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Clinical annotations are one of the most popular resources available on the Pharmacogenomics Knowledgebase (PharmGKB). Each clinical annotation summarizes the association between variant-drug pairs, shows relevant findings from the curated literature, and is assigned a level of evidence (LOE) to indicate the strength of support for that association. Evidence from the pharmacogenomic literature is curated into PharmGKB as variant annotations, which can be used to create new clinical annotations or added to existing clinical annotations. This means that the same clinical annotation can be worked on by multiple curators over time. As more evidence is curated into PharmGKB, the task of maintaining consistency when assessing all the available evidence and assigning an LOE becomes increasingly difficult. To remedy this, a scoring system has been developed to automate LOE assignment to clinical annotations. Variant annotations are scored according to certain attributes, including study size, reported P value, and whether the variant annotation supports or fails to find an association. Clinical guidelines or US Food and Drug Administration (FDA)-approved drug labels which give variant-specific prescribing guidance are also scored. The scores of all annotations attached to a clinical annotation are summed together to give a total score for the clinical annotation, which is used to calculate an LOE. Overall, the system increases transparency, consistency, and reproducibility in LOE assignment to clinical annotations. In combination with increased standardization of how clinical annotations are written, use of this scoring system helps to ensure that PharmGKB clinical annotations continue to be a robust source of pharmacogenomic information., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: (1) To measure caregiver satisfaction with a nonstandardized postoperative pain regimen after pediatric tonsillectomy. (2) To implement a quality improvement project (QIP) to reduce the number and volume of narcotics prescribed and to describe the effect on caregiver satisfaction., Methods: A prospective cohort study at a tertiary children's hospital examined postoperative narcotics prescribed to children following adenotonsillectomy. A QIP was implemented 3 months into the observation, with the goal to standardize nonnarcotic analgesics and reduce the volume of narcotics prescribed. Caregivers were called 2 to 3 weeks postoperatively to assess pain control and caregiver satisfaction., Results: Over an 8-month period, 118 patients were recruited (66 before the QIP, 52 after induction). Prior to the QIP, 47% of patients were prescribed postoperative narcotics, as opposed to 27% after the QIP ( P < .05). There was a significant reduction in the volume of narcotics prescribed before (mean ± SD, 300 ± 150 mL) versus after (180 ± 111 mL) the initiative ( P < .05). The per-kilogram dose did not change over the study time frame. On a 5-point Likert scale, there was no difference in the caregivers' satisfaction regarding pain control before (4.37 ± 0.85) versus after (4.35 ± 1.0) the project started., Discussion: A system shift was identified with the establishment of a posttonsillectomy pain control protocol associated with a reduction in prescribed narcotics without a significant change in caregiver satisfaction., Implications for Practice: Implementing a standardized plan for the use of nonnarcotic medications was associated with reduced frequency and volume of narcotics prescribed. Future work will further standardize our postoperative pain regimen.

Objective: Opioid use disorder (OUD), which includes the morbidity of dependence and mortality of overdose, has reached epidemic proportions in the United States. Overprescription of opioids can lead to chronic use and misuse, and unused narcotics after surgery can lead to their diversion. Research supports that most patients do not take all the prescribed opioids after surgery and that surgeons are the second largest prescribers of opioids in the United States. The introduction of opioids in those with OUD often begins with prescription opioids. Reducing the number of extra opioids available after surgery through smaller prescriptions, safe storage, and disposal should reduce the risk of opioid use disorder in otolaryngology patients and their families., Purpose: The purpose of this specialty-specific guideline is to identify quality improvement opportunities in postoperative pain management of common otolaryngologic surgical procedures. These opportunities are communicated through clear actionable statements with explanation of the support in the literature, evaluation of the quality of the evidence, and recommendations on implementation. Employing these action statements should reduce the variation in care across the specialty and improve postoperative pain control while reducing risk of OUD. The target patients for the guideline are any patients treated for anticipated or reported pain within the first 30 days after undergoing common otolaryngologic procedures. The target audience of the guideline is otolaryngologists who perform surgery and clinicians who manage pain after surgical procedures. Outcomes to be considered include whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.The guideline addresses assessment of the patient for OUD risk factors, counseling on pain expectations, and identifying factors that can affect pain duration and/or severity. It also discusses the use of multimodal analgesia as first-line treatment and the responsible use of opioids. Last, safe disposal of unused opioids is discussed.This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not a comprehensive guide on pain management in otolaryngologic procedures. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experiences and assessments of individual patients., Action Statements: The guideline development group made strong recommendations for the following key action statements: (3A) prior to surgery, clinicians should identify risk factors for opioid use disorder when analgesia using opioids is anticipated; (6) clinicians should advocate for nonopioid medications as first-line management of pain after otolaryngologic surgery; (9) clinicians should recommend that patients (or their caregivers) store prescribed opioids securely and dispose of unused opioids through take-back programs or another accepted method.The guideline development group made recommendations for the following key action statements: (1) prior to surgery, clinicians should advise patients and others involved in the postoperative care about the expected duration and severity of pain; (2) prior to surgery, clinicians should gather information specific to the patient that modifies severity and/or duration of pain; (3B) in patients at risk for OUD, clinicians should evaluate the need to modify the analgesia plan; (4) clinicians should promote shared decision making by informing patients of the benefits and risks of postoperative pain treatments that include nonopioid analgesics, opioid analgesics, and nonpharmacologic interventions; (5) clinicians should develop a multimodal treatment plan for managing postoperative pain; (7) when treating postoperative pain with opioids, clinicians should limit therapy to the lowest effective dose and the shortest duration; (8A) clinicians should instruct patients and caregivers how to communicate if pain is not controlled or if medication side effects occur; (8B) clinicians should educate patients to stop opioids when pain is controlled with nonopioids and stop all analgesics when pain has resolved; (10) clinicians should inquire, within 30 days of surgery, whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.

