Ximena Camacho

Summary: Background: We used sequential target trial emulation (TTE) to examine associations between opioid analgesic initiation and adverse maternal and neonatal outcomes while accounting for gestational timing, time at risk, and potential confounding. Methods: Using the Early Life Course platform, comprising linked population-based data for births in New South Wales, Australia (2013–2019), we emulated a new trial at each gestational week, comparing women who initiated a prescribed opioid analgesic with eligible non-initiators. Baseline covariates were balanced using inverse probability weighting. Weighted logistic regression estimated odds ratios (ORs) for neonatal outcomes, postpartum haemorrhage, and severe maternal morbidity. Pooled logistic regression estimated hazard ratios (HRs) for other maternal outcomes, combined across gestational weeks using fixed-effects meta-analysis. Sensitivity analyses assessed unmeasured confounding, exposure misclassification, and potential reverse causation. Findings: Among 511,357 pregnancies, over 80% of opioid initiators received only one dispensing. Opioid initiation was not associated with increased risks of placental abruption (HR 0.94, 95% CI 0.75–1.16), severe maternal morbidity (OR 1.05, 0.97–1.11), postpartum haemorrhage (OR 0.98, 0.95–1.02), low Apgar score (OR 0.99, 0.87–1.08), small for gestational age (OR 0.90, 0.85–0.95), or neonatal abstinence syndrome (OR 0.98, 0.72–1.30). Risks were elevated for PPROM (HR 1.10, 0.98–1.23), preterm birth (HR 1.26, 1.19–1.33), severe neonatal morbidity (OR 1.08, 1.02–1.17), and perinatal death (OR 1.29, 1.10–1.52). Perinatal death estimates attenuated in analyses addressing potential reverse causation. Interpretation: Using a TTE approach that accounted for gestational timing and time at risk, we found no appreciable increase in most maternal or neonatal outcomes following predominantly short-term opioid initiation. Elevated risks of preterm birth, perinatal death, and third-trimester PPROM may reflect causal effects or confounding by pregnancy-related indications. Studies using time-appropriate designs and detailed information on prescribing indications and their timing are needed to clarify these associations. Research in Context: Evidence before this study: We searched the electronic databases MEDLINE (PubMed) for published articles, without language restrictions, from 1 January 2000 until 9 September 2026. The search strategy included terms for exposure (e.g. analgesic opioids), population (e.g. pregnancy and neonatal) and maternal and neonatal outcomes (e.g. preterm birth). Our search identified 10 observational studies which examined maternal and neonatal outcomes following opioid analgesic exposure during pregnancy. In these studies, prenatal opioid exposure above certain levels was consistently associated with neonatal abstinence syndrome (NAS). Beyond NAS, findings were inconsistent: some studies reported increased risks of peripartum haemorrhage, stillbirth, small for gestational age, low Apgar scores, preterm birth, and placental abruption, whereas others found no increased risk. It remains unclear whether observed associations are causal or reflect residual confounding. Methodological limitations may also have obscured associations, including immortal time bias when treatment initiation and follow-up were not aligned, and analyses that did not adequately account for gestational timing and therefore may have missed periods of greater susceptibility. As opioid analgesics are among the few options for managing pain during pregnancy, high-quality evidence on their safety is essential for informed clinical decision-making. Added value of this study: This study applied a sequential target trial emulation framework to estimate the effects of opioid analgesic initiation during pregnancy across a broad range of maternal and neonatal outcomes, aligning eligibility, treatment initiation, and follow-up while accounting for gestational timing. Opioid initiation was not associated with appreciably increased risks of most outcomes, including placental abruption, postpartum haemorrhage, severe maternal morbidity, and low Apgar scores. A small increase was observed for severe neonatal morbidity. Relative risks increased across trimesters for preterm birth, while PPROM and perinatal death were most elevated following third-trimester initiation. These findings may reflect opioid effects, although evolving pregnancy complications that both prompt opioid treatment and independently increase outcome risk remain a plausible explanation. NAS risk was not increased overall, although estimates were higher for oxycodone and higher oral morphine equivalent (OME) exposure. Implications of all available evidence: Taken together with broader evidence showing no substantial increase in the risk of major congenital malformations or adverse neurodevelopmental outcomes, these findings are generally reassuring for short-term opioid analgesic use in pregnancy, particularly codeine. The observed signals for preterm birth, PPROM and perinatal death, should not, in isolation, deter clinically indicated use, but support existing guidance to use opioids at the lowest effective dose for the shortest necessary duration and highlight the need for further studies that can distinguish direct opioid effects from shared clinical pathways.

