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1.  Medication reconciliation as a medication safety initiative in Ethiopia: a study protocol 
BMJ Open  2016;6(11):e012322.
Introduction
Medication related adverse events are common, particularly during transitions of care, and have a significant impact on patient outcomes and healthcare costs. Medication reconciliation (MedRec) is an important initiative to achieve the Quality Use of Medicines, and has been adopted as a standard practice in many developed countries. However, the impact of this strategy is rarely described in Ethiopia. The aims of this study are to explore patient safety culture, and to develop, implement and evaluate a theory informed MedRec intervention, with the aim of minimising the incidence of medication errors during hospital admission.
Methods and analyses
The study will be conducted in a resource limited setting. There are three phases to this project. The first phase is a mixed methods study of healthcare professionals' perspectives of patient safety culture and patients' experiences of medication related adverse events. In this phase, the Hospital Survey on Patient Safety Culture will be used along with semi-structured indepth interviews to investigate patient safety culture and experiences of medication related adverse events. The second phase will use a semi-structured interview guide, designed according to the 12 domains of the Theoretical Domains Framework, to explore the barriers and facilitators to medication safety activities delivered by hospital pharmacists. The third phase will be a single centre, before and after study, that will evaluate the impact of pharmacist conducted admission MedRec in an emergency department (ED). The main outcome measure is the incidence and potential clinical severity of medication errors. We will then analyse the differences in the incidence and severity of medication errors before and after initiation of an ED pharmacy service.
doi:10.1136/bmjopen-2016-012322
PMCID: PMC5168529  PMID: 27884844
medication reconciliation; medication history; medication safety; medication review; medication errors; medication discrepancies
2.  Measuring anticholinergic drug exposure in older community-dwelling Australian men: a comparison of four different measures 
Aims
Anticholinergic drug exposure is associated with adverse outcomes in older people. While a number of tools have been developed to measure anticholinergic drug exposure, there is limited information about the agreement and overlap between the various scales. The aim of this study was to investigate the agreement and overlap between different measures of anticholinergic drug exposure in a cohort of community-dwelling older men.
Methods
A cross-sectional study was used to compare anticholinergic drug exposure calculated using the Anticholinergic Risk Scale (ARS), the Anticholinergic Drug Scale (ADS), the Anticholinergic Cognitive Burden (ACB) and the Drug Burden Index anticholinergic subscale (DBI-ACH) in a cohort of community-dwelling men aged 70 years and older (n = 1696). Statistical agreement, expressed as Cohen's kappa (κ), between these measurements was calculated.
Results
Differences were found between the tools regarding the classification of anticholinergic drug exposure for individual participants. Thirteen percent of the population used a drug listed as anticholinergic on the ARS, 39% used a drug listed on the ADS and the ACB, and 18% of the population used one or more anticholinergic drugs listed on the DBI-ACH. While agreement was good between the ACB and ADS (κ = 0.628, 95% CI 0.593, 0.664), little agreement was found between remaining tools (κ = 0.091–0.264).
Conclusions
With the exception of the ACB and ADS, there was poor agreement regarding anticholinergic drug exposure among the four tools compared in this study. Great care should be taken when interpreting anticholinergic drug exposure using existing scales due to the wide variability between the different scales.
doi:10.1111/bcp.12670
PMCID: PMC4631189  PMID: 25923961
anticholinergic burden; anticholinergic drug exposure; drug utilization; methodology; older people
3.  OPAL: a randomised, placebo-controlled trial of opioid analgesia for the reduction of pain severity in people with acute spinal pain. Trial protocol 
BMJ Open  2016;6(8):e011278.
Introduction
Low back pain and neck pain are extremely prevalent and are responsible for an enormous burden of disease globally. Strong analgesics, such as opioid analgesics, are recommended by clinical guidelines for people with acute low back pain or neck pain who are slow to recover and require more pain relief. Opioid analgesics are widely and increasingly used, but there are no strong efficacy data supporting the use of opioid analgesics for acute low back pain or neck pain. Concerns regarding opioid use are further heightened by the risks of adverse events, some of which can be serious (eg, dependency, misuse and overdose).
