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.

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).

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)

Estimation of methadone clearance: application in the management of cancer pain.

The long half-life and wide inter-patient variability in clearance of methadone make this drug difficult to use optimally. If a patient's methadone clearance is known, however, dose regimens can be devised to maintain any desired blood concentration and hence, since the effect of methadone is related to its concentration in the blood, pain relief. We investigated methods for determining methadone clearance. In 25 patients, clearance was estimated by monitoring blood methadone concentrations following an intravenous infusion. Estimates of clearance adequate for clinical purposes could be obtained by assaying only 10-12 blood samples collected over 30 h following the infusion. The blood sampling schedules were such that it was not necessary to collect samples during the night, so the procedure could be done on an outpatient basis. An advantage of this procedure is that it also allows estimation of the blood methadone concentration required to relieve pain. We also conducted a retrospective study of data from 185 patients whose methadone clearance we had determined, to identify factors which may give rise to the large inter-patient variation in clearance. Clearance tended to be high in patients taking phenytoin, spironolactone, verapamil or oestrogens, and low in patients taking amitriptyline. Patients with malignant disease as opposed to chronic benign pain, and patients 65 years of age or older, tended to have low clearance. Clearance was positively associated with haematocrit. An equation was constructed allowing methadone clearance to be predicted from knowledge of these factors. The predicted clearance, however, showed only a moderately strong correlation with measured clearance (r = 0.75), indicating that factors not investigated also had a major influence on methadone clearance.

The influence of drug polarity on the absorption of opioid drugs into CSF and subsequent cephalad migration following lumbar epidural administration: application to morphine and pethidine.

This study examines the influence of drug polarity on the rate and extent of drug absorption into cerebrospinal fluid (CSF) following lumbar epidural administration. Twelve patients with pain secondary to cancer were simultaneously administered both morphine (10 mg) and pethidine (50 mg) in 10 ml of normal saline via an epidural catheter inserted in the lumbar region (usually L2,3) and attached to a subcutaneously implanted portal reservoir. Frequent blood samples were collected to characterise the vascular uptake of both opioids. In addition, a single CSF sample was collected in each patient from the C7-T1 interspace at one of the following times: 10, 30, 60, 120, 180 and 240 min. There was a rapid vascular uptake of morphine from the epidural space with a mean (+/- S.D.) peak concentration of 173 +/- 80 ng/ml (range 52-345 ng/ml) and a time-to-peak concentration of 8 +/- 6 min (range 2-17 min). In contrast, the vascular uptake of pethidine was more variable with a mean (+/- S.D.) concentration of 274 +/- 294 ng/ml (range 80-1113 ng/ml) and the time-to-peak concentration was 21 +/- 26 min (range 2-75 min). There was a rapid absorption of pethidine across the dura mater into the CSF with peak CSF concentrations between 1400 and 1650 ng/ml occurring between 10 and 60 min in samples collected cephalad (C7-T1 interspace) from the administration point in the lumbar region. However, the peak morphine concentration in CSF was delayed relative to the pethidine peak and occurred at 120 min.(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.

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.

Influence of polarity on dose-response relationships of intrathecal opioids in rats.

Dose-response curves were constructed for intrathecal morphine (M), oxymorphone (OM), hydromorphone (HM), diamorphine (DM), 14-hydroxydihydromorphine (OHM), oxycodone (OC), hydrocodone (HC) and fentanyl (F). Intrathecal catheters were placed in 69 rats under halothane/N2O anaesthesia. After recovery, baseline hot plate and tail flick latencies were measured, and a dose of opioid was given. Hot plate and tail flick latencies were assessed at 5, 15, 30, 60, 90, 120 min and then hourly until they returned to within 25% of baseline. Response latencies were converted to per cent of maximum possible effect (% MPE) and the area under the % MPE X time curve was taken as the response. This measure includes information about both potency and duration of action. Each rat received 3 opioids and saline at intervals of 2-3 days. On a fifth occasion, the animal's first treatment was repeated. Each opioid was studied over an 8-fold dose range. Results of both hot plate and tail flick were best described by a model including log(dose), a component due to development of tolerance over the 5 experimental days, and an among-rat variation term. In the hot plate test, doses equieffective in producing a response (AUC) over the dose range studied were in the order OHM less than OM less than HM less than M less than F less than DM less than HC less than OC. Slopes of the log(dose)-response curves were similar for all drugs except OHM, which had a steeper slope. A model is proposed in which hot plate and tail flick latencies are prolonged while CSF concentrations of a drug are above its minimum effective concentration, and drug is cleared from the CSF by a first-order process, possibly uptake into the spinal cord and removal via the blood. This model predicts that log(dose)-response curves will be linear, as was observed, with slopes inversely proportional to the rate constant for clearance from CSF. According to this model the steeper slope of the OHM log(dose)-response may be interpreted as indicating slower clearance from CSF. OHM has the lowest octanol/pH 7.4 buffer distribution coefficient (0.34) of all opioids studied, possibly leading to a lower rate of uptake into the spinal cord.

