Life course socioeconomic position, alcohol drinking patterns in midlife, and cardiovascular mortality:Analysis of Norwegian population-based health surveys

<div><p>Background</p><p>Socioeconomically disadvantaged groups tend to experience more harm from the same level of exposure to alcohol as advantaged groups. Alcohol has multiple biological effects on the cardiovascular system, both potentially harmful and protective. We investigated whether the diverging relationships between alcohol drinking patterns and cardiovascular disease (CVD) mortality differed by life course socioeconomic position (SEP).</p><p>Methods and findings</p><p>From 3 cohorts (the Counties Studies, the Cohort of Norway, and the Age 40 Program, 1987–2003) containing data from population-based cardiovascular health surveys in Norway, we included participants with self-reported information on alcohol consumption frequency (<i>n</i> = 207,394) and binge drinking episodes (≥5 units per occasion, <i>n</i> = 32,616). We also used data from national registries obtained by linkage. Hazard ratio (HR) with 95% confidence intervals (CIs) for CVD mortality was estimated using Cox models, including alcohol, life course SEP, age, gender, smoking, physical activity, body mass index (BMI), systolic blood pressure, heart rate, triglycerides, diabetes, history of CVD, and family history of coronary heart disease (CHD). Analyses were performed in the overall sample and stratified by high, middle, and low strata of life course SEP. A total of 8,435 CVD deaths occurred during the mean 17 years of follow-up. Compared to infrequent consumption (p = 0.002; middle versus high), 1.23 (95% CI 0.96, 1.58, <i>p</i> = 0.10; low versus high), and 0.96 (95% CI 0.76, 1.21, <i>p</i> = 0.73; low versus middle). In the group with data on binge drinking, 2,284 deaths (15 years) from CVDs occurred. In comparison to consumers who did not binge during the past year, HRs among frequent bingers (≥1 time per week) were 1.58 (95% CI 1.31, 1.91) overall, and 1.22 (95% CI 0.84, 1.76), 1.71 (95% CI 1.31, 2.23), and 1.85 (95% CI 1.16, 2.94) in the strata, respectively. HRs for effect modification were 1.36 (95% CI 0.87, 2.13, <i>p</i> = 0.18; middle versus high), 1.63 (95% CI 0.92, 2.91, <i>p</i> = 0.10; low versus high), and 1.32 (95% CI 0.79, 2.20, <i>p</i> = 0.29; low versus middle). A limitation of this study was the use of a single measurement to reflect lifetime alcohol consumption.</p><p>Conclusions</p><p>Moderately frequent consumers had a lower risk of CVD mortality compared with infrequent consumers, and we observed that this association was more pronounced among participants with higher SEP throughout their life course. Frequent binge drinking was associated with a higher risk of CVD mortality, but it was more uncertain whether the risk differed by life course SEP. It is unclear if these findings reflect differential confounding of alcohol consumption with health-protective or damaging exposures, or differing effects of alcohol on health across socioeconomic groups.</p></div

Impact of liver fibrosis and clinical characteristics on dose-adjusted serum methadone concentrations

Background There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements. Objectives We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations. Methods We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016–2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis. Results When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5, the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: −2.16, 3.57; P: 0.631), even among those with advanced cirrhosis (−0.50; −4.59, 3.59; 0.810). Conclusions Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.publishedVersio

Dynamic assessment of the pupillary reflex in patients on high-dose opioids

Background and aims Pupil size and reaction are influenced by opioids, an effect that is not considered to be affected by opioid tolerance. As clinicians have observed patients on high-dose opioids who exhibited seemingly normal pupil sizes, we wanted to dynamically assess the pupillary reflex in cancer patients on high-dose opioids. Methods We performed a dynamic assessment of the pupillary reflex in cancer patients on high-dose opioids and a control group of healthy volunteers using a portable, monocular, infrared pupillometer. We also performed a clinical examination and measured blood concentrations of opioids and their active metabolites. Results Sixty three patients who were on opioids for 2 months (median time) and on an oral morphine equivalent dose of 250 mg (median dose) were investigated. Most patients used more than one opioid. When correcting for age, pupil size in the group that had received no increase of opioid dose over the last 14 days was not significantly different from pupil size in the healthy volunteer group (p = 0.76), while the group that had increased the dose of opioids differed significantly from healthy volunteers (p = 0.006). We found no statistically significant correlation between total oral morphine equivalents and pupillary reactions or between blood opioid or opioid metabolite concentrations and baseline pupillary changes. Conclusion Pupillary changes do take place in patients on opioids. However, tolerance to these changes occurs when medication is not increased over time. Dynamic pupillometry can give additional information about the degree of tolerance to opioids. Implications These findings elucidate previous misconceptions regarding pupillary effects and tolerance to opioids