Methods and analysis
OPAL is a randomised, placebo-controlled, triple-blinded trial that will investigate the judicious use of an opioid analgesic in 346 participants with acute low back pain and/or neck pain who are slow to recover. Participants will be recruited from general practice and randomised to receive the opioid analgesic (controlled release oxycodone plus naloxone up to 20 mg per day) or placebo in addition to guideline-based care (eg, reassurance and advice of staying active) for up to 6 weeks. Participants will be followed-up for 3 months for effectiveness outcomes. The primary outcome will be pain severity. Secondary outcomes will include physical functioning and time to recovery. Medication-related adverse events will be assessed and a cost-effectiveness analysis will be conducted. We will additionally assess long-term use and risk of misuse of opioid analgesics for up to 12 months.
Ethics and dissemination
Ethical approval has been obtained. Trial results will be disseminated by publications and conference presentations, and via the media.
Trial registration number
ACTRN12615000775516: Pre-results.
doi:10.1136/bmjopen-2016-011278
PMCID: PMC5013345  PMID: 27558901
Opioid analgesics; low back pain; neck pain
4.  Impact of electronic medication reconciliation interventions on medication discrepancies at hospital transitions: a systematic review and meta-analysis 
Background
Medication reconciliation has been identified as an important intervention to minimize the incidence of unintentional medication discrepancies at transitions in care. However, there is a lack of evidence for the impact of information technology on the rate and incidence of medication discrepancies identified during care transitions. This systematic review was thus, aimed to evaluate the impact of electronic medication reconciliation interventions on the occurrence of medication discrepancies at hospital transitions.
Methods
Systematic literature searches were performed in MEDLINE, PubMed, CINHAL, and EMBASE from inception to November, 2015. We included published studies in English that evaluated the effect of information technology on the incidence and rate of medication discrepancies compared with usual care. Cochrane’s tools were used for assessment of the quality of included studies. We performed meta-analyses using random-effects models.
Results
Ten studies met our inclusion criteria; of which only one was a randomized controlled trial. Interventions were carried out at various hospital transitions (admission, 5; discharge, 2 and multiple transitions, 3 studies). Meta-analysis showed a significant reduction of 45 % in the proportion of medications with unintentional discrepancies after the use of electronic medication reconciliation (RR 0.55; 95 % CI 0.51 to 0.58). However, there was no significant reduction in either the proportion of patients with medication discrepancies or the mean number of discrepancies per patient. Drug omissions were the most common types of unintended discrepancies, and with an electronic tool a significant but heterogeneously distributed reduction of omission errors over the total number of medications reconciled have been observed (RR 0.20; 95 % CI 0.06 to 0.66). The clinical impact of unintended discrepancies was evaluated in five studies, and there was no potentially fatal error identified and most errors were minor in severity.
Conclusion
Medication reconciliation supported by an electronic tool was able to minimize the incidence of medications with unintended discrepancy, mainly drug omissions. But, this did not consistently reduce other process outcomes, although there was a lack of rigorous design to conform these results.
Electronic supplementary material
The online version of this article (doi:10.1186/s12911-016-0353-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12911-016-0353-9
PMCID: PMC4994239  PMID: 27549581
Electronic medication reconciliation; Medication history; Medication safety; Medication errors; Medication discrepancies; Care transition
5.  Timing of Administration: For Commonly-Prescribed Medicines in Australia 
Pharmaceutics  2016;8(2):13.
Chronotherapy involves the administration of medication in coordination with the body’s circadian rhythms to maximise therapeutic effectiveness and minimise/avoid adverse effects. The aim of this study is to investigate the “time of administration” recommendations on chronotherapy for commonly-prescribed medicines in Australia. This study also aimed to explore the quality of information on the timing of administration presented in drug information sources, such as consumer medicine information (CMI) and approved product information (PI). Databases were searched for original research studies reporting on the impact of “time of administration” of the 30 most commonly-prescribed medicines in Australia for 2014. Further, time of administration recommendations from drug information sources were compared to the evidence from chronotherapy trials. Our search revealed 27 research studies, matching the inclusion and exclusion criteria. In 56% (n = 15) of the research studies, the therapeutic effect of the medicine varied with the time of administration, i.e., supported chronotherapy. For some medicines (e.g., simvastatin), circadian-based optimal administration time was evident in the information sources. Overall, dedicated studies on the timing of administration of medicines are sparse, and more studies are required. As it stands, information provision to consumers and health professionals about the optimal “time” to take medications lags behind emerging evidence.