Objectives: To determine changes in the prescriptions of postoperative opioids in response to Florida state legislation restricting the number of days for which these medications could be prescribed to 3 days in most circumstances or 7 days at provider discretion., Study Design: A retrospective review was performed for all patients undergoing 7 common outpatient otolaryngology surgical procedures., Setting: Single-institution academic center in Florida., Methods: Query of the state's online prescription drug monitoring program was used to compare prescription habits 3 months before and after the law and then again 1 year later., Results: A total of 561 patients were identified meeting criteria. The number of days that opioids were prescribed decreased significantly, from 6.42 to 4.48 to 3.03 days. There was a significant decrease in the proportion of patients receiving any postoperative opioid prescription, from 0.80 to 0.52 to 0.32. The total morphine milligram equivalents prescribed decreased from 28.4 before the law to 18.4 at 1 year after., Conclusions: Legislative restrictions on the length of opioid prescriptions were associated with significant decreases in the proportion of patients receiving any opioids, the number of days that opioids were prescribed, and the total morphine milligram equivalents 3 months after the law went into effect, with even more dramatic changes at the 1-year time point. We opine that these changes are due to providers learning that many procedures do not require postoperative opioids and therefore increasingly considering and utilizing nonopioid alternatives in this setting.

Objective: The objective of our study was to review the current literature pertaining to perioperative opioids in sinus surgery and to determine the effects of implementing opioid stewardship recommendations in the setting of endoscopic sinonasal surgery., Study Design: Single-institution retrospective case-control study., Setting: Academic medical center outpatient area., Methods: This retrospective review comprised 163 patients who underwent routine functional endoscopic sinus surgery, septoplasty, and/or inferior turbinate reduction before and after implementation of a standardized pain control regimen based on published opioid stewardship recommendations. The regimen consisted of an oral dose of gabapentin (400 mg) and acetaminophen (1000 mg) at least 30 minutes prior to surgery, absorbable nasal packing soaked in 0.5% tetracaine intraoperatively, and a postoperative regimen of acetaminophen and nonsteroidal anti-inflammatory medications. Tramadol tablets (50 mg) were prescribed postoperatively for breakthrough pain. The primary outcome measure for the study was the average number of hydrocodone equivalents (5 mg) prescribed before and after the new protocol., Results: The average number of opioid medications prescribed, measured as hydrocodone equivalents (5 mg), decreased from 24.59 preprotocol to 18.08 after the initiation of the new perioperative regimen ( P < .001). There was no significant difference between the periods ( P > .05) in number of postoperative phone calls regarding pain or in patient satisfaction scores., Conclusion: Opioid stewardship recommendations can be instituted for sinonasal surgery, including multimodal perioperative pain management and substitution of tramadol for breakthrough pain, as a method to decrease the volume of opioids prescribed, without increasing patient phone calls or affecting the likelihood of physician recommendation Press Ganey scores.

