Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial.

BACKGROUND: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain. METHODS: OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone-naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516). FINDINGS: Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI -0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group). INTERPRETATION: Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions. FUNDING: National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and SafeWork SA.

Effect of Salt Substitution on Cardiovascular Events and Death.

BACKGROUND: Salt substitutes with reduced sodium levels and increased potassium levels have been shown to lower blood pressure, but their effects on cardiovascular and safety outcomes are uncertain. METHODS: We conducted an open-label, cluster-randomized trial involving persons from 600 villages in rural China. The participants had a history of stroke or were 60 years of age or older and had high blood pressure. The villages were randomly assigned in a 1:1 ratio to the intervention group, in which the participants used a salt substitute (75% sodium chloride and 25% potassium chloride by mass), or to the control group, in which the participants continued to use regular salt (100% sodium chloride). The primary outcome was stroke, the secondary outcomes were major adverse cardiovascular events and death from any cause, and the safety outcome was clinical hyperkalemia. RESULTS: A total of 20,995 persons were enrolled in the trial. The mean age of the participants was 65.4 years, and 49.5% were female, 72.6% had a history of stroke, and 88.4% a history of hypertension. The mean duration of follow-up was 4.74 years. The rate of stroke was lower with the salt substitute than with regular salt (29.14 events vs. 33.65 events per 1000 person-years; rate ratio, 0.86; 95% confidence interval [CI], 0.77 to 0.96; P = 0.006), as were the rates of major cardiovascular events (49.09 events vs. 56.29 events per 1000 person-years; rate ratio, 0.87; 95% CI, 0.80 to 0.94; P<0.001) and death (39.28 events vs. 44.61 events per 1000 person-years; rate ratio, 0.88; 95% CI, 0.82 to 0.95; P<0.001). The rate of serious adverse events attributed to hyperkalemia was not significantly higher with the salt substitute than with regular salt (3.35 events vs. 3.30 events per 1000 person-years; rate ratio, 1.04; 95% CI, 0.80 to 1.37; P = 0.76). CONCLUSIONS: Among persons who had a history of stroke or were 60 years of age or older and had high blood pressure, the rates of stroke, major cardiovascular events, and death from any cause were lower with the salt substitute than with regular salt. (Funded by the National Health and Medical Research Council of Australia; SSaSS ClinicalTrials.gov number, NCT02092090.).

The effect of salt substitution on frequency and severity of headache: results from the SSaSS cluster-randomised controlled trial of 20,995 participants.

BACKGROUND: Headache is one of the most common neurological symptoms. Headache disorders are associated with a high global burden of disease. Prior studies indicate that short-to-medium term sodium reduction reduces headache symptom. This study evaluated the effects of long-term reduced-sodium, added-potassium salt on headache frequency and severity in rural China. METHODS: The Salt substitute and stroke study (SSaSS) was an open-label cluster-randomised trial in rural China designed to evaluate the effect of salt substitution on mortality and cardiovascular events. Participants included adults with a history of prior stroke and those aged ≥60 years with uncontrolled high blood pressure (BP). Villages were randomly assigned in a 1:1 ratio either to intervention with salt substitute (75% sodium chloride and 25% potassium chloride by mass) or to control with continued use of regular salt (100% sodium chloride). In this pre-specified analysis, between-group differences in headache frequency and severity were evaluated. The study was registered with ClinicalTrials.gov (identifier number: NCT02092090). RESULTS: A total of 20,995 participants were included in the trial (mean age 64.3 years, 51% female, mean follow-up 4.7 years). At final follow-up at the end of the study, headache outcome data including frequency and severity of headaches was available for 16,486 (98%) of 16,823 living participants. Overall, 4454/16,486 (27%) individuals reported having headache: 27.4% in the intervention group (2301/8386) vs 26.6% in the control group (2153/8100) (RR 1.04, 95% CI: 0.93, 1.16, p = 0.48). There was no difference in headache severity between intervention and control groups (p = 0.90). CONCLUSION: Long term salt substitution did not reduce the frequency or severity of headaches in this population.

The Efficacy and Safety of Reduced-Dose Oral Methylprednisolone in High-Risk Immunoglobulin A Nephropathy.