doi:10.3390/pharmaceutics8020013
PMCID: PMC4932476  PMID: 27092523
chronotherapy; circadian rhythm; medicines; statins; antihypertensives; proton pump inhibitors; timing of drug administration; Australia
6.  Effectiveness of pharmacist-led medication reconciliation programmes on clinical outcomes at hospital transitions: a systematic review and meta-analysis 
BMJ Open  2016;6(2):e010003.
Objectives
Pharmacists play a role in providing medication reconciliation. However, data on effectiveness on patients’ clinical outcomes appear inconclusive. Thus, the aim of this study was to systematically investigate the effect of pharmacist-led medication reconciliation programmes on clinical outcomes at hospital transitions.
Design
Systematic review and meta-analysis.
Methods
We searched PubMed, MEDLINE, EMBASE, IPA, CINHAL and PsycINFO from inception to December 2014. Included studies were all published studies in English that compared the effectiveness of pharmacist-led medication reconciliation interventions to usual care, aimed at improving medication reconciliation programmes. Meta-analysis was carried out using a random effects model, and subgroup analysis was conducted to determine the sources of heterogeneity.
Results
17 studies involving 21 342 adult patients were included. Eight studies were randomised controlled trials (RCTs). Most studies targeted multiple transitions and compared comprehensive medication reconciliation programmes including telephone follow-up/home visit, patient counselling or both, during the first 30 days of follow-up. The pooled relative risks showed a more substantial reduction of 67%, 28% and 19% in adverse drug event-related hospital revisits (RR 0.33; 95% CI 0.20 to 0.53), emergency department (ED) visits (RR 0.72; 95% CI 0.57 to 0.92) and hospital readmissions (RR 0.81; 95% CI 0.70 to 0.95) in the intervention group than in the usual care group, respectively. The pooled data on mortality (RR 1.05; 95% CI 0.95 to 1.16) and composite readmission and/or ED visit (RR 0.95; 95% CI 0.90 to 1.00) did not differ among the groups. There was significant heterogeneity in the results related to readmissions and ED visits, however. Subgroup analyses based on study design and outcome timing did not show statistically significant results.
Conclusion
Pharmacist-led medication reconciliation programmes are effective at improving post-hospital healthcare utilisation. This review supports the implementation of pharmacist-led medication reconciliation programmes that include some component aimed at improving medication safety.
doi:10.1136/bmjopen-2015-010003
PMCID: PMC4769405  PMID: 26908524
Medication reconciliation; medication review; medication errors; medication discrepancies; pharmacists
7.  PRECISE — pregabalin in addition to usual care: statistical analysis plan 
Trials  2016;17:53.
Background
Sciatica is a severe, disabling condition that lacks high quality evidence for effective treatment strategies. This a priori statistical analysis plan describes the methodology of analysis for the PRECISE study.
Methods/design
PRECISE is a prospectively registered, double blind, randomised placebo controlled trial of pregabalin compared to placebo, in addition to usual care in patients with sciatica. The aim of this study is to determine the efficacy and cost-effectiveness of pregabalin in reducing leg pain intensity (primary outcome). Secondary outcomes include disability (key secondary), back pain intensity, quality of life, participants’ perceived global effect, work absenteeism and health utilisation. Information about medication usage and tolerability are also collected. Outcomes are collected over one year (weeks 2, 4, 8, 12, 26 and 52). Double data entry will be conducted for primary and key secondary outcomes. Other outcomes will be checked using a risk-based approach. Analyses will be consistent with the intention-to-treat principle. Statistical tests will be two-tailed with a p value <0.05 considered significant. Group allocation will remain masked until analyses and interpretation are finalised. Repeated-measure linear mixed models will assess the effect of treatment (pregabalin versus placebo) on primary and secondary outcomes at all time points. Fixed effects will include group allocation, visit as a categorical variable and the interaction between group and visit. Covariates will include baseline leg pain and symptom duration, with an interaction term between baseline leg pain and visit. Pairwise differences between groups will be tested at weeks 8 and 52. The number of serious adverse events and adverse events will be reported, and the proportion of patients per group who have at least one event will be compared using Fisher’s exact test. An economic evaluation will be conducted if there is a treatment effect on the primary outcome at week 8. A subgroup analysis will assess whether presenting features of neuropathic pain at baseline modify the treatment effect of leg pain at week 8.