Objective: Opioid use disorder (OUD), which includes the morbidity of dependence and mortality of overdose, has reached epidemic proportions in the United States. Overprescription of opioids can lead to chronic use and misuse, and unused narcotics after surgery can lead to their diversion. Research supports that most patients do not take all the prescribed opioids after surgery and that surgeons are the second largest prescribers of opioids in the United States. The introduction of opioids in those with OUD often begins with prescription opioids. Reducing the number of extra opioids available after surgery through smaller prescriptions, safe storage, and disposal should reduce the risk of opioid use disorder in otolaryngology patients and their families., Purpose: The purpose of this specialty-specific guideline is to identify quality improvement opportunities in postoperative pain management of common otolaryngologic surgical procedures. These opportunities are communicated through clear actionable statements with explanation of the support in the literature, evaluation of the quality of the evidence, and recommendations on implementation. Employing these action statements should reduce the variation in care across the specialty and improve postoperative pain control while reducing risk of OUD. The target patients for the guideline are any patients treated for anticipated or reported pain within the first 30 days after undergoing common otolaryngologic procedures. The target audience of the guideline is otolaryngologists who perform surgery and clinicians who manage pain after surgical procedures. Outcomes to be considered include whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.The guideline addresses assessment of the patient for OUD risk factors, counseling on pain expectations, and identifying factors that can affect pain duration and/or severity. It also discusses the use of multimodal analgesia as first-line treatment and the responsible use of opioids. Last, safe disposal of unused opioids is discussed.This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not a comprehensive guide on pain management in otolaryngologic procedures. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experiences and assessments of individual patients., Action Statements: The guideline development group made strong recommendations for the following key action statements: (3A) prior to surgery, clinicians should identify risk factors for opioid use disorder when analgesia using opioids is anticipated; (6) clinicians should advocate for nonopioid medications as first-line management of pain after otolaryngologic surgery; (9) clinicians should recommend that patients (or their caregivers) store prescribed opioids securely and dispose of unused opioids through take-back programs or another accepted method.The guideline development group made recommendations for the following key action statements: (1) prior to surgery, clinicians should advise patients and others involved in the postoperative care about the expected duration and severity of pain; (2) prior to surgery, clinicians should gather information specific to the patient that modifies severity and/or duration of pain; (3B) in patients at risk for OUD, clinicians should evaluate the need to modify the analgesia plan; (4) clinicians should promote shared decision making by informing patients of the benefits and risks of postoperative pain treatments that include nonopioid analgesics, opioid analgesics, and nonpharmacologic interventions; (5) clinicians should develop a multimodal treatment plan for managing postoperative pain; (7) when treating postoperative pain with opioids, clinicians should limit therapy to the lowest effective dose and the shortest duration; (8A) clinicians should instruct patients and caregivers how to communicate if pain is not controlled or if medication side effects occur; (8B) clinicians should educate patients to stop opioids when pain is controlled with nonopioids and stop all analgesics when pain has resolved; (10) clinicians should inquire, within 30 days of surgery, whether the patient has stopped using opioids, has disposed of unused opioids, and was satisfied with the pain management plan.

This plain language summary explains pain management and careful use of opioids after common otolaryngology operations. The summary applies to patients of any age who need treatment for pain within 30 days after having a common otolaryngologic operation (having to do with the ear, nose, or throat). It is based on the 2021 "Clinical Practice Guideline: Opioid Prescribing for Analgesia After Common Otolaryngology Operations." This guideline uses available research to best advise health care providers, and it includes recommendations that are explained in this summary. Recommendations may not apply to every patient but can be used to facilitate shared decision making between patients and their health care providers.

Objective: Approximately 5% of children develop new persistent opioid use after tonsillectomy. Critical review of our prescribing practices revealed inconsistent and excessive opioid prescribing after this procedure in children. We sought to improve our practice by using a standardized electronic medical record (EMR)-based order set., Methods: Retrospective chart review of outpatient tonsillectomy performed before and after institution of an EMR intervention with comparison of opioid and nonopioid analgesic (NOA) prescription characteristics as well as outcomes including hemorrhage and readmission., Results: Analysis of 276 preorder set and 128 post-order set tonsillectomies revealed a significant increase in NOA utilization following initiation of the order set and a significant reduction in doses of opioid prescribed. Due to a change to a stronger opioid in the order set, morphine dose equivalents (MDEs) prescribed were not decreased in the post-order set cohort. Variability between prescriptions and providers was significantly decreased in the post-order set group in terms of doses and MDEs, and dangerously high outlier prescriptions were eliminated. No differences in pain control, postoperative hemorrhage, presentation to the emergency department, or readmission were identified., Discussion: An EMR-based intervention improved the quality and safety of posttonsillectomy opioid prescribing at our institution. Moving forward, this order set provides a platform with which to titrate opioid prescriptions and NOA to optimal pain control and safety levels., Implications for Practice: A standardized EMR-based order set can improve the quality of opioid prescribing after tonsillectomy.