Background: Stroke mortality rates have declined in recent decades; however, data on contemporary drivers of this trend are limited. This study compared the contribution of trends in stroke event rates and 30-day case fatality to declines in stroke mortality from 2002 to 2018. Methods: Linked hospitalization and mortality data were obtained from Western Australia (WA), England, New Zealand, British Columbia (BC), and Ontario. Age-standardized and age-specific stroke mortality and event rates and 30-day case fatality were calculated and age-adjusted trends estimated from Poisson and binomial regression models. The relative contribution of trends in stroke events and 30-day case fatality to trends in stroke mortality were calculated. Results: There were 2 248 242 stroke events identified. Age-adjusted reductions in event rates ranged from −0.96%/year [95% confidence interval (CI) − 1.22, 0.70%] in men in WA to −2.51%/year (95% CI −2.61, −2.40%) in women in Ontario. Age-standardized 30-day case fatality was highest in England in 2002 (men 43.7%, women 45.5%), but declined at a greater rate than in other jurisdictions. Declines in stroke mortality ranged from −3.3%/year to −5.5%/year. Reductions in 30-day case fatality were the major contributor to declines in stroke mortality [range: men, 63.5% (Ontario)–80.9% (England); women, 55.3% (BC)–73.1% (England)]. In people aged <65 years, stroke mortality declines were almost completely driven by reductions in 30-day case fatality with increasing or attenuated event rates among those aged 35–64 years. Conclusion: Improvements in 30-day case fatality had a greater impact on stroke mortality than trends in event rates, suggesting that further gains could be achieved with targeted prevention. Adverse trends in event rates in people aged <65 years could signal future increases in stroke mortality.

Background: Clinical trials comparing sustained-release (SR) tapentadol with controlled-release (CR) oxycodone have suggested that tapentadol (SR) may be associated with fewer nervous system side effects. However, it remains important to evaluate the relative safety of these agents in real-world clinical settings. Given the potential severity and economic burden of falls, together with their established association with opioid use, we compared the short-term risk of falls following initiation of tapentadol (SR) versus oxycodone (CR) in routine clinical practice. Methods and findings: We conducted an active comparator, new user retrospective cohort study using linked routinely collected health data on residents of New South Wales, Australia (2014–2020). We included people aged ≥18 years initiating publicly subsidised tapentadol (SR) or oxycodone (CR). Our outcome was a composite measure of fall-related emergency department presentations, hospitalisations or deaths. We used propensity score matching to adjust for baseline confounding and approximated relative risks (RR) of falls at 7, 14, and 28 days after initiation using conditional logistic regression models. We calculated absolute risk differences and estimated the number of people that would need to be treated with oxycodone (CR) versus tapentadol (SR) for one additional fall to occur (NNTH). We conducted subgroup analyses restricted to people aged ≥65 and ≥80 years and by recent opioid exposure (within 90 days prior to initiation). We identified 103,924 tapentadol (SR) and 419,732 oxycodone (CR) initiators; after matching each cohort comprised 103,758 initiators. Most people (74%) were aged between 45 and 84 years, and slightly more than half were female. Within 28 days of initiation, 652 (0.6%) oxycodone (CR) initiators and 457 (0.4%) tapentadol initiators experienced a fall. Across all time points, tapentadol (SR) initiation was associated with a lower risk of falls compared with oxycodone (CR) (7 days: RR 0.57 [95% CI: 0.48, 0.69]; 14 days: RR 0.62 [95% CI: 0.54, 0.71]; 28 days: RR 0.70 [95% CI: 0.62, 0.79]). Absolute differences were small at all time points (approximately 1–2 fewer falls per 1,000 patients treated), corresponding to NNTH for one additional fall ranging from 739 to 529. These patterns persisted regardless of recent opioid exposure. Relative risks were similar in the older age groups while absolute differences were slightly larger (≥65 years: 2–3 fewer falls/1,000; ≥80 years: 4–8 fewer falls/1,000). The greatest absolute differences were among opioid-naïve people aged ≥80 years (6–10 fewer falls/1,000, corresponding to NNTH ranging from 173 to 97). Fall risks were attenuated among people aged ≥80 years with recent opioid exposure. The main limitations of this study were that we did not have data on immediate-release tapentadol, or on falls that did not result in emergency department presentations or hospitalisations but may have otherwise impacted independence and mobility. Conclusions: Tapentadol (SR) was associated with a lower risk of falls than oxycodone (CR) up to four weeks after initiation, although absolute differences were small. The reduction in risk may be an important consideration in older patients where the consequences of falls are most severe.