Discussion
This statistical analysis plan provides detailed methodology for the analysis of the PRECISE study, which aims to deliver much needed evidence about effective and affordable management of sciatica.
Trial registration
Australian and New Zealand Clinical Trials Registry (ACTRN12613000530729. Registered 13 May 2013)
doi:10.1186/s13063-016-1174-y
PMCID: PMC4730769  PMID: 26818733
Sciatica; Pregabalin; Statistical analysis plan; Randomised controlled trial; Placebo
8.  Evaluating the effectiveness of a peer-led education intervention to improve the patient safety attitudes of junior pharmacy students: a cross-sectional study using a latent growth curve modelling approach 
BMJ Open  2015;5(12):e010045.
Objective
Despite the recognition that educating healthcare students in patient safety is essential, changing already full curricula can be challenging. Furthermore, institutions may lack the capacity and capability to deliver patient safety education, particularly from the start of professional practice studies. Using senior students as peer educators to deliver practice-based education can potentially overcome some of the contextual barriers in training junior students. Therefore, this study aimed to evaluate the effectiveness of a peer-led patient safety education programme for junior pharmacy students.
Design
A repeat cross-sectional design utilising a previously validated patient safety attitudinal survey was used to evaluate attitudes prior to, immediately after and 1 month after the delivery of a patient safety education programme. Latent growth curve (LGC) modelling was used to evaluate the change in attitudes of first-year students using second-year students as a comparator group.
Setting
Undergraduate university students in Sydney, Australia.
Participants
175 first-year and 140 second-year students enrolled in the Bachelor of Pharmacy programme at the University of Sydney.
Intervention
An introductory patient safety programme was implemented into the first-year Bachelor of Pharmacy curriculum at the University of Sydney. The programme covered introductory patient safety topics including teamwork, communication skills, systems thinking and open disclosure. The programme consisted of 2 lectures, delivered by a senior academic, and a workshop delivered by trained final-year pharmacy students.
Results
A full LGC model was constructed including the intervention as a non-time-dependent predictor of change (χ2 (51)=164.070, root mean square error of approximation=0.084, comparative fit index=0.913, standardised root mean square=0.056). First-year students’ attitudes significantly improved as a result of the intervention, particularly in relation to internalising errors (p=0.010), questioning behaviours (p<0.001) and open disclosure (p=0.008).
Conclusions
Peer-led education is an effective method that can be adopted to improve junior pharmacy students’ attitudes towards patient safety.
doi:10.1136/bmjopen-2015-010045
PMCID: PMC4680010  PMID: 26646830
MEDICAL EDUCATION & TRAINING; STATISTICS & RESEARCH METHODS
9.  Optimal sampling of antipsychotic medicines: a pharmacometric approach for clinical practice 
Aim
To determine optimal sampling strategies to allow the calculation of clinical pharmacokinetic parameters for selected antipsychotic medicines using a pharmacometric approach.
Methods
This study utilized previous population pharmacokinetic parameters of the antipsychotic medicines aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone (including 9-OH risperidone) and ziprasidone. d-optimality was utilized to identify time points which accurately predicted the pharmacokinetic parameters (and expected error) of each drug at steady-state. A standard two stage population approach (STS) with MAP-Bayesian estimation was used to compare area under the concentration–time curves (AUC) generated from sparse optimal time points and rich extensive data. Monte Carlo Simulation (MCS) was used to simulate 1000 patients with population variability in pharmacokinetic parameters. Forward stepwise regression analysis was used to determine the most predictive time points of the AUC for each drug at steady-state.