Exploring and combining results from more than one real-world data (RWD) source might be necessary in order to explore variability and demonstrate generalizability of the results or for regulatory requirements. However, the heterogeneous nature of RWD poses challenges when working with more than one source, some of which can be solved by analyzing databases converted into a common data model (CDM). The main objective of the study was to evaluate the implementation of the Observational Medical Outcome Partnership (OMOP) CDM on IQVIA Medical Research Data (IMRD)-UK data. A drug utilization study describing the prescribing of codeine for pain in children was used as a case study to be replicated in IMRD-UK and its corresponding OMOP CDM transformation. Differences between IMRD-UK source and OMOP CDM were identified and investigated. In IMRD-UK updated to May 2017, results were similar between source and transformed data with few discrepancies. These were the result of different conventions applied during the transformation regarding the date of birth for children younger than 15 years and the start of the observation period, and of a misclassification of two drug treatments. After the initial analysis and feedback provided, a rerun of the analysis in IMRD-UK updated to September 2018 showed almost identical results for all the measures analyzed. For this study, the conversion to OMOP CDM was adequate. Although some decisions and mapping could be improved, these impacted on the absolute results but not on the study inferences. This validation study supports six recommendations for good practice in transforming to CDMs., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: To analyze the evolution of the prevalence of polypharmacy and excessive polypharmacy in a Spanish population, and to improve the identification of patients with polypharmacy., Methods: A descriptive, annual cross-sectional observational study was carried out., Patients: individuals over 14 years of age included in a multiregional primary care database of the Spanish population (BIFAP)., Analysis: prescription data. Period 2005-2015., Variables: proportion of patients with polypharmacy (simultaneous prescription of ≥5 drugs) and excessive polypharmacy (≥10 drugs) for at least 6 months, according to sex and age groups. A trend analysis of the studied period was performed (overall, and by sex and age groups)., Results: The data are reported on a comparative basis (2005 vs 2015). Number of patients analyzed: 2664743 vs 4 002 877. The prevalence of polypharmacy increased significantly (2.5% vs 8.9%, P-value for trend <0.001), being greater in females throughout the study period and in the group aged ≥80 years (P-value for trends <0.001). The prevalence of excessive polypharmacy also increased significantly (0.1% vs 1%, P-value for trend <0.001), being higher in the group aged ≥80 years (P-value for trend <0.001). The proportion of patients with no chronic treatment decreased (80.2% vs 63.1%)., Conclusions: The prevalence of polypharmacy in this Spanish population has tripled in the period 2005-2015, while excessive polypharmacy has increased 10-fold. These increments are seen in both sexes and in all age groups, particularly in individuals over 80 years of age. The proportion of patients without chronic treatments has decreased., (© 2020 John Wiley & Sons Ltd.)

With the aim to modernize and harmonize prescribing education, the European Association for Clinical Pharmacology and Therapeutics (EACPT) Working Group on education recommended the extensive use and distribution of digital learning resources (DLRs). However, it is unclear whether the complex task of prescribing medicine can be taught digitally. Therefore, the aim of this review was to investigate the effect of diverse DLRs in clinical pharmacology and therapeutics education. Databases PubMed, EMBASE, CINAHL, ERIC, and CENTRAL were systematically searched. Sixty-five articles were included in the analyses. Direct effects on patients were studied, but not detected, in six articles. Skills and behavior were studied in 11 articles, 8 of which reported positive effects. Knowledge acquisition was investigated in 19 articles, all with positive effects. Qualitative analyses yielded 10 recommendations for the future development of DLRs. Digital learning is effective in teaching knowledge, attitudes, and skills associated with safe and effective prescribing., (© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Pre-emptive pharmacogenetics (PGx) testing of a panel of germline genetic variants represents a new model for personalized medicine. Clinical impact of PGx testing is maximized when all variant alleles for which actionable clinical guidelines are available are included in the test panel. However, no such standardized panel has been presented to date, impeding adoption, exchange, and continuity of PGx testing. We, therefore, developed such a panel, hereafter called the PGx-Passport, based on the actionable Dutch Pharmacogenetics Working Group (DPWG) guidelines. Germline-variant alleles were systematically selected using predefined criteria regarding allele population frequencies, effect on protein functionality, and association with drug response. A PGx-Passport of 58 germline variant alleles, located within 14 genes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, HLA-A, HLA-B, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1) was composed. This PGx-Passport can be used in combination with the DPWG guidelines to optimize drug prescribing for 49 commonly prescribed drugs., (© 2019 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Patient-centered labels may improve safe medication use, but implementation challenges limit use. We assessed implementation of a patient-centered "PRN" (as needed) label entitled "Take-Wait-Stop" (TWS) with three deconstructed steps replacing traditional wording., Methods: As part of a larger investigation, patients received TWS prescriptions (eg, Take: 1 pill if you have pain; Wait: at least 4 h before taking again; Stop: do not take more than 6 pills in 24 h). Prescriptions labels recorded at follow-up were classified into three categories: (1) one-step wording (Take 1 pill every 4 h [without daily limits]), (2) two-step wording (Take 1 pill every 4 h; do not exceed 6 pills/day), and (3) three-step wording. There were three subtypes of three-step wording: (3a) three-step, not TWS (three deconstructed steps, not necessarily TWS wording), (3b) TWS format, employing three steps with leading verbs, but "with additions or replacements" (eg, replaced "do not take" with "do not exceed"), and (3c) verbatim TWS., Results: Two hundred eleven participants completed follow-up. Mean age was 44.3 years (SD 14.3); 44% were male. One-step bottles represented 12% (n = 25) of the sample, whereas 26% (n = 55) had two-step wording. The majority (44%, n = 93) had three-deconstructed steps, not TWS (3a); 16% (n = 34) retained TWS structure, but not verbatim (3b). Only 2% (n = 4) displayed verbatim TWS wording (3c). All category three labels (utilizing deconstructed instructions) were considered adequate implementation (62%)., Conclusions: Exact intervention adherence was not achieved in the majority of cases, limiting impact. Nonetheless, community pharmacies were responsive to new instructions, but higher implementation reliability requires additional supports., (© 2019 John Wiley & Sons, Ltd.)