Introduction: The therapeutic effects of steroids in immunoglobulin A nephropathy (IgAN) global (TESTING) study reported that methylprednisolone reduces the risk of major kidney events in individuals with IgAN at high risk of disease progression compared to supportive care alone but is associated with increased serious adverse events (SAEs) primarily with full-dose therapy. The risk benefit balance of the reduced-dose methylprednisolone regimen is examined in this prespecified analysis of the reduced-dose cohort of the TESTING trial. Methods: Between 2017 and 2019, patients with IgAN, proteinuria ≥1 g/d despite 3 months of renin-angiotensin-system blockade and estimated glomerular filtration rate (eGFR) 30 to 120 ml/min per 1.73 m2 were randomized to reduced-dose methylprednisolone 0.4 mg/kg/d or placebo. The primary outcome was a composite of a 40% eGFR decline, kidney failure, or death due to kidney disease. Results: A total of 241 participants were randomized and followed-up with for a median of 2.5 years (mean age: 37 years; baseline eGFR: 65 ml/min per 1.73 m2; proteinuria: 2.48 g/d). Methylprednisolone was associated with fewer primary outcome events compared to placebo (7/121 vs. 22/120; hazard ratio [HR]: 0.24; 95% confidence interval [CI]: 0.10-0.58, P = 0.002), lowered proteinuria, and reduced eGFR rate of decline from baseline. The mean difference between methylprednisolone and placebo in proteinuria and eGFR from baseline was -1.15 g/d and 7.9 ml/min per 1.73 m2 (P < 0.001) at 12 months, respectively; however, these benefits were lost over time. There were 7 versus 3 SAEs in the methylprednisolone versus placebo group (HR: 1.97; 95% CI: 0.49-7.90), including 5 versus 2 infections. Conclusion: Reduced-dose methylprednisolone is effective in improving kidney outcomes in high risk IgAN; however, it is associated with a modestly higher number of SAEs compared to placebo.

Fludrocortisone dose-response relationship in septic shock: a randomised phase II trial.

BACKGROUND: The combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear. METHODS: In a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption. RESULTS: Out of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156-334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5-4.5), 3 (2-4), 3 (2-6) and 3 (2-5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes. CONCLUSIONS: Enteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution.

Integrating Pharmacy and Registry Data Strengthens Clinical Assessments of Patient Adherence.

Background: Accurate clinical assessment of patient adherence using reliable and valid measures is essential in establishing the presence of adherence issues and support practices for pharmacists. Objective: This investigation aims to conduct a novel assessment of patient adherence to asthma controller therapy by combining 1) patient-specific dosage data found in pharmacy dispensing data with 2) centrally collected administrative claims records, to determine the added value of using both sources of data. Methods: A total of 381 clinically uncontrolled asthma patients, from 95 community pharmacies across three Australian States were recruited and provided consent for the retrieval of their claims records and pharmacy dispensing data. Patients were stratified as multiple or single pharmacy users and adherence scores were calculated via the proportion of days covered (PDC) method using 1) patient claims records, 2) patient pharmacy dispensing data, and 3) combined claims records and pharmacy dispensing data. Cohort and subgroup adherence estimates were then compared. Results: Low levels of adherence were evident amongst the cohort irrespective of the data source used. PDC estimates based on claims records alone or combined claims records and pharmacy dispensing data were significantly higher than estimates based on pharmacy dispensing data for the total cohort (56%, 52%, 42% respectively, p < 0.001) and more noticeably for multiple pharmacy users (67%, 64%, 35% respectively, p < 0.001). PDC estimates based on combined claims records and pharmacy dispensing data were significantly lower than estimates based on claims records alone, indicating that perhaps standard daily dose is not a robust proxy for prescribed dosage to inhaled respiratory devices in adherence approximations. Poorer adherence was found amongst single pharmacy users than multiple pharmacy users when combined claims records and pharmacy dispensing data (46% compared to 64% respectively, p < 0.001) or claims records alone (51% compared to 67% respectively, p < 0.001) were compared. Conclusion: Access to routine collected data increases clinical acuity over patient adherence to asthma controller medications and is a valuable resource for health care professionals. A policy of secure accessibility of such data at the patient-pharmacist or patient-GP interface may allow real-time intervention and assist in decision making across numerous therapeutic areas.

