Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences

Analgesics which affect prostaglandin (PG) pathways are used by most pregnant women. As germ cells (GC) undergo developmental and epigenetic changes in fetal life and are PG targets, we investigated if exposure of pregnant rats to analgesics (indomethacin or acetaminophen) affected GC development and reproductive function in resulting offspring (F1) or in the F2 generation. Exposure to either analgesic reduced F1 fetal GC number in both sexes and altered the tempo of fetal GC development sex-dependently, with delayed meiotic entry in oogonia but accelerated GC differentiation in males. These effects persisted in adult F1 females as reduced ovarian and litter size, whereas F1 males recovered normal GC numbers and fertility by adulthood. F2 offspring deriving from an analgesic-exposed F1 parent also exhibited sex-specific changes. F2 males exhibited normal reproductive development whereas F2 females had smaller ovaries and reduced follicle numbers during puberty/adulthood; as similar changes were found for F2 offspring of analgesic-exposed F1 fathers or mothers, we interpret this as potentially indicating an analgesic-induced change to GC in F1. Assuming our results are translatable to humans, they raise concerns that analgesic use in pregnancy could potentially affect fertility of resulting daughters and grand-daughters.

Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial

Background: The phase 3 ALSYMPCA trial enrolled metastatic castration-resistant prostate cancer patients with or without baseline opioid use.

Objective: To assess the efficacy and safety of radium-223 dichloride (radium-223) versus placebo in ALSYMPCA patients by baseline opioid use.

Design, setting, and participants: Nine hundred and twenty one patients enrolled at 136 centers globally.

Intervention: Radium-223 (50 kBq/kg, intravenous injection) every 4 wk for six cycles or matching placebo, each plus best standard of care.

Outcome measurements and statistical analysis: Primary endpoint (overall survival [OS]), main secondary efficacy endpoints, and safety were evaluated by baseline opioid use. Additional analyses included time to first opioid use, time to first external beam radiation therapy for bone pain, and safety of concomitant external beam radiation therapy.

Results and limitations: At baseline, 408 (44%) patients had no pain and no analgesic use or mild pain with nonopioid therapy (World Health Organization ladder pain score 0–1 [nonopioid subgroup]), and 513 (56%) had moderate pain with occasional opioids or severe pain with regular daily opioids (World Health Organization ladder pain score 2–3 [opioid subgroup]). Radium-223 significantly prolonged OS versus placebo in nonopioid (hazard ratio [HR] = 0.70; 95% confidence interval [CI]: 0.52–0.93; p = 0.013) and opioid (HR = 0.68; 95% CI: 0.54–0.86; p = 0.001) subgroups, and significantly reduced risk of symptomatic skeletal events versus placebo, regardless of baseline opioid use (nonopioid subgroup: HR = 0.56, 95% CI: 0.39–0.82, p = 0.002; opioid subgroup: HR = 0.72, 95% CI: 0.53–0.98, p = 0.038). Time to first opioid use for bone pain was significantly delayed with radium-223 versus placebo (HR = 0.62, 95% CI: 0.46–0.85,p = 0.002). Adverse event incidences were similar between opioid subgroups.

Conclusions: Radium-223 versus placebo significantly prolonged OS and reduced symptomatic skeletal event risk with a favorable safety profile in castration-resistant prostate cancer patients with symptomatic bone metastases, regardless of baseline opioid use.

Patient summary: In this ALSYMPCA opioid subgroup analysis, baseline symptom levels did not appear to impact radium-223 dichloride efficacy or safety.

Polypharmacy and inappropriate medication use in patients with dementia: an underresearched problem

Multimorbidity and polypharmacy are increasingly prevalent across healthcare systems and settings as global demographic trends shift towards increased proportions of older people in populations. Numerous studies have demonstrated an association between polypharmacy and potentially inappropriate prescribing (PIP), and have reported high prevalence of PIP across settings of care in Europe and North America and, as a consequence, increased risk of adverse drug reactions, healthcare utilisation, morbidity and mortality. These studies have not focused specifically on people with dementia, despite the high risk of adverse drug reactions and PIP in this patient cohort. This narrative review considers the evidence currently available in the area, including studies examining prevalence of PIP in older people with dementia, how appropriateness of prescribing is assessed, the medications most commonly implicated, the clinical consequences, and research priorities to optimise prescribing for this vulnerable patient group. Although there has been considerable research effort to develop criteria to assess medication appropriateness in older people in recent years, the majority of tools do not focus on people with dementia. Of the limited number of tools available, most focus on the advanced stages of dementia in which life-expectancy is limited. The development of tools to assess medication appropriateness in people with mild-to-moderate dementia or across the full spectrum of disease severity represents an important gap in the research literature and is beginning to attract research interest, with recent studies considering the medication regimen as a whole, or misprescribing, overprescribing or underprescribing of certain medications/medication classes including anticholinergics, psychotropics, antibiotics and analgesics. Further work is required in development and validation of criteria to assess prescribing appropriateness in this vulnerable patient population, to determine prevalence of PIP in large cohorts of people with the full spectrum of dementia variants and severities and to examine the impact of PIP on health outcomes.