Purpose: Countries worldwide are developing a variety of strategies to combat the opioid epidemic, such as restricting access to high-strength opioid formulations. We aimed to examine the dispensing patterns of strong opioids by dose units (DUs), age, and sex., Methods: We used Australian population-level dispensing data from January 2003 to December 2015 and categorised strong opioids by DU: very low, low, moderate, and high, corresponding to total daily doses of less than or equal to 25, 26 to 50, 51 to 100, and greater than 100 morphine milligramme equivalents, respectively. We measured trends in strong opioid use as dispensings/1000 population/year and stratified dispensing in 2015 by patient age and sex., Results: From 2003 to 2015, strong opioid dispensing of very low, low, moderate, and high DU increased 6.7-, 6.2-, 2.2-, and 1.8-fold, respectively. The increase in very low and low DU dispensing was driven primarily by oxycodone (5, 10, and 15 mg tablets and capsules) and buprenorphine transdermal patches. In 2015, the number of dispensings/1000 population for very low, low, moderate, and high DU were 180.3, 77.0, 52.7, and 34.8, respectively. Females aged greater than or equal to 85 years had the highest opioid use, ranging from 157.1 dispensings/1000 population for high DU to 2104.5 dispensings/1000 population for very low DU. In contrast, the high DU dispensings in males aged 25 to 64 years exceeded their female counterparts by approximately 1.3-fold., Conclusion: Relative to moderate and high DU strong opioids, dispensing of very low and low DU strong opioids increased dramatically during the study period in Australia. Future studies investigating opioids use and harms in elderly females and males between 25 to 64 years are warranted., (© 2019 John Wiley & Sons, Ltd.)

Purpose: Increasing use of tramadol for chronic non-cancer pain is concerning since tramadol users may be at risk of developing recurrent opioid use with increasing opioid consumption and co-medication. Therefore, we investigated a complete national cohort of tramadol users., Methods: The study population (154 042 adult individuals in Norway, who redeemed ≥ one tramadol prescription in 2012) was stratified into four groups according to their opioid use 2 years before their first tramadol prescription in 2012 and followed until 2016. Information on all dispensed opioid analgesics, benzodiazepines (BZDs), and BZD-related Z-hypnotics were retrieved from the Norwegian Prescription Database., Results: Six percent of opioid naïve tramadol users (no opioid use 2 years before tramadol use in 2012) became recurrent users (received opioids annually during 4-year follow-up), almost doubled their mean opioid consumption (66 to 108 defined daily doses [DDD]). One-quarter proceeded to strong opioids or was co-medicated with BZDs, one-third with Z-hypnotics. Among former weak opioid users, 39.8% became recurrent users, 18.7% proceeded to strong opioids, mean opioid consumption increased slightly, one-third used BZDs, or Z-hypnotics concurrently. Among former strong opioid and users in palliative care; 61%, 70% became recurrent users and developed a similar prescription pattern (high and increasing mean opioid consumption, 301 to 318, 413 to 430 DDD); half of them proceeded to strong opioids and/or used BZDs or Z-hypnotics concurrently., Conclusions: Many patients who developed recurrent opioid use received prescriptions which substantially conflicted with existing guidelines and might lead to problematic opioid use., (© 2018 John Wiley & Sons, Ltd.)

Purpose: The aims of this study were to examine a national database to assess codeine poisonings before and after the new guidance for pharmacists while also evaluating rates of codeine prescriptions following the introduction of restrictions on supply., Methods: Anonymised enquiry data of reported poisoning cases were reviewed for a period from 2005 to 2016 inclusive. The rate of pharmacy claims for codeine containing products was also examined using the national pharmacy claims database. Segmented regression analysis was used to detect changes in poisonings and claims before and after the new guidance., Results: There were 1851 codeine-related poisonings reported over the study period. An annual decline was evident with a significant 33% reduction from 2010 to 2011 (β2 coefficient for level change, 42.1; 95% CI, -68.1 to -16.0; P = 0.006). Following 2011, the declining rate of codeine poisonings plateaued. Analysis of the national pharmacy claims data revealed no change in the reimbursement rate for co-codamol products restricted by the guidance in 2010 (Incidence rate ratio 1.04, 95% CI, 0.997-1.08; P = 0.07). There was no corresponding increase in the reimbursement of alternative opioid medications., Conclusions: New guidance on codeine supply coincided with an initial reduction in reported codeine poisoning cases. This reduction was in keeping with the previous trend. However, this was without an increase in the prevailing rate of prescription claims for these products or potential substitutes. Policymakers may consider further restriction of codeine products to improve public health outcomes., (© 2019 John Wiley & Sons, Ltd.)

