a double-blind manner. The primary outcome from the last two days (steady state) on both arms was averaged four-hourly pain scores while awake on a 100 mm visual analogue scale (VAS). Secondary outcomes included VAS and categorical scales for other pain parameters, quality of sleep, nausea, vomiting, constipation, confusion, and somnolence. Twenty-six of 42 participants completed the study and provided adequate power for analysis. Mean VAS was 16 mm for morning dosing and 14 mm for evening dosing (P=0.76, difference of adjusted means 2 mm, 95% confidence interval: -2, 6). No differences were found in pain control, pain during the day, pain disturbing sleep, or with breakthrough medication use. This study suggests that any difference between morning and evening dosing of once-daily sustained-release morphine in people with significant opioid-responsive pain and advanced cancer is small and unlikely to be clinically significant for most people.

Comparison of three simulation-based training methods for management of medical emergencies.

Trainee medical officers (TMOs) participated in a study comparing three methods of simulation-based training to treat medical emergencies occurring in a hospital setting. The methods were: All groups had the same total teaching time. Participants (n=61) had an initial (pre-training) assessment by written tests, self assessment and simulations of medical emergencies ('VT' and 'HYPOglycaemia'). Participants were tested again post-training using similar simulations to the initial scenario and a new scenario ('ANAphylaxis'). Trained 'experts', blinded to the teaching group of participants, watched video-CDs of the simulations to assess participants' performance. All groups demonstrated increased knowledge and confidence (pre-training scores compared to post-training) but no differences could be detected between the three groups. In simulated emergencies, post-training scores were also improved. There was no difference between groups in the 'HYPO' scenario but in the 'VT' scenario there was moderate evidence that Group 3 was superior. In the 'ANA' scenario, Group 3 had far better test scores, especially in behavioural items. There did not appear to be any significant advantage of using whole body manikins over CSBT and simple part-task trainers. Full-mission simulation training helped develop the ability to recognise when skills learnt to manage one type of medical emergency can be useful in managing another emergency not previously encountered.

Self-selected exercise intensity during household/garden activities and walking in 55 to 65-year-old females.

This study determined whether some of the more vigorous household and garden tasks (sweeping, window cleaning, vacuuming and lawn mowing) were performed at a moderate intensity (3-6 METs or metabolic equivalents) by a representative sample of 50, 55 to 65-year-old women (X +/- SD; 59.3 +/- 3.1 years, 161.5 +/- 5.2 cm, 69.4 +/- 12.4 kg, 38.4 +/- 7.3% BF). Data collection was conducted in a standardised laboratory environment and in the subjects' homes. Energy expenditure during self-perceived moderate paced walking around a quadrangle was also used as a marker of exercise intensity. Energy expenditure measured via indirect calorimetry was also predicted from: HR, CSA accelerometer counts, Quetelet's index and the Borg rating of perceived exertion. Ninety-six percent of the subjects walked at an intensity of >or= 3.0 METs. Except for vacuuming in the laboratory (X = 2.9 METs; P = 0.19), the intensity of each of the other activities was significantly (P or= 3.0 METs when the four household/garden activities were performed in the subjects' homes. These activities therefore have the potential to contribute to the 30 min day(-1) of moderate intensity physical activity required to confer health benefits but there was much inter-individual variability in the intensity at which these tasks were performed. Random intercept regression analyses yielded prediction equations with 95% confidence intervals of +/- 0.80 and +/- 0.84 METs for the laboratory and home based equations, respectively. Considering the means for the five activities ranged from 2.9 to 5.5 METs, these 95% confidence intervals lack predictive precision at the individual level. Nevertheless, the laboratory and home-based equations predicted with correct classification rates of 89 and 90%, respectively, whether energy expenditure was < 3.0 or >or= 3.0 METs.

Predicting walking METs and energy expenditure from speed or accelerometry.

PURPOSE: a) Compare the predictive potential of speed and CSA(hip) (Computer Science Applications accelerometer positioned on the hip) for level terrain walking METs (1 MET = VO2 of 3.5 mL.kg(-1).min(-1)) and energy expenditure (kcal.min(-1)); b) cross-validate previously published CSA(hip)- and speed-based MET and energy expenditure prediction equations; c) measure self-paced walking speed, exercise intensity (METs) and energy expenditure in the middle aged population. METHODS: Seventy-two 35- to 45-yr-old volunteers walked around a level, paved quadrangle at what they perceived to be a moderate pace. Oxygen consumption was measured using the criterion Douglas bag technique. Speed, CSA(hip), heart rate, and Borg rating of perceived exertion were also monitored. RESULTS: Speed explained 10% more variance of walking METs than CSA(hip). Speed and mass explained 8% more variance of walking energy expenditure (kcal.min) than CSA(hip) and mass. The best previously published regression equations predict our walking METs and energy expenditures within 95% prediction limits of +/- 0.7 METs and +/- 1.0 kcal.min(-1), respectively. Women paced themselves at a significantly higher mean speed (5.5 km.h(-1)) and intensity (4.1 METs) than their male counterparts (5.2 km.h(-1) and 3.8 METs). Both genders expended approximately 0.75 kcal.kg(-1) for every kilometer of level terrain walked. CONCLUSION: Speed-based MET and energy expenditure predictions during level terrain walking were more accurate than those utilizing CSA(hip).