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.

The efficacy of transdermal fentanyl in the treatment of postoperative pain: a double-blind comparison of fentanyl and placebo systems.

Forty consenting patients scheduled for abdominal surgery were entered into a double-blind comparison of the efficacy of transdermal fentanyl (TTS-fentanyl) and placebo (TTS-placebo) in the treatment of postoperative pain. All patients were allowed supplementary pethidine (25-50 mg) if pain relief was inadequate provided that their respiratory rate was greater than 10 breaths/min and there was no pronounced CNS depression. Visual analogue pain scores (VAPS), sedation rating scores (SRS), blood samples for the determination of fentanyl concentration, blood pressure, pulse and respiratory rate were determined hourly for 48 h from the time of TTS system application. The first lot of TTS systems were removed after 24 h and a second lot were applied which remained in situ for a further 24 h. There was no significant difference between the patients in the TTS-fentanyl and TTS-placebo groups in the VAPS throughout the 0-12, 12-24, 24-36 and 36-48 h periods suggesting that the quality of pain relief was similar between the 2 groups. However, significantly less supplementary pethidine was administered to the TTS-fentanyl group in the 12-24, 24-36 and 36-48 h periods. In contrast, the amount of supplementary pethidine administered in the 0-12 h period was similar in both groups which was consistent with the long delay time (mean +/- S.D. value of 16.6 +/- 10 h) before clinically effective concentrations of fentanyl were obtained from the systems. The profile of side effects was similar in the 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of intermittent bolus with continuous infusion of epidural morphine in the treatment of severe cancer pain.

Twenty-eight patients with severe pain due to cancer, who could no longer obtain acceptable pain relief from optimised doses of oral opioids, were entered into a study which compared pain relief, satisfaction with pain therapy and estimates of neuropsychological functioning during treatment with spinally administered (i.e., epidural and intrathecal) morphine as either repeated bolus doses or as a continuous infusion. These measures of efficacy and side effects were repeated every 2 weeks until either the patient died (82% of patients), withdrew from the study or were no longer able to complete the tests due to deterioration of their condition. The mean (range) duration of treatment was 169 (6-537) days for those patients receiving continuous infusion and 140 (28-378) days for those patients receiving repeated bolus doses. There was no significant difference in visual analogue pain scores, pain relief scores and satisfaction scores between the bolus and infusion groups. Furthermore, low pain scores and high pain relief scores indicated that both treatment modalities provided effective pain control. Similarly, there was no significant difference between the two groups in the various tests used to assess depression or neuropsychological function (i.e., memory, vigilance, attention and processing). There was a significantly greater degree of dose escalation in patients receiving continuous infusion compared to patients receiving repeated bolus doses. For 6 patients in the infusion group the catheter was sited in the intrathecal space, as the dose requirements by the epidural route exceeded the delivery capacity of the pump. For 4 patients in the bolus group the catheter was similarly sited, due to pain on injection and leakage/blockage.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term spinal administration of morphine in cancer and non-cancer pain: a retrospective study.