Purpose: To estimate the proportion of residents newly initiating long-acting opioids in comparison to residents initiating short-acting opioids and examine variation in long-acting opioid initiation by region and resident characteristics., Methods: This cross-sectional study included 182 735 long-stay nursing home residents in 13 881 US nursing homes who were Medicare beneficiaries during 2011 to 2013 and initiated a short-acting or long-acting opioid (excluding residents <50 years old, those with cancer, or receiving hospice care). Medicare Part D prescription claims were used to identify residents as newly initiating short-acting or long-acting opioids, defined as having a prescription claim for an opioid with no prior opioid prescriptions in the preceding 60 days. We estimated the overall proportion of initiators prescribed long-acting opioids. Regional variation was examined by mapping results by state and hospital referral regions. Logistic models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs)., Results: Two percent of opioid initiators were prescribed long-acting opioids. State variation in long-acting opioid initiation ranged from 0.6% to 7.5% (5th-95th percentiles: 0.6-6.4%). Resident characteristics associated with increased long-acting opioid initiation included severe physical limitations (vs none/mild limitations; aOR: 2.13, 95% CI: 1.92-2.37) and pain (staff-assessed vs no pain; aOR: 1.59 95% CI: 1.40-1.80), whereas being non-White was inversely associated (non-Hispanic black vs non-Hispanic white; aOR: 0.70, 95% CI: 0.62-0.79)., Conclusion: United States nursing home residents predominantly initiate short-acting opioids in accordance with Center for Disease Control and Prevention guidelines. Documented variation by geographic and resident characteristics suggests that improvements are possible., (© 2018 John Wiley & Sons, Ltd.)

Background: In recognition of potential for increased overdose risk, drug labels for extended-release and long-acting (ER/LA) opioids emphasize the need for established opioid tolerance prior to initiating high dosages., Objectives: Describe the proportion of patients with opioid tolerance prior to initiation of 90 morphine milligram equivalents (MME) ER/LA opioids and examine subsequent risk of opioid poisoning., Methods: We used Truven Health Analytics' MarketScan Databases (2006-2015) to identify patients initiating ER/LA opioids ≥90 MME. We examined prescription histories and describe the proportion of initiators with opioid tolerance (defined as ≥7 days of 60 MME in the prior 14 days). We adjusted for age, sex, year of initiation, and baseline comorbidities using inverse probability of treatment weighted Cox proportional hazards models. We estimated adjusted hazard ratios and 95% confidence intervals for the effect of opioid tolerance on the risk of clinically recognized opioid poisoning (based on diagnosis codes) in specific periods (0-7, 8-30, 31-90, and 91-365 days) following initiation., Results: Among 372 038 initiators, 38% did not meet opioid tolerance criteria. The proportion of nontolerant initiators was highest among those initiating methadone (44%) and fentanyl (42%). Nontolerant patients were 37% more likely to be diagnosed with opioid poisoning (adjusted hazard ratios = 1.37 [1.07, 1.76]) in the week following ER/LA initiation., Conclusions: Over one-third of patients initiating ≥90 MME ER/LA opioids did not have evidence of opioid tolerance. The 7 days following high dose ER/LA initiation may represent a high-risk period for clinically diagnosed opioid poisoning in patients who do not have prior opioid tolerance., (© 2018 John Wiley & Sons, Ltd.)

Purpose: The purpose of the study is to determine whether initiatives to improve the safety of opioid prescribing decreased injuries in people using chronic opioid therapy (COT)., Methods: We conducted an interrupted time series analysis using data from Group Health (GH), an integrated health care delivery system in the United States. In 2007, GH implemented initiatives which substantially reduced daily opioid dose and increased patient monitoring. Among GH members age 18 or older receiving COT between 2006 and 2014, we compared injury rates for patients in GH's integrated group practice (IGP; exposed to the initiatives) vs patients cared for by contracted providers (not exposed). Injuries were identified using a validated algorithm. We calculated injury incidence during the baseline (preintervention) period from 2006 to 2007; the dose reduction period, 2008 to 2010; and the risk stratification and monitoring period, 2010 to 2014. Using modified Poisson regression, we estimated adjusted relative risks (RRs) representing the relative change per year in injury rates., Results: Among 21 853 people receiving COT in the IGP and 8260 in contracted care, there were 2679 injuries during follow-up. The baseline injury rate was 1.0% per calendar quarter in the IGP and 0.9% in contracted care. Risk reduction initiatives did not decrease injury rates: Within the IGP, the RR in the dose reduction period was 1.01 (95% CI, 0.95-1.07) and in the risk stratification and monitoring period, 0.99 (95% CI, 0.95-1.04). Injury trends did not differ between the two care settings., Conclusions: Risk reduction initiatives did not decrease injuries in people using COT., (© 2018 John Wiley & Sons, Ltd.)