Results
Three optimal sampling times were identified for each antipsychotic medicine. For aripiprazole, clozapine, olanzapine, perphenazine, risperidone, 9-OH risperidone, quetiapine and ziprasidone the CV% of the apparent clearance using optimal sampling strategies were 19.5, 8.6, 9.5, 13.5, 12.9, 10.0, 16.0 and 10.7, respectively. Using the MCS and linear regression approach to predict AUC, the recommended sampling windows were 16.5–17.5 h, 10–11 h, 23–24 h, 19–20 h, 16.5–17.5 h, 22.5–23.5 h, 5–6 h and 5.5–6.5 h, respectively.
Conclusion
This analysis provides important sampling information for future population pharmacokinetic studies and clinical studies investigating the pharmacokinetics of antipsychotic medicines.
doi:10.1111/bcp.12410
PMCID: PMC4239974  PMID: 24773369
antipsychotic medicines; optimal sampling; pharmacometrics; population pharmacokinetics; therapeutic drug monitoring
10.  Validation of a survey tool to assess the patient safety attitudes of pharmacy students 
BMJ Open  2015;5(9):e008442.
Objective
Patient safety education is a key strategy to minimise harm, and is increasingly being introduced into junior pharmacy curricula. However, currently there is no valid and reliable survey tool to measure the patient safety attitudes of pharmacy students. This study aimed to validate a modified survey tool, originally developed by Madigosky et al, to evaluate patient safety attitudes of junior pharmacy students.
Design
A 23-item cross-sectional patient safety survey tool was utilised to evaluate first and second year pharmacy students’ attitudes during May 2013 with both exploratory and confirmatory factor analyses performed to understand the psychometric properties of the survey tool and to establish construct validity.
Setting
Undergraduate university students in Sydney, Australia
Participants
245 first year and 201 second year students enrolled in the Bachelor of Pharmacy Programme at The University of Sydney, Australia in May 2013.
Results
After exploratory factor analysis on first year student responses (55.76% variance explained) and confirmatory factor analysis on second year responses, a 5-factor model consisting of 14 items was obtained with satisfactory model fit (χ2 (66)=112.83, p<0.001, RMSEA=0.06, CFI=0.91) and nesting between year groups (Δχ2(7)=3.079, p=0.878). The five factors measured students’ attitudes towards: (1) being quality improvement focused, (2) internalising errors regardless of harm, (3) value of contextual learning, (4) acceptability of questioning more senior healthcare professionals’ behaviour and (5) attitude towards open disclosure.
Conclusions
This study has established the reliability and validity of a modified survey tool to evaluate patient safety attitudes of pharmacy students, with the potential for use in course development and evaluation.
doi:10.1136/bmjopen-2015-008442
PMCID: PMC4567665  PMID: 26359285
PRIMARY CARE; EDUCATION & TRAINING (see Medical Education & Training)
11.  Terbinafine in Combination with Other Antifungal Agents for Treatment of Resistant or Refractory Mycoses: Investigating Optimal Dosing Regimens Using a Physiologically Based Pharmacokinetic Model 
Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.
doi:10.1128/AAC.02006-13
PMCID: PMC3910715  PMID: 24126579
12.  Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis 
Antimicrobial Agents and Chemotherapy  2014;58(11):6879-6885.
Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drug-drug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.
doi:10.1128/AAC.03777-14
PMCID: PMC4249414  PMID: 25199779
14.  Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials 
Objective To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014.
Eligibility criteria for selecting studies Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee.
Data extraction Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration’s tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions.
Results 12 reports (13 randomised trials) were included. There was “high quality” evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was “high quality” evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. “High quality” evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain.
Conclusions Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.
Systematic review registration PROSPERO registration number CRD42013006367.
doi:10.1136/bmj.h1225
PMCID: PMC4381278  PMID: 25828856
15.  Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials 
The BMJ  2015;350:h1225.
Objective To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee.
Design Systematic review and meta-analysis.
Data sources Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014.
Eligibility criteria for selecting studies Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee.
