Characterizing OPRM1 DNA methylation in prescription opioid users with chronic musculoskeletal pain.

Introduction: Many patients with chronic pain use prescription opioids. Epigenetic modification of the µ-opioid receptor 1 (OPRM1) gene, which codes for the target protein of opioids, may influence vulnerability to opioid abuse and response to opioid pharmacotherapy, potentially affecting pain outcomes. Objective: Our objective was to investigate associations of clinical and sociodemographic factors with OPRM1 DNA methylation in patients with chronic musculoskeletal pain on long-term prescription opioids. Methods: Sociodemographic variables, survey data (Rapid Estimate of Adult Health Literacy in Medicine-Short Form, Functional Comorbidity Index [FCI], PROMIS 43v2.1 Profile, Opioid Risk Tool, and PROMIS Prescription Pain Medication Misuse), and saliva samples were collected. The genomic DNA extracted from saliva samples were bisulfite converted, amplified by polymerase chain reaction, and processed for OPRM1-targeted DNA methylation analysis on a Pyrosequencing instrument (Qiagen Inc, Valencia, CA). General linear models were used to examine the relationships between the predictors and OPRM1 DNA methylation. Results: Data from 112 patients were analyzed. The best-fitted multivariable model indicated, compared with their counterparts, patients with > eighth grade reading level, degenerative disk disease, substance abuse comorbidity, and opioid use < 1 year (compared with >5 years), had average methylation levels that were 7.7% (95% confidence interval [CI] 0.95%, 14.4%), 11.7% (95% CI 2.7%, 21.1%), 21.7% (95% CI 10.7%, 32.5%), and 16.1% (95% CI 3.3%, 28.8%) higher than the reference groups, respectively. Methylation levels were 2.2% (95% CI 0.64%, 3.7%) lower for every 1 unit increase in FCI and greater by 0.45% (95% CI 0.08%, 0.82%) for every fatigue T score unit increase. Conclusions: OPRM1 methylation levels varied by several patient factors. Further studies are warranted to replicate these findings and determine potential clinical utility.

A randomized, cross-over trial of metoprolol succinate formulations to evaluate PK and PD end points for therapeutic equivalence.

There are limited comparison data throughout the dosing interval for generic versus brand metoprolol extended-release (ER) tablets. We compared the pharmacokinetics (PKs) and pharmacodynamics of brand name versus two generic formulations (drugs 1 and 2) of metoprolol ER tablets with different time to maximum concentration (Tmax ) in adults with hypertension. Participants were randomized to equal drug doses (50-150 mg/day) administered in one of two sequences (brand-drug1-brand-drug2 or brand-drug2-brand-drug1) and completed 24-h PK, digital heart rate (HR), ambulatory blood pressure (BP), and HR studies after taking each formulation for greater than or equal to 7 days. Metoprolol concentrations were determined by liquid chromatography tandem mass spectrometry, with noncompartmental analysis performed to obtain PK parameters in Phoenix WinNonlin. Heart rate variability (HRV) low-to-high frequency ratio was determined per quartile over the 24-h period. Thirty-six participants completed studies with the brand name and at least one generic product. Among 30 participants on the 50 mg dose, the primary PK end points of area under the concentration-time curve and Cmax were similar between products; Tmax was 6.1 ± 3.6 for the brand versus 3.5 ± 4.9 for drug 1 (p = 0.019) and 9.6 ± 3.2 for drug 2 (p < 0.001). Among all 36 participants, 24-h BPs and HRs were similar between products. Mean 24-h HRV low-to-high ratio was also similar for drug 1 (2.04 ± 1.35), drug 2 (1.86 ± 1.35), and brand (2.04 ± 1.77), but was more sustained over time for the brand versus drug 1 (drug × quartile interaction p = 0.017). Differences in Tmax between metoprolol ER products following repeated doses may have implications for drug effects on autonomic balance over the dosing interval.

The effect of EHR-integrated patient-reported outcomes on satisfaction with chronic pain care.

OBJECTIVES: Given its complexity, chronic noncancer pain presents an opportunity to use health information technology (IT) to improve care experiences. The objective of this study was to assess whether integrating patient-reported outcomes (PROs) data in an electronic health record (EHR) affects provider and patient satisfaction with chronic noncancer pain care. STUDY DESIGN: We conducted a pragmatic cluster randomized trial involving 4 family medicine clinics. METHODS: We enrolled primary care providers (PCPs) and their patients with chronic noncancer pain. In the first 7 months (education phase), PCPs in intervention practices received education on how to use PROs for pain care. In the second 7 months (PRO phase), patients in intervention practices reported pain-related outcomes on arrival at their visits. PROs were immediately reported to PCPs through the EHR. Control group PCPs provided usual care. We compared intervention and control practices in terms of provider and patient satisfaction with care. RESULTS: During the education phase, patients' mean ratings of their visits did not differ between control and intervention (9.33 vs 9.08; P = .20). During the PRO phase, patients' mean ratings did not differ between control and intervention (9.28 vs 9.01; P = .20). Similarly, there were no differences between the intervention and control groups in terms of provider satisfaction. CONCLUSIONS: Delivering EHR-integrated PROs did not consistently improve patient or provider satisfaction. Positively, we found no evidence that the PRO tools negatively affected satisfaction. Future studies and technological innovations are needed to translate point-of-care health IT tools into improvements in patient and provider experiences.

Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to ß-Blockers in Hypertensive African Americans.

African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to ß-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10(-8) and suggestive variants with P<5×10(-7) were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: -9.3 versus -4.6, -9.6 versus -4.8, and -9.7 versus -6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10(-8), ß=-4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to ß-blocker therapy with 3-group meta-analysis P=7.2×10(-8) and ß=-3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to ß-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

PTPRD gene associated with blood pressure response to atenolol and resistant hypertension.

OBJECTIVE: The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the ß-blocker atenolol. METHODS: Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114). RESULTS: In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10 and P = 5.9 × 10, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 × 10). rs12346562 had a similar trend in association with response to bisoprolol (a different ß-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10). CONCLUSION: PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.

Predictors for glucose change in hypertensive participants following short-term treatment with atenolol or hydrochlorothiazide.

STUDY OBJECTIVE: To develop and validate a predictive model for glucose change and risk for new-onset impaired fasting glucose in hypertensive participants following treatment with atenolol or hydrochlorothiazide (HCTZ). DESIGN: Randomized multicenter clinical trial. PATIENTS: A total of 735 white or African-American men and women with uncomplicated hypertension. MEASUREMENTS AND MAIN RESULTS: Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) is a randomized clinical trial to assess the genetic and nongenetic predictors of blood pressure response and adverse metabolic effects following treatment with atenolol or HCTZ. To develop and validate predictive models for glucose change, PEAR participants were randomly divided into a derivation cohort of 367 and a validation cohort of 368. Linear and logistic regression modeling were used to build models of drug-associated glucose change and impaired fasting glucose (IFG), respectively, in the derivation cohorts. These models were then evaluated in the validation cohorts. For glucose change after atenolol or HCTZ treatment, baseline glucose was a significant (p<0.0001) predictor, explaining 13% of the variability in glucose change after atenolol and 12% of the variability in glucose change after HCTZ. Baseline glucose was also the strongest and most consistent predictor (p<0.0001) for development of IFG after atenolol or HCTZ monotherapy. The area under the receiver operating curve was 0.77 for IFG after atenolol and 0.71 after HCTZ treatment, respectively. CONCLUSION: Baseline glucose is the primary predictor of atenolol or HCTZ-associated glucose increase and development of IFG after treatment with either drug.

Atenolol exposure and risk for development of adverse metabolic effects: a pilot study.

STUDY OBJECTIVE: To evaluate whether the level of systemic exposure to atenolol explains observed interindividual differences in adverse metabolic responses. DESIGN: Open-label, prospective, pharmacokinetic pilot substudy of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. SETTING: General clinical research center. PATIENTS: Fifteen hypertensive adults (mean age 46 +/- 8.9 yrs) who were enrolled in the PEAR study. INTERVENTION: Patients received atenolol therapy for at least 8 weeks, with 5 of those weeks at a dosage of 100 mg/day, and then underwent a 2-hour oral glucose tolerance test during a pharmacokinetic study visit. MEASUREMENTS AND MAIN RESULTS: Twenty-hour plasma atenolol concentrations were measured during the pharmacokinetic visit. Glucose and insulin levels were measured during the 2-hour oral glucose tolerance test, and fasting plasma lipid, glucose, and insulin levels were measured at baseline and after 8 weeks of atenolol treatment. A significant association was noted between atenolol area under the concentration-time curve (AUC) and change in fasting glucose level when adjusted for covariates (p=0.0025); the effect was strongest in women. No significant relationship was noted between plasma atenolol concentration and glucose AUC during oral glucose tolerance testing (r=0.08, p=0.78), nor between atenolol AUC and change in triglyceride levels (r=0.13, p=0.63). CONCLUSION: Higher plasma atenolol exposure may be a risk factor for an increase in fasting plasma glucose level during atenolol treatment. These findings require confirmation in a larger sample.

Evaluation of a quality improvement intervention for diabetes management.

The purpose of this study was to develop and test two interventions designed to improve provider compliance with diabetes management guidelines: the use of a diabetes management flowsheet inserted into patient charts and the use of a diabetes management flowsheet plus quarterly provider feedback about compliance levels. Diabetic patient charts from six family practice clinics were randomly selected and audited at baseline and at 12 months. The analysis indicated that the use of the flowsheet was associated with improved provider compliance in the completion of foot examinations only. Providers involved in the study believed that the process of the flowsheet plus feedback contributed to their greater awareness of diabetes management guidelines.