Prenatal exposure to methadone or buprenorphine and long-term outcomes: A meta-analysis

Aim To combine meta-analyses of multiple long-term outcomes in children prenatally exposed to methadone or buprenorphine through their mothers' Opioid maintenance therapy (OMT) with a systematic review of similar outcomes in experimental animals. Method The Medline, Embase, Web of Science, CINAHL, Cochrane and Epistemonikos databases were searched through August 30, 2018. Clinical studies measuring effects on cognitive, behavioral or visual outcomes in 3 months or older children prenatally exposed to OMT and control group(s) were included for meta-analyses. Experimental animal studies with similar exposures and outcomes were included in a systematic review. The three authors independently performed abstract screenings and full-text reviews, and extracted the data. One author performed the meta-analyses. Results The pooled results of the meta-analyses showed worse cognitive, psychomotor, behavioral, attentional and executive functioning, and affected vision in children born to mothers who were in OMT during pregnancy compared to children without prenatal drug exposure (overall effect size = 0.49, 95% confidence interval = 0.38, 0.59, p < 0.00001). Many of the experimental animal studies showed impaired outcomes after prenatal exposure to methadone or buprenorphine. The clinical results may be biased, e.g., with the OMT group having more concurrent risk factors than the unexposed comparison group. There are few studies of older children. Conclusion Children born to mothers in OMT show worse outcomes for a number of different behaviors and impaired vision compared to children born to nonusers. Experimental animal studies indicate that there might be a causal relationship between prenatal methadone or buprenorphine exposure and subsequent negative outcomes

The relationship between ingested dose of ethanol and amount of ethyl glucuronide formed in blood

Abstract A positive non-linear relation between the dose of ethanol ingested and the area under the curve (AUC) for ethyl glucuronide (EtG) in urine is previously observed. The relation between both doses and AUC of ethanol and the AUC for EtG in blood is not previously published, and this study aimed to investigate this relationship. After an overnight fast, 10 healthy volunteers ingested 0.5-g ethanol per kilo body weight (low dose) in one occasion and 1.0-g ethanol per kilo body weight (high dose) in the next occasion. Results showed that there was a significant higher median ratio between blood AUC for EtG and dose of ethanol in the high-dose (8.99; range 7.37–10.94) group compared to the low-dose (5.02; range 4.25–6.15) group (P = 0.005). The median ratio between the AUC for EtG and AUC for ethanol was actually significantly higher in the low-dose (1.77; range 1.51–2.24) group compared to the high-dose (1.67; range 1.30–2.02) group (P = 0.005), although values are quite similar. This study therefore showed that the ratio between the AUC for EtG in blood and dose of ethanol is higher after intake of 1.0 g/kg than 0.5 g/kg. This pattern is however not seen when AUC for EtG is compared to AUC for ethanol. Results therefore support that the percentage of ethanol converted to EtG is not increasing when the doses increase. An explanation for the positive non-linear relation previously observed between the dose of ethanol ingested and amount of EtG formed may be a relative higher first-pass metabolism of ethanol at lower doses