Rethinking the gold standard - The feasibility of randomized controlled trials within health services effectiveness research.

BACKGROUND: An evidence-based randomized controlled trial for a novel Pharmacy Asthma Service was tested in 3 Australian states. Positive asthma outcomes were achieved after the 12-month intervention, albeit in both the intervention and comparator arms. The current investigation uses a mixed methods approach to 1) qualitatively explore how comparator arm pharmacists implemented the trial protocol and 2) quantitatively examine how this may have impacted patient outcomes in this trial. METHODS: Post-intervention semi-structured qualitative interviews were conducted with 20 pharmacists, representing 21 of 37 (57%) comparator arm pharmacies that completed the trial. Based on these interviews, pharmacies were classified as 'adherent' to the trial protocol (reporting no interventions other than general practitioner referral) or 'non-adherent' (reporting at least one extra intervention to the trial protocol), or 'inconclusive'. These subgroups were compared descriptively in relation to patient outcomes. RESULTS: Overall, 33% (n = 8/24) of the comparator pharmacies who were interviewed (n = 21) or determined to have monitoring by a project officer to ensure adherence to the protocol (n = 3) were classified as adherent), 58% (n = 14/24) as non-adherent, 8% inconclusive (n = 2/24). While all patients commenced with uncontrolled asthma (Asthma Control Questionnaire score (ACQ) > 1.5), after 12 months the mean ACQ score for patients from adherent comparator pharmacies ('true control') was 1.8 (still uncontrolled asthma) compared to a score of 1.4 (controlled asthma) in the non-adherent comparator group. Quality of life significantly improved in the non-adherent comparator group over the 12 months of the trial. CONCLUSION: The majority of pharmacists in the comparator arm who were interviewed, introduced their own interventions, which may have influenced the outcomes of the trial. The naturalistic setting of the study was not protective against these confounders. These findings question the feasibility of comparator arms within primary care settings and that alternative study designs should be considered when designing future intervention studies in pharmacy practice.

A Targeted Approach to Improve Asthma Control Using Community Pharmacists.

Background: Building on lessons learnt from evidence-based community pharmacy asthma management models, a streamlined and technology supported Pharmacy Asthma Service (PAS) was developed to promote the integration of the service into routine practice. Objective: This study investigates the efficacy of the PAS in improving asthma symptom control and other health outcomes. Methods: A two-arm pragmatic cluster randomized controlled trial was implemented in 95 pharmacies across three Australian States. Participants were adults with poorly controlled asthma as per the Asthma Control Questionnaire (ACQ), with or without allergic rhinitis. Patients within the PAS arm engaged in four consultations with the pharmacist over a 12-month period. An evidence-based algorithm guided pharmacies, via a trial specific software, to deliver a series of interventions targeting three issues underpinning uncontrolled asthma (medication use and adherence, inhaler technique, and allergic rhinitis management) to patient clinical asthma status and patient need. Comparator arm patients received a minimal intervention likened to usual practice involving referral of eligible patients to the GP and two follow-up consultations with their pharmacist to collect comparative data. Results: In total, 143 of 221 PAS patients (65%) and 111 of 160 comparator patients (69%) completed the trial. Improvements in asthma control were achieved in both the PAS (mean difference (MD) in ACQ from baseline = -1.10, p <.0001) and comparator (MD in ACQ from baseline = -0.94, p <.0001) arms at the trial end; however, there were no significant differences between the two arms (MD = -0.16, 95% CI -0.41 to 0.08, p = 0.19). Patients' quality of life in the PAS arm improved significantly when compared with the comparator arm (MD in Impact of Asthma on Quality-of-Life Questionnaire (IAQLQ) = -0.52, 95% CI -0.89 to -0.14, p = 0.0079). Conclusion: Despite the PAS achieving a greater improvement in patients' quality of life, the pharmacist-led service and usual practice arm produced comparable improvements in asthma control. These results ask us to reflect on current standards of usual care, as it appears the standard of asthma care in usual practice has evolved beyond what is reported in the literature.