The energy cost of household and garden activities in 55- to 65-year-old males.

This study measured the energy expenditure of four self-paced household and garden tasks to determine whether 55- to 65-year-old men performed them at a moderate intensity [3-6 metabolic equivalents (METs)] and to predict the activity intensity via indirect methods. Resting metabolic rate and oxygen consumption were measured using Douglas bags in 50 men (X +/- SD: 60.6 +/-3.2 years, 175.8 +/- 5.6 cm, 82.6 +/- 10.1 kg ) who performed self-perceived moderate paced walking and self-paced sweeping, window cleaning, vacuuming and lawn mowing. Heart rate, CSA accelerometer counts (hip and arm), Quetelet's index, Borg rating of perceived exertion and respiratory frequency were measured as possible predictors of energy expenditure. Each of the four household and garden activities was performed at a mean intensity of > or = 3.0 METs in both the standardised laboratory environment (sweeping = 3.4, window cleaning = 3.8, vacuuming = 3.0 and lawn mowing = 5.3 METs) and the subjects' homes (sweeping = 4.1, window cleaning = 3.5, vacuuming = 3.6 and lawn mowing = 5.0 METs). Comparisons between the two settings were significantly different (p < or =0.008). Except for window cleaning, the MET values were not different from those of our previous younger sample (35-45 years). Regression analysis yielded prediction equations with 95% confidence intervals of +/-0.8 METs for both the laboratory and home environments. Although the energy expenditure means for these activities indicate that they can contribute to the 30 min day(-1) of moderate intensity physical activity required to confer health benefits, there was substantial inter-individual variability. While the regression equations lack predictive precision at the individual level, they were able to determine whether energy expenditure was above the 3.0 MET threshold with correct classification rates of 91% and 94% in the laboratory and home, respectively.

Anxiety in children having elective surgery.

One hundred and twenty children aged 5-12 years and their parents were interviewed preoperatively about anxiety and fear. Needles, postoperative pain, the unknown, and many unrecognizable people in the induction room were all reported as increasing anxiety for children. Effective modes of reducing children's anxiety were considered to be the prospect of eating after surgery, staff speaking directly to children in a friendly way, and having a television to watch. Parents' suggestions for reducing children's anxiety included giving better explanations, ensuring that children who have had their operations do not return to the same ward where other children are still waiting, and providing more distractions.

Conventional coagulation and thromboelastograph parameters and longevity of continuous renal replacement circuits.

OBJECTIVE: To determine the relationship between conventional and thromboelastograph (TEG) coagulation parameters and continuous renal replacement therapy (CRRT) circuit longevity. DESIGN: Conventional coagulation and TEG parameters were measured at the commencement of and during CRRT. Time to circuit cessation was measured and only circuits reaching a predetermined rise from baseline in the pressure gradient across the haemofilter were diagnosed as failing due to clotting. All other circuits were excluded from analysis. SETTING: A general critical care unit of a metropolitan tertiary hospital. PATIENTS AND PARTICIPANTS: Fourteen consecutive patients requiring CRRT were studied. The CRRT technique used was continuous veno-venous haemodialysis. INTERVENTIONS: Thromboelastograph measurements were made prior to the commencement of CRRT and daily thereafter for each circuit. The international normalised ratio (INR), activated partial thromboplastin time (APTT) and platelet numbers were measured at commencement and 8 hourly thereafter. Heparin was used for anticoagulation unless considered contraindicated. MEASUREMENTS AND RESULTS: Forty-seven circuits with a mean (SD) circuit life of 33.0 (30.2) h were entered. Twenty-five circuits fulfilled circuit clotting criteria; the mean circuit life was 30.8 (22.1) h. Heparin anticoagulation was found to prolong circuit life significantly despite adequate mean circuit life, 33.2 (35.7) h, in heparin-free circuits. The starting APTT and the TEG variables reaction time (R) and coagulation time (RK) were significantly correlated. The starting APTT, starting RK and mean time taken for the amplitude to increase from 2 to 20 mm (K) were predictive of circuit life. None of these variables predicted which patients would need heparin. CONCLUSION: While TEG variables more closely predicted circuit longevity than conventional coagulation variables, the clinical benefit of TEG monitoring of anticoagulation for CRRT would appear to be minimal.