Impact of CYP2D6 on serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol

Aims To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose‐adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose‐adjusted serum concentrations in the perphenazine‐treated patients. Methods Serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol from CYP‐genotyped patients were extracted retrospectively from a routine TDM database in the period March 2005 to May 2019. Samples were divided into three CYP2D6 phenotype subgroups according to genotype; normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The effect of CYP2D6 phenotype on dose‐adjusted serum concentrations of the four antipsychotics was evaluated by multivariable mixed model analyses. Results Mean dose‐adjusted serum concentrations of perphenazine (564 samples) were 3.9‐fold and 1.6‐fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .001 and P < .01). For zuclopenthixol (658 samples), mean dose‐adjusted serum concentrations were about 1.5‐fold and 1.3‐fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P < .01 and P < .001). CYP2D6 was of minor or no importance to haloperidol (320 samples) and flupentixol (115 samples). In our data material, the genotype CYP2D6 *1/*41 appears to have a similar impact on dose‐adjusted serum concentrations of perphenazine as *1/null (null = variant allele encoding no enzyme function). Conclusions This study shows that CYP2D6 is important for the metabolism of perphenazine and zuclopenthixol, but not for haloperidol and flupentixol. The CYP2D6*41 allele appears to have a reduced function close to nonfunctional variant alleles

Impact of age and CYP2D6 genotype on exposure of zuclopenthixol in patients using long-acting injectable versus oral formulation-an observational study including 2044 patients

Purpose Zuclopenthixol is an antipsychotic available as oral and long-acting injectable (LAI) formulations. The aim of this study was to investigate the effect of age on zuclopenthixol exposure during oral and LAI administrations without and with adjustment for CYP2D6 genotype. Methods Data on serum concentrations of zuclopenthixol and CYP2D6 genotype (available for 28.2% of the population) from patients using oral or LAI zuclopenthixol were included retrospectively from a therapeutic drug monitoring service during the period 2005–2019. As a measure of exposure, dose-adjusted serum concentration (C/D ratio) was used. Based on age, patients were grouped to older (≥ 65 years) or younger (18–64 years). Linear mixed model analyses without and with adjustment for CYP2D6 genotype were used. Results Serum concentrations of zuclopenthixol from 1145 (14.1% older) and 899 patients (24.6% older) in the LAI and oral groups were included, respectively. Compared with younger patients, older patients had a higher C/D ratio of zuclopenthixol for LAI (+ 25–33%, p < 0.001) and oral formulation (+ 25–29%, p ≤ 0.003) without and with adjustment for CYP2D6 genotype. The doses were lower in older versus younger patients (oral: − 30%; LAI: − 20%; p < 0.001). Compared with the younger LAI users without reduced CYP2D6 function, a higher C/D ratio was observed in the older LAI users with reduced CYP2D6 function (+ 104%, p < 0.001). Conclusion The present study showed that zuclopenthixol exposure increases in older patients and that the older LAI users with reduced CYP2D6 function are exposed to high serum concentrations. Also, the present study showed that similar dose reductions are required for oral and LAI users

Correlates of major medication side effects interfering with daily performance: results from a cross-sectional cohort study of older psychiatric patients

Background: Polypharmacy is common among older persons who are also vulnerable to side effects. We aimed to characterize patients who on admission to a geriatric psychiatric hospital had major medication side effects interfering with daily performance. Methods: Cross-sectional cohort study of patients consecutively admitted to a geriatric psychiatric hospital from 2006, 06 December to 2008, 24 October. The UKU side effect rating scale was performed, and patients were divided into those with no/minor side effects versus those with major side effects. Blood levels of 56 psychotropic drugs and 27 safety laboratory tests were measured upon admission. Results: Of 206 patients included in the analysis, 70 (34%) had major side effects related to drug treatment. The most frequent side effects were asthenia (31%), reduced salivation (31%), concentration difficulties (28%), memory impairment (24%), and orthostatic dizziness (18%). The significant characteristics predicting major side effects were female gender (OR = 2.4, 95% confidence interval (CI) = 1.1–5.5), main diagnosis of affective disorder (OR = 4.3, 95% CI = 1.5–12.3), unreported use of psychotropic medications (OR = 2.0, 95% CI = 1.0–4.1), a higher number of reported psychotropic medications (OR = 1.7, 95% CI = 1.2–2.3), a higher number of reported medications for somatic disorders (OR = 1.2, 95% CI = 1.1–1.5), and a higher score on the Charlson comorbidity index (OR = 1.2, 95% CI = 1.0–1.4) (r2 = 0.238, p < 0.001). Conclusions: Clinicians should be especially aware of side effects related to drug treatment in geriatric psychiatric female patients with a high use of psychotropic and other medications and somatic comorbidity. Unreported use of psychotropic medications was also related to the risk for side effects, and clinicians should make an effort to ascertain all medications taken by geriatric psychiatric patients