Data extraction Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration’s tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions.
Results 12 reports (13 randomised trials) were included. There was “high quality” evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference −0.5, 95% confidence interval −2.9 to 1.9) and disability (0.4, −1.7 to 2.5) or improving quality of life (0.4, −0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was “high quality” evidence that paracetamol provides a significant, although not clinically important, effect on pain (−3.7, −5.5 to −1.9) and disability (−2.9, −4.9 to −0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. “High quality” evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain.
Conclusions Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines.
Systematic review registration PROSPERO registration number CRD42013006367.
doi:10.1136/bmj.h1225
PMCID: PMC4381278  PMID: 25828856
16.  Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration 
Antimicrobial Agents and Chemotherapy  2012;56(11):5503-5510.
Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H2 antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.
doi:10.1128/AAC.00802-12
PMCID: PMC3486529  PMID: 22890761
17.  Clinical pharmacology of analgesic medicines in older people: impact of frailty and cognitive impairment 
Pain is highly prevalent in frail older people who often have multiple co-morbidities and multiple medicines. Rational prescribing of analgesics in frail older people is complex due to heterogeneity in drug disposition, comorbid medical conditions, polypharmacy and variability in analgesic response in this population. A critical issue in managing older people with pain is the need for judicious choice of analgesics based on a comprehensive medical and medication history. Care is needed in the selection of analgesic medicine to avoid drug–drug or drug–disease interactions. People living with dementia and cognitive impairment have suboptimal pain relief which in part may be related to altered pharmacodynamics of analgesics and challenges in the systematic assessment of pain intensity in this patient group. In the absence of rigorously controlled trials in frail older people and those with cognitive impairment a pharmacologically-guided approach can be used to optimize pain management which requires a systematic understanding of the pharmacokinetics and pharmacodynamics of analgesics in frail older people with or without changes in cognition.
doi:10.1111/j.1365-2125.2010.03847.x
PMCID: PMC3045544  PMID: 21284694
frailty; oxycodone; pain; paracetamol; pharmacodynamics; pharmacokinetics
18.  Clinical Pharmacology of Chemotherapy Agents in Older People with Cancer 
Populations around the world are aging, and the associated increase in cancer incidence has led to the recognition of the importance of geriatric oncology. Chronological age is a poor determinant of pharmacological response to cancer chemotherapy agents. Age-associated changes in physiology and organ function have a significant impact on the clinical pharmacology of cancer chemotherapy agents used in cancer treatment. Altered response to medicines in older people is a consequence of changes in body composition, organ function, concomitant pathophysiology, multiple medications, genetic determinants of drug response, and patient's clinical status. These issues highlight the need to individualize the management of cancer in the older people with consideration of age-related changes in the clinical pharmacology of cancer drugs, analgesics, and adjunctive therapies.
doi:10.1155/2011/628670
PMCID: PMC3154497  PMID: 21845189
19.  Hepatic Disposal of Advanced Glycation End Products During Maturation and Aging 
Experimental gerontology  2013;48(6):549-556.
Aging is characterized by progressive loss of metabolic and biochemical functions and accumulation of metabolic by-products, including advanced glycation end products (AGEs), which are observed in several pathological conditions. A number of waste macromolecules, including AGEs are taken up from the circulation by endocytosis mainly into liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs). However, AGEs still accumulate in different tissues with ageing, despite the presence of this clearance mechanism. The aim of the present study was to determine whether the efficiency of LSECs and KCs for disposal of AGEs changes through aging.
Results
After intravenous administration of 14C-AGE-albumin in pre-pubertal, young adult, middle aged and old mice, more than 90% of total recovered 14C-AGE was liver associated, irrespective of age. LSECs and KCs represented the main site of uptake. A fraction of the 14C-AGE degradation products (14C-AGE-DPs) was stored for months in the lysosomes of these cells after uptake. The overall rate of elimination of 14C-AGE-DPs from the liver was markedly faster in pre-pubertal than in all post-pubertal age groups. The ability to eliminate 14C-AGE-DPs decreased to similar extents after puberty in LSECs and KCs. A rapid early removal phase was characteristic for all age groups except the old group, where this phase was absent.