Records of 313 patients who had been treated with spinal morphine via an implanted Port-A-Cath were reviewed. In 284 cases the Port-A-Cath was implanted for epidural delivery of morphine in patients with cancer-related pain. These patients were treated for a mean of 96 (range 1-1215) days. There was a wide variation in dose requirements, minimum daily dose ranging from 0.5 to 200 mg and maximum daily dose from 1 to 3072 mg. However, there was no clear trend to increasing dose as period of epidural morphine administration increased. The most frequent complications were pain on injection (12.0% incidence), occlusion of the portal system (10.9%), infection (8.1%) and leakage of administered morphine such that it did not all reach the epidural space (2.1%). In all but 1 case infections were limited to the area around the portal or along the catheter track. All infections resolved without sequelae following removal of the portal and/or administration of antibiotics. In 17 patients Port-A-Caths were implanted for the intrathecal delivery of morphine to control cancer-related pain. These patients also exhibited wide variations in morphine dose requirements. Port-A-Caths were also implanted for delivery of spinal morphine in 12 patients with chronic pain which was not related to cancer and which failed to respond to other therapies. These patients were treated for a mean of 155 (range 2-575) days. Port-A-Caths were removed from 7 of these patients, primarily due to infection (2 cases) and inadequate pain relief and pain on injection (2 cases).

The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects.

A transdermal formulation of fentanyl (TTS-fentanyl, Alza Corp., Palo Alto, CA) was evaluated in 13 surgical patients after an abdominal operation. An intraoperative dose of fentanyl (100-200 micrograms i.v.) was administered at the same time as the TTS-fentanyl systems (50-125 micrograms/h) were applied to the antero-lateral chest wall. The TTS-fentanyl systems remained in situ for 24 h and were then removed and a second lot of systems were applied to the contra-lateral chest wall. There was a mean (S.D.) delay time of 12.7 (9.6) h before minimum effective blood fentanyl concentrations (MEC) were obtained from the systems and pseudo-steady state was reached between 36 and 48 h. There was a decay time of 16.1 (7.1) h after the systems were removed for the blood fentanyl concentration to decrease to less than the mean MEC for the control of postoperative pain. There was marked variability between patients in the actual hourly fentanyl dose rate determined from the residual amount of fentanyl remaining in the system and the duration of application. Significantly more supplementary pethidine was administered for inadequate postoperative analgesia between 0 and 12 h compared to the 12-24, 24-36 and 36-48 h periods; this was consistent with the observed delay time. Three patients required a reduction in the hourly fentanyl dose rate because of bradypnoea while 1 patient required an increase in dose because of inadequate pain relief. Nausea was the most frequently reported side effect (85% of patients) while bradypnoea, drowsiness, unpleasant dreams and headache were also reported. These effects were due to the combined effects of a sustained blood fentanyl concentration and the intermittent supplementary pethidine doses. Side effects due to the topical formulation were transient and included erythema (8 patients) and a minor rash (2 patients) in the area occluded by the systems. The TTS-fentanyl systems provided a significant contribution to postoperative pain control but, at the TTS dose rates used, supplementary doses of pethidine were required by all patients probably to control 'incident' pain.

Pharmacokinetics of fentanyl in lumbar and cervical CSF following lumbar epidural and intravenous administration.

Fentanyl (1 microgram/kg body weight) was administered intravenously and via a lumbar epidural catheter (in random order) on 2 separate occasions to 6 patients with chronic pain associated with non-terminal disease states. Frequent blood samples were collected from an indwelling intravenous catheter and CSF samples were collected via spinal needles inserted in the cervical (C7-T1 interspace) and lumbar (L3.4 interspace) regions at 0, 5, 10, 20, 30 and 45 min after fentanyl administration. The concentration of fentanyl in blood and CSF samples were quantified by a sensitive and selective gas-liquid chromatography assay. Visual analogue pain scores (VAPS) were recorded every 5 min for the first hour. Coded syringes (one containing the appropriate fentanyl dose while the other contained an equivalent volume of saline) allowed the investigator administering the fentanyl and assessing VAPS to remain blinded as to which route of administration actually contained the fentanyl. There was minimal vascular uptake of fentanyl following epidural administration. Similarly, the permeation of fentanyl into cervical and lumbar CSF following intravenous administration was minimal and erratic such that only 4 of the 60 CSF samples had detectable fentanyl concentrations. In contrast, there was a rapid penetration of fentanyl across the dura mater following lumbar epidural administration. There was significantly fentanyl in lumbar CSF samples by 10 min in 5 patients, and by 20 min in all 6 patients. The mean maximum lumbar CSF concentration was 19.1 ng/ml, while the time associated with these maximum concentrations was 22.5 min. The mean maximum cervical CSF fentanyl concentrations were 10% of the lumbar CSF concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.