Objective Given the potential severity and economic burden of falls, we compared the short-term risk of falls following initiation of sustained-release (SR) tapentadol versus controlled-release (CR) oxycodone in real-world clinical practice. Design Active comparator, new user retrospective cohort study using routinely collected health data from 2014 to 2020. Setting New South Wales, Australia. Participants People aged ≥18 years initiating publicly subsidised tapentadol (SR) or oxycodone (CR). Interventions Initiation of tapentadol (SR) or oxycodone (CR). Main outcome measures Composite measure of fall-related emergency department presentations, hospitalisations or deaths. We used propensity score matching to adjust for baseline confounding and approximated relative risks (RR) of falls at 7, 14, and 28 days after initiation using conditional logistic regression models. We calculated absolute risk differences and estimated the number of people that would need to be treated with oxycodone (CR) vs tapentadol (SR) for one additional fall to occur (NNTH). We conducted subgroup analyses restricted to people aged ≥65 and ≥80 years and by recent opioid exposure (within 90 days prior to initiation). Results We identified 103,924 tapentadol (SR) and 419,732 oxycodone (CR) initiators; after matching each cohort comprised 103,758 initiators. Most people (74%) were aged between 45-84 years, and slightly more than half were female. Within 28 days of initiation, 652 (0.6%) oxycodone (CR) initiators and 457 (0.4%) tapentadol initiators suffered a fall. Across all time points, tapentadol (SR) initiation was associated with a lower risk of falls compared with oxycodone (CR) (7 days: RR 0.57 [95% CI 0.48 to 0.69]; 14 days: 0.62 [0.54 to 0.71]; 28 days: 0.70 [0.62 to 0.79]). Absolute differences were small at all time points (approximately 1-2 fewer falls per 1,000 patients treated), corresponding to NNTH for one additional fall ranging from 739 to 529. These patterns persisted regardless of recent opioid exposure. Relative risks were similar in the older age groups while absolute differences were slightly larger (≥65 years: 2-3 fewer falls/1,000; ≥80 years: 4-8 fewer falls/1,000). The greatest absolute differences were among opioid-naïve people aged ≥80 years (6-10 fewer falls/1,000, corresponding to NNTH ranging from 173 to 97). Fall risks were attenuated among people aged ≥80 years with recent opioid exposure. Conclusions Tapentadol (SR) was associated with a lower risk of falls than oxycodone (CR) up to four weeks after initiation, although absolute differences were small. The reduction in risk may be an important consideration in older patients where the consequences of falls are most severe.

Background: The Medicines Intelligence (MedIntel) Data Platform is an anonymised linked data resource designed to generate real‐world evidence on prescribed medicine use, effectiveness, safety, costs and cost‐effectiveness in Australia.Results: The platform comprises Medicare‐eligible people who are ≥18 years and residing in New South Wales (NSW), Australia, any time during 2005–2020, with linked administrative data on dispensed prescription medicines (Pharmaceutical Benefits Scheme), health service use (Medicare Benefits Schedule), emergency department visits (NSW Emergency Department Data Collection), hospitalisations (NSW Admitted Patient Data Collection) plus death (National Death Index) and cancer registrations (NSW Cancer Registry). Data are currently available to 2022, with approval to update the cohort and data collections annually. The platform includes 7.4 million unique people across all years, covering 36.9% of the Australian adult population; the overall population increased from 4.8 M in 2005 to 6.0 M in 2020. As of 1 January 2019 (the last pre‐pandemic year), the cohort had a mean age of 48.7 years (51.1% female), with most people (4.4 M, 74.7%) residing in a major city. In 2019, 4.4 M people (73.3%) were dispensed a medicine, 1.2 M (20.5%) were hospitalised, 5.3 M (89.4%) had a GP or specialist appointment, and 54 003 people died. Anti‐infectives were the most prevalent medicines dispensed to the cohort in 2019 (43.1%), followed by nervous system (32.2%) and cardiovascular system medicines (30.2%).Conclusion: The MedIntel Data Platform creates opportunities for national and international research collaborations and enables us to address contemporary clinically‐ and policy‐relevant research questions about quality use of medicines and health outcomes in Australia and globally.