Conclusions
Removal of AGE-DPs from the liver scavenger cells is a very slow process that changes with age. The ability of these cells to dispose of AGEs declines after puberty. Decreased AGE removal efficiency early in life may lead to AGE accumulation.
doi:10.1016/j.exger.2013.03.005
PMCID: PMC3722431  PMID: 23531498
aging; scavenger cell; liver; lysosome; AGE accumulation; AGE disposal
20.  Population pharmacokinetics and dosing regimen design of milrinone in preterm infants 
Aims
To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth.
Methods
A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10).
Results
Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study.
Conclusion
Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology.
doi:10.1136/adc.2005.092817
PMCID: PMC2675339  PMID: 16690639
FOCE; first‐order approximation with condition estimation; HPLC; high performance liquid chromatography; P/IVH; peri/intraventricular haemorrhage; SVC; superior vena cava
21.  Adverse Selection? A Multi-Dimensional Profile of People Dispensed Opioid Analgesics for Persistent Non-Cancer Pain 
PLoS ONE  2013;8(12):e80095.
Objectives
This study investigates utilisation patterns for prescription opioid analgesics in the Australian community and how these are associated with a framework of individual-level factors related to healthcare use.
Methods
Self-reported demographic and health information from participants in the 45 and Up Study cohort were linked to pharmaceutical claims from 2006–2009. Participants comprised 19,816 people with ≥1 opioid analgesic dispensing in the 12-months after recruitment to the cohort and 79,882 people not dispensed opioid analgesics. All participants were aged ≥45 years, were social security pharmaceutical beneficiaries, with no history of cancer. People dispensed opioid analgesics were classified as having acute (dispensing period <90 days), episodic (≥90 days and <3 ‘authority’ prescriptions for increased quantity supply) or long-term treatment (≥90 days and ≥3 authority prescriptions).
Results
Of participants dispensed opioid analgesic 52% received acute treatment, 25% episodic treatment and 23% long-term treatment. People dispensed opioid analgesics long-term had an average of 14.9 opioid analgesic prescriptions/year from 2.0 doctors compared with 1.5 prescriptions from 1.1 doctors for people receiving acute treatment. People dispensed opioid analgesics reported more need-related factors such as poorer physical functioning and higher psychological distress. Long-term users were more likely to have access-related factors such as low-income and living outside major cities. After simultaneous adjustment, association with predisposing health factors and access diminished, but indicators of need such as osteoarthritis treatment, paracetamol use, and poor physical function were the strongest predictors for all opioid analgesic users.
Conclusions
People dispensed opioid analgesics were in poorer health, reported higher levels of distress and poorer functioning than people not receiving opioid analgesics. Varying dispensing profiles were evident among people dispensed opioid analgesics for persistent pain, with those receiving episodic and long-term treatment dispensed the strongest opioid analgesics. The findings highlight the broad range of factors associated with longer term opioid analgesics use.
doi:10.1371/journal.pone.0080095
PMCID: PMC3846564  PMID: 24312456
22.  Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate 
Aims
To characterize the population pharmacokinetics of gemcitabine and its metabolite (dFdU) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design.
Methods
Gemcitabine and dFdU plasma concentration–time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates.
Results
Gemcitabine and dFdU pharmacokinetics were described by a two-compartment model with first-order elimination. The population mean (and between-subject variability, CV%) for clearance and volume of distribution of the central compartment (VC) for gemcitabine were 2.7 l min−1 (31%) and 15 l (39%), respectively, and 0.04 l min−1 (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co-administration significantly decreased dFdU VC by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone.
Conclusions
Co-administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.
What is already known about this subject Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin.The impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood.
What this study adds This study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions.Gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co-administration with oxaliplatin and were dependent on the order of administration.The clinical implications of this observation remain to be established.
doi:10.1111/j.1365-2125.2007.03040.x
PMCID: PMC2291243  PMID: 17961191
chemotherapy; dFdU; gemcitabine; metabolism; oxaliplatin; pharmacokinetics
23.  The pharmacokinetics of oxypurinol in people with gout 
AIMS
Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.