The effect of the addition of epinephrine on early systemic absorption of epidural ropivacaine in humans.

UNLABELLED: The addition of epinephrine to ropivacaine has not been recommended because ropivacaine has intrinsic vasoconstrictor properties. However, few pharmacokinetic data are available on the addition of epinephrine to epidural ropivacaine in humans. In this prospective, double-blinded study, we randomized patients having elective abdominal hysterectomy to receive epidural ropivacaine 1.5 mg/kg, diluted in 15 mL, either with (epinephrine group, n = 12) or without (plain group, n = 12) epinephrine 5 microg/mL and then measured arterial and venous plasma concentrations of ropivacaine at intervals up to 180 min. We found that arterial and venous plasma ropivacaine concentrations were smaller in the epinephrine group compared with the plain group in the first 60 min after the drug administration (P < 0.01). Mean (+/- SD) maximum total plasma ropivacaine concentration was smaller in the epinephrine group (arterial, 0.92 +/- 0.32 microg/mL; venous, 0.82 +/- 0.33 microg/mL) compared with the plain group (1.31 +/- 0.39 microg/mL and 1.31 +/- 0.50 microg/mL, respectively; P = 0.01). Time to maximum total plasma ropivacaine concentration was not significantly different between groups (mean +/- SD; arterial, 16 +/- 2 min; venous, 23 +/- 2 min in the epinephrine group versus 9 +/- 2 min and 12 +/- 3 min, respectively, in the plain group; P = 0.08). Arterial plasma ropivacaine concentrations were larger than venous concentrations during the first hour (P < 0.01); the arterio-venous difference decreased exponentially, and the rate and magnitude of this decrease was unaffected by epinephrine. We conclude that the addition of epinephrine 5 microg/mL to ropivacaine reduced the early systemic plasma concentrations of ropivacaine after epidural injection and may be useful for decreasing the risk of toxicity from systemic absorption of epidural ropivacaine. IMPLICATIONS: The addition of epinephrine 5 microg/mL to epidural ropivacaine reduced the systemic arterial and venous plasma concentrations of ropivacaine in the first hour and the maximum plasma concentration of ropivacaine. Epinephrine may be a useful additive for reducing the risk of systemic toxicity when large doses of ropivacaine are given epidurally.

Effects of CNS site-directed carotid arterial infusions of bupivacaine, levobupivacaine, and ropivacaine in sheep.

BACKGROUND: Previous preclinical safety studies in ewes have found intravenous levobupivacaine and ropivacaine to be less potent toward causing central nervous system (CNS) and cardiac toxicity than bupivacaine. Analogous cardiotoxicity has been demonstrated directly in various cardiac preparations ex vivo. Moreover, drug-related arrhythmogenicity has been demonstrated from direct CNS injection of local anesthetic agents in vivo, suggesting CNS-related cardiotoxicity. This study investigated whether CNS site-directed blood-borne drug administration (with minimal systemic recirculation) would demonstrate drug-related cardiotoxicity. METHODS: Direct CNS effects and indirect cardiotoxic sequelae were determined after bilateral carotid arterial infusions of levobupivacaine, bupivacaine, or ropivacaine in ewes. After pilot studies to validate the procedures, equimolar doses (24-96 micromol, approximately 7.5-30 mg) were infused over 3 min using a crossover design. Behavioral CNS signs, quantitative electroencephalographic (EEG), cardiovascular, and electrocardiographic effects were recorded. Drug blood concentrations in superior sagittal sinus and aorta were measured serially. RESULTS: Blood drug concentrations in the superior sagittal sinus were 5-10 times those concurrently in the aorta, confirming highly selective CNS delivery with minimal systemic recirculation. Dose-dependent CNS excitatory behavior and EEG changes, with increased mean arterial blood pressure, heart rate, cardiac output, and myocardial contractility, were found, consistent with sympathetic nervous system stimulation. The overall rank order of potency for these effects was ropivacaine < levobupivacaine < bupivacaine. Nonfatal cardiac arrhythmias were observed, but the type or frequency did not differ between drugs. CONCLUSIONS: Although CNS site-selective drug delivery produced quantitative differences between bupivacaine, levobupivacaine, and ropivacaine in some CNS effects and cardiac sequelae, no differences were found in their arrhythmogenic potential.