Aims: The aim of this work is to describe opioid initiation and long‐term use after emergency department (ED) visits or hospitalizations in New South Wales, Australia, by patient, admission and clinical characteristics.Methods: This is a population‐based cohort study, including all hospitalizations and ED visits between 2014 and 2020, linked to medicine dispensings, deaths and cancer registrations (Medicines Intelligence Data Platform), among adults with no opioid dispensings in the previous year. Outcome measures were opioid initiations (dispensed within 7 days of discharge) and long‐term use (90 days of continuous exposure, 90–270 days after initiation).Results: The cohort included 16 153 096 admissions by 4.2 million opioid‐naïve adults; 39.0% were ED presentations without hospital admission, 16.8% hospital admissions via ED and 44.2% direct hospital admissions. Opioids were initiated post‐discharge for 6.2% of ED, 8.3% of hospital via ED and 10.0% of direct hospital admissions; of these 1.0%, 2.5% and 0.5% progressed to long‐term opioid use, respectively. Initiation was lowest in obstetric admissions without surgery (1.0%), and highest among trauma admissions (25.4%), obstetric admissions with surgical intervention (19.8%) and non‐trauma surgical admissions (12.0%). Long‐term use was highest among medical admissions via ED (3.5%), trauma admissions (2.3%) and ED alone (1.0%). From 2014 to 2020, overall opioid initiations decreased 16% from 8.7% to 7.2%, and long‐term opioid use decreased 33% from 1.3% to 0.8%.Conclusions: Both opioid initiation and long‐term use decreased over time; however, the higher rates of long‐term use following trauma, and medical admissions via ED, warrant further surveillance. Strategies supporting appropriate prescribing and access to multidisciplinary pain services will facilitate best practice care.

The Medicines Intelligence (MedIntel) Data Platform is an anonymised linked data resource designed to generate real-world evidence on prescribed medicine use, safety, costs and cost-effectiveness in Australia. The platform comprises Medicare-eligible people who are ≥18 years and residing in New South Wales (NSW), Australia, any time during 2005-2020, with linked data on dispensed prescription medicines (Pharmaceutical Benefits Scheme), health service use (Medicare Benefits Schedule), emergency department visits (NSW Emergency Department Data Collection), hospitalisations (NSW Admitted Patient Data Collection), cancer notifications (NSW Cancer Registry), fact and cause of death (National Death Index). Data are currently available to 2022, with approval to update the cohort and data collections annually. The platform includes 7.4 million unique people across all years, covering 36.9% of the Australian adult population; the overall population increased from 4.8M in 2005 to 6.0M in 2020. As of 1 January 2019 (the last pre-pandemic year), the cohort had a mean age of 48.7 years (51.1% female), with most people (4.4M, 74.7%) residing in a major city. In 2019, 4.4M people (73.3%) were dispensed a medicine, 1.2M (20.5%) were hospitalised, 5.3M (89.4%) had a GP or specialist appointment, and 54 003 people died. Anti-infectives were the most prevalent medicines dispensed to the cohort in 2019 (43.1%), followed by nervous system (32.2%) and cardiovascular system medicines (30.2%). The MedIntel Data Platform creates opportunities for national and international research collaborations and enables us to address contemporary clinically- and policy-relevant research questions about quality use of medicines and health outcomes in Australia and globally. Five Key Points: The Medicines Intelligence (MedIntel) Data Platform is a purpose-built, real-world data resource designed to generate evidence on prescribed medicine use, safety, costs and cost-effectiveness in Australia This is a whole of population anonymised linkage of medicine and health records of Medicare-eligible adults (≥18 years) residing in Australia’s most populous state, New South Wales, from 2005 onwards The platform comprised 7.4M unique people across all years, representing 36.9% of the Australian adult population; the population increased from 4.8M in 2005 to 6.0M in 2020 As of 1 January 2019 (the last pre-pandemic year), the cohort had a mean age of 48.7 years (51.1% female), with most people (4.4M, 74.7%) residing in a major city The MedIntel Data Platform creates unique research opportunities for national and international research collaborations exploring population-level medicine use and outcomes Plain Language Summary: The Medicines Intelligence (MedIntel) Data Platform is a new linked data resource established to generate evidence on prescribed medicine use, safety, costs, and cost-effectiveness in Australia. It adheres to best practice privacy principles, with no identifying information available to researchers. The platform comprises Medicare-eligible people who are ≥18 years and residing in New South Wales (NSW), Australia, any time during 2005-2020, with linked data on dispensed prescription medicines, Medicare services, emergency department visits, hospitalisations, cancer notifications, and deaths. In total, the platform includes 7.4 million unique people across all years, covering 36.9% of the Australian adult population. As of 1 January 2019 (the last pre-pandemic year), the cohort had a mean age of 48.7 years (51.1% female), with most people (4.4M, 74.7%) residing in a major city. In 2019, 4.4M people (73.3%) were dispensed a medicine (most commonly anti-infective, nervous system, and cardiovascular medicines), 1.2M (20.5%) were hospitalised, 5.3M (89.4%) had a GP or specialist appointment, and 54 003 people died. Data are available until 2022 with approval for annual updates. This platform creates opportunities for national and international research collaborations and enables us to address important questions about quality use of medicines and health outcomes.