Purpose: The ongoing opioid epidemic has claimed more than a quarter million Americans' lives over the past 15 years. The epidemic began with an escalation of prescription opioid deaths and has now evolved to include secondary waves of illicit heroin and fentanyl deaths, while the deaths due to prescription opioid overdoses are still increasing. In response, the Centers for Disease Control and Prevention (CDC) moved to limit opioid prescribing with the release of opioid prescribing guidelines for chronic noncancer pain in March 2016. The guidelines represent a logical and timely federal response to this growing crisis. However, CDC acknowledged that the evidence base linking opioid prescribing to opioid use disorders and overdose was grades 3 and 4., Methods: Motivated by the need to strengthen the evidence base, this review details limitations of the opioid safety studies cited in the CDC guidelines with a focus on methodological limitations related to internal and external validity., Results: Internal validity concerns were related to poor confounding control, variable misclassification, selection bias, competing risks, and potential competing interventions. External validity concerns arose from the use of limited source populations, historical data (in a fast-changing epidemic), and issues with handling of cancer and acute pain patients' data. We provide a nonexhaustive list of 7 recommendations to address these limitations in future opioid safety studies., Conclusion: Strengthening the opioid safety evidence base will aid any future revisions of the CDC guidelines and enhance their prevention impact., (© 2018 John Wiley & Sons, Ltd.)

Purpose: Overuse of antibiotics is of concern, but may differ between European countries. This study compares outpatient use of oral antibiotics between Germany (DE) and the Netherlands (NL)., Methods: For DE, we used the DAPI database with information on dispensings at the expense of the Statutory Health Insurance Funds from > 80% of community pharmacies. For NL, data were obtained from the Dutch Foundation for Pharmaceutical Statistics. Use of oral antibiotics was estimated as defined daily doses per 1000 inhabitants per day (DID), except for age comparisons as packages per 1000 inhabitants annually. National time trends were assessed with linear regression, stratified for the major antibiotic classes, and individual substances., Results: From 2012 to 2016, outpatient antibiotic use was lower in NL than in DE (9.64 vs 14.14 DID in 2016) and non-significantly decreased slightly over time in both countries. In DE, dispensings of oral antibiotics to children were higher compared with NL for the age groups 2 to 5 (2.0-fold in 2016) and 6 to 14 years (2.7-fold in 2016). Use of cephalosporins was very low in NL (0.02 DID in 2016), but the second most frequently dispensed class in DE (2.95 DID in 2016)., Conclusion: From 2012 to 2016, outpatient use of oral antibiotics was lower in NL than in DE. Differences were primarily observed in the age groups 2 to 5 and 6 to 14 years, although the recommendations of evidence-based guidelines in both countries were in agreement., (© 2018 The Authors Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.)

Purpose: Our aim was to describe trends in the prescription of domperidone for insufficient lactation in England, the characteristics of women prescribed it postpartum, and the impact of a 2014 European Medicines Agency (EMA) recommendation to restrict its use due to a potential increased risk of sudden cardiac death associated with its use., Methods: We conducted a population-based cohort study with interrupted time series analysis using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified women with live births from 2002 to 2015, excluding those with nonlactation indications for domperidone (n = 247 349). We evaluated trends in the prescription rate of domperidone in the 6 months postpartum and differences in this rate before and after the EMA recommendation., Results: Domperidone was prescribed among 1438 deliveries at a rate of 1.24 per 100 person-years. This rate increased from 0.56 to 2.1 per 100 person-years between 2002-2004 and 2011-2013 (rate ratio: 3.8; 95% confidence interval [CI], 3.2-4.6). Prescribing decreased in level by 0.35 (95% CI, -0.86 to 0.16) per 100 person-years immediately following the recommendation with little change in trend (0.003; 95% CI, -0.059 to 0.065 per 100 person-years). Following the recommendation, prescription of doses >30 mg and coprescription of drugs with a risk of torsade de pointes decreased. No arrhythmic events were observed among domperidone users., Conclusions: Although we observed an important increase in prescribing during the study period, domperidone remains infrequently prescribed postpartum in England. While overall prescribing changed little, some prescribing practices became more restricted following the EMA's recommendation., (© 2018 John Wiley & Sons, Ltd.)