Improving learning of a clinical skill: the first year's experience of teaching endotracheal intubation in a clinical simulation facility.

BACKGROUND: All medical practitioners should be able to manage the airway of an unconscious patient. Endotracheal intubation is the most effective method of securing the airway but is a complex skill requiring much practice. Traditionally, endotracheal intubation has been taught on patients, but this is not ideal. METHODS: We have developed a short course on endotracheal intubation taught in a clinical simulation unit (CSU). This unit has a large range of airway trainers and patient simulators, some of which can be manipulated to make intubation more difficult. Endotracheal intubation is taught in a series of steps in order to avoid cognitive overload. Each step is taught on an airway trainer that has no difficult features. Once this is mastered, more difficult situations are presented which require application of new techniques and/or equipment. In this way, students learn useful schemas to apply clinically. RESULTS: In 1 year, over 100 students and trainees were taught endotracheal intubation in the CSU. The ideal group size was found to be two students and one trainer. It took 75 to 90 minutes for most students to reach a standard where they could be expected to safely perform the technique on a patient. All comments on learning endotracheal intubation in this setting were positive. Many students felt more comfortable learning on a model than on a patient. CONCLUSION: Learning clinical procedures on simulators is becoming an essential part of medical education. More than one airway trainer may be needed to give students the expertise to perform endotracheal intubation on patients.

Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain.

Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin.

Ketamine as an adjunct to morphine in the treatment of pain.

A double-blind multidose trial of the addition of ketamine (0-40 mg, i.m., 8 times per day) to intramuscular morphine therapy was undertaken in a 61-year-old man with chronic back pain related to osteoporosis who had received inadequate pain relief from anterior interbody fusion, dorsal column stimulation and morphine alone. The patient reported only mild side effects. Nausea, tiredness and well-being were not significantly influenced by the ketamine dose level. Visual analogue pain scores prior to each dose were not associated with the ketamine dose level, but pain scores 30 min after doses were significantly reduced in a dose-related manner. In addition, the amount of morphine used by the patient was significantly reduced as the ketamine dose increased. This patient experienced substantial benefit from the addition of ketamine to intramuscular morphine therapy.

Chronopharmacokinetic variability in plasma morphine concentrations following oral doses of morphine solution.

Twenty-six patients with severe pain associated with cancer were entered into a study where they were required to take morphine mixture for 7 days. Prior to this, their morphine dose had been optimised to provide the most favourable balance between pain relief and side effects. After 6 days of taking their optimised morphine dose at 4-hourly intervals, the patients were admitted to the Pain Management Unit such that the doses from 18:00 h on day 6 were taken under direct nursing supervision. Frequent blood samples were collected after the 10:00 h (dose 1), 14:00 h (dose 2) and 18:00 h (dose 3) on day 7. There was a significant difference between the 3 doses with respect to Cmax values for morphine with dose 3 > dose 1 > dose 2. Further, there was considerable variability in the percentage change of either dose 1 or dose 3 Cmax values relative to dose 2. The Cmax values of the active metabolite morphine-6-glucuronide (M6G), measured in 6 of the patients, for the 3 dosing intervals followed a similar trend to the parent drug, but only doses 1 and 2 differed significantly. Similar but less pronounced changes were observed in the area-under-curve parameter calculated for both morphine and M6G during the 3 dosing intervals. There were no significant differences in the Cmin or Tmax parameters for either morphine or M6G between the 3 dosing intervals. These results suggest intra-individual variation in the absorption of morphine or changes in the volume of distribution during the day.(ABSTRACT TRUNCATED AT 250 WORDS)

Antinociceptive and motor effects of intrathecal morphine combined with intrathecal clonidine, noradrenaline, carbachol or midazolam in rats.

This study investigated antinociceptive effects of intrathecal morphine combined with intrathecal clonidine, noradrenaline, carbachol or midazolam in rats. Each animal received intrathecally, on 3 separate occasions (i) 2 micrograms morphine (M), (ii) a dose (D) of one of the non-opioid drugs, and (iii) a combination, 1/2(M+D), consisting of 1 microgram morphine plus half the dose of the non-opioid drug. Antinociceptive effects were assessed by the hot-plate and tail-flick tests over the duration of drug action. All non-opioid drugs studied led to dose-related antinociceptive effects when given alone. Addition of morphine caused a left shift in the dose-response curves of all the non-opioid drugs, indicating at least some degree of additive effects. Effects were considered supra-additive when the effect of the combination, 1/2(M+D), was significantly greater than both the effect of 2 micrograms morphine and the dose of non-opioid. Evidence of supra-additive antinociceptive effects was obtained only with the clonidine-morphine combination.