Aims: Oxycodone is the most commonly prescribed strong opioid in Australia. This study describes health service antecedents and sociodemographic factors associated with oxycodone initiation.Methods: Population‐based new user cohort study linking medicine dispensings, hospitalizations, emergency department visits, medical services and cancer notifications from New South Wales (NSW) for 2014–2018. New users had no dispensings of any opioid in the preceding year. We analysed health service use in the 5 days preceding initiation and proportion of people on treatment over 1 year and fitted an area‐based, multivariable initiation model with sociodemographic covariates.Results: Oxycodone accounted for 30% of opioid initiations. Annually, 3% of the NSW population initiated oxycodone, and 5–6% were prevalent users; the new user cohort comprised 830 963 people. Discharge from hospital (39.3%), therapeutic procedures (21.4%) and emergency department visits (19.7%) were common; a hospital admission for injury (6.0%) or a past‐year history of cancer (7.2%) were less common. At 1 year after initiation, 4.6% of people were using oxycodone. In the multivariable model, new use of oxycodone increased with age and was higher for people outside major cities, for example, an incidence rate ratio of 1.43 (95% confidence interval 1.36–1.51) for inner regional areas relative to major cities; there was no evidence of variation in rates of new use by social disadvantage.Conclusion: About half of new oxycodone use in NSW was preceded by a recent episode of hospital care or a therapeutic procedure. Higher rates of oxycodone initiation in rural and regional areas were not explained by sociodemographic factors.

Background: Sustained‐release (SR) tapentadol was listed on Australia's Pharmaceutical Benefits Scheme (PBS) in 2014 for chronic severe pain requiring long‐term opioid treatment. Dispensings have increased since listing despite declining trends in other PBS‐listed opioids. Preferential prescribing of SR opioids may increase the risk of dependence and accidental overdose, particularly when used to treat acute pain.Aims: To explore the quality use of publicly subsidised tapentadol in Australia.Methods: We examined annual initiation rates and patterns of use of tapentadol (SR) in the dispensing records of a 10% random sample of PBS‐eligible Australians (2014–2021). We used national tapentadol sales data to assess the proportion of sales attributable to the PBS.Results: Tapentadol initiation increased from 2014, peaking at 7.5/1000 adult population in 2019 before declining to 5.3/1000 in 2021. We identified 63 766 new users between 2014 and 2020, of whom 92.8% discontinued in the first year following initiation, 58.0% had only a single dispensing and 34.3% had no other opioids dispensed in the 3 months before or after initiation. 27.8% of new users were dispensed tapentadol on the same day as potentially interacting medicines. There was a sustained drop in the proportion of sales attributable to the PBS from June 2020 onwards, from an average of 69.1%, to 63.9% of pack sales.Conclusions: Patterns of use suggest tapentadol (SR) is generally used for short duration. Although most tapentadol sold in Australia is subsidised, there is evidence of a shift towards private sales.