METHODS
Non-linear mixed effects modelling was applied to concentration–time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.
RESULTS
A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration–time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/Fm) from 65% to 29%. CL/Fm for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h−1, respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.
CONCLUSIONS
In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.
doi:10.1111/j.1365-2125.2012.04207.x
PMCID: PMC3477349  PMID: 22300439
allopurinol; gout; oxypurinol; pharmacogenetics; pharmacokinetics; urate
24.  PACE – the first placebo controlled trial of paracetamol for acute low back pain: statistical analysis plan 
Trials  2013;14:248.
Background
Paracetamol (acetaminophen) is recommended in most clinical practice guidelines as the first choice of treatment for low back pain, however there is limited evidence to support this recommendation. The PACE trial is the first placebo controlled trial of paracetamol for acute low back pain. This article describes the statistical analysis plan.
Results
PACE is a randomized double dummy placebo controlled trial that investigates and compares the effect of paracetamol taken in two regimens for the treatment of low back pain. The protocol has been published. The analysis plan was completed blind to study group and finalized prior to initiation of analyses. All data collected as part of the trial were reviewed, without stratification by group, and classified by baseline characteristics, process of care and trial outcomes. Trial outcomes were classified as primary and secondary outcomes. Appropriate descriptive statistics and statistical testing of between-group differences, where relevant, have been planned and described.
Conclusions
A standard analysis plan was developed for the results of the PACE study. This plan comprehensively describes the data captured and pre-determined statistical tests of relevant outcome measures. The plan demonstrates transparent and verifiable use of the data collected. This a priori plan will be followed to ensure rigorous standards of data analysis are strictly adhered to.
Trial registration
Australia and New Zealand Clinical Trials Registry ACTRN12609000966291
doi:10.1186/1745-6215-14-248
PMCID: PMC3750911  PMID: 23937999
Acetaminophen; Back pain; Paracetamol; Statistical analysis plan; Randomised controlled trial
25.  PRECISE - pregabalin in addition to usual care for sciatica: study protocol for a randomised controlled trial 
Trials  2013;14:213.
Background
Sciatica is a type of neuropathic pain that is characterised by pain radiating into the leg. It is often accompanied by low back pain and neurological deficits in the lower limb. While this condition may cause significant suffering for the individual, the lack of evidence supporting effective treatments for sciatica makes clinical management difficult. Our objectives are to determine the efficacy of pregabalin on reducing leg pain intensity and its cost-effectiveness in patients with sciatica.
Methods/Design
PRECISE is a prospectively registered, double-blind, randomised placebo-controlled trial of pregabalin compared to placebo, in addition to usual care. Inclusion criteria include moderate to severe leg pain below the knee with evidence of nerve root/spinal nerve involvement. Participants will be randomised to receive either pregabalin with usual care (n = 102) or placebo with usual care (n = 102) for 8 weeks. The medicine dosage will be titrated up to the participant’s optimal dose, to a maximum 600 mg per day. Follow up consultations will monitor individual progress, tolerability and adverse events. Usual care, if deemed appropriate by the study doctor, may include a referral for physical or manual therapy and/or prescription of analgesic medication. Participants, doctors and researchers collecting participant data will be blinded to treatment allocation. Participants will be assessed at baseline and at weeks 2, 4, 8, 12, 26 and 52. The primary outcome will determine the efficacy of pregabalin in reducing leg pain intensity. Secondary outcomes will include back pain intensity, disability and quality of life. Data analysis will be blinded and by intention-to-treat. A parallel economic evaluation will be conducted from health sector and societal perspectives.
Discussion
This study will establish the efficacy of pregabalin in reducing leg pain intensity in patients with sciatica and provide important information regarding the effect of pregabalin treatment on disability and quality of life. The impact of this research may allow the future development of a cost-effective conservative treatment strategy for patients with sciatica.
Trial registration
ClinicalTrial.gov, ACTRN 12613000530729
doi:10.1186/1745-6215-14-213
PMCID: PMC3711833  PMID: 23845078
Sciatica; Pregabalin; Neuropathic pain; Randomised control trial

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