Background: Inappropriate polypharmacy is a particular concern in older people and is associated with negative health outcomes. Choosing the best interventions to improve appropriate polypharmacy is a priority, hence interest in appropriate polypharmacy, where many medicines may be used to achieve better clinical outcomes for patients, is growing. This is the second update of this Cochrane Review., Objectives: To determine which interventions, alone or in combination, are effective in improving the appropriate use of polypharmacy and reducing medication-related problems in older people., Search Methods: We searched CENTRAL, MEDLINE, Embase, CINAHL and two trials registers up until 7 February 2018, together with handsearching of reference lists to identify additional studies., Selection Criteria: We included randomised trials, non-randomised trials, controlled before-after studies, and interrupted time series. Eligible studies described interventions affecting prescribing aimed at improving appropriate polypharmacy in people aged 65 years and older, prescribed polypharmacy (four or more medicines), which used a validated tool to assess prescribing appropriateness. These tools can be classified as either implicit tools (judgement-based/based on expert professional judgement) or explicit tools (criterion-based, comprising lists of drugs to be avoided in older people)., Data Collection and Analysis: Two review authors independently reviewed abstracts of eligible studies, extracted data and assessed risk of bias of included studies. We pooled study-specific estimates, and used a random-effects model to yield summary estimates of effect and 95% confidence intervals (CIs). We assessed the overall certainty of evidence for each outcome using the GRADE approach., Main Results: We identified 32 studies, 20 from this update. Included studies consisted of 18 randomised trials, 10 cluster randomised trials (one of which was a stepped-wedge design), two non-randomised trials and two controlled before-after studies. One intervention consisted of computerised decision support (CDS); and 31 were complex, multi-faceted pharmaceutical-care based approaches (i.e. the responsible provision of medicines to improve patient's outcomes), one of which incorporated a CDS component as part of their multi-faceted intervention. Interventions were provided in a variety of settings. Interventions were delivered by healthcare professionals such as general physicians, pharmacists and geriatricians, and all were conducted in high-income countries. Assessments using the Cochrane 'Risk of bias' tool, found that there was a high and/or unclear risk of bias across a number of domains. Based on the GRADE approach, the overall certainty of evidence for each pooled outcome ranged from low to very low.It is uncertain whether pharmaceutical care improves medication appropriateness (as measured by an implicit tool), mean difference (MD) -4.76, 95% CI -9.20 to -0.33; 5 studies, N = 517; very low-certainty evidence). It is uncertain whether pharmaceutical care reduces the number of potentially inappropriate medications (PIMs), (standardised mean difference (SMD) -0.22, 95% CI -0.38 to -0.05; 7 studies; N = 1832; very low-certainty evidence). It is uncertain whether pharmaceutical care reduces the proportion of patients with one or more PIMs, (risk ratio (RR) 0.79, 95% CI 0.61 to 1.02; 11 studies; N = 3079; very low-certainty evidence). Pharmaceutical care may slightly reduce the number of potential prescribing omissions (PPOs) (SMD -0.81, 95% CI -0.98 to -0.64; 2 studies; N = 569; low-certainty evidence), however it must be noted that this effect estimate is based on only two studies, which had serious limitations in terms of risk bias. Likewise, it is uncertain whether pharmaceutical care reduces the proportion of patients with one or more PPOs (RR 0.40, 95% CI 0.18 to 0.85; 5 studies; N = 1310; very low-certainty evidence). Pharmaceutical care may make little or no difference in hospital admissions (data not pooled; 12 studies; N = 4052; low-certainty evidence). Pharmaceutical care may make little or no difference in quality of life (data not pooled; 12 studies; N = 3211; low-certainty evidence). Medication-related problems were reported in eight studies (N = 10,087) using different terms (e.g. adverse drug reactions, drug-drug interactions). No consistent intervention effect on medication-related problems was noted across studies., Authors' Conclusions: It is unclear whether interventions to improve appropriate polypharmacy, such as reviews of patients' prescriptions, resulted in clinically significant improvement; however, they may be slightly beneficial in terms of reducing potential prescribing omissions (PPOs); but this effect estimate is based on only two studies, which had serious limitations in terms of risk bias.

Harmonizing clinical pharmacology and therapeutics (CPT) education in Europe is necessary to ensure that the prescribing competency of future doctors is of a uniform high standard. As there are currently no uniform requirements, our aim was to achieve consensus on key learning outcomes for undergraduate CPT education in Europe. We used a modified Delphi method consisting of three questionnaire rounds and a panel meeting. A total of 129 experts from 27 European countries were asked to rate 307 learning outcomes. In all, 92 experts (71%) completed all three questionnaire rounds, and 33 experts (26%) attended the meeting. 232 learning outcomes from the original list, 15 newly suggested and 5 rephrased outcomes were included. These 252 learning outcomes should be included in undergraduate CPT curricula to ensure that European graduates are able to prescribe safely and effectively. We provide a blueprint of a European core curriculum describing when and how the learning outcomes might be acquired., (© 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Cancer pain remains a feared consequence of the disease and its treatment. Although prevalent, cancer pain can usually be managed through the skillful application of pharmacologic and nonpharmacologic interventions. Unfortunately, access to these therapies has been hampered by interventions designed to contain another serious public health problem: the opioid misuse epidemic. This epidemic and the unintended consequences of efforts to control this outbreak are leading to significant barriers to the provision of cancer pain relief. Oncologists and other professionals treating those with cancer pain will require new knowledge and tools to provide safe and effective pain control while preventing additional cases of substance use disorders (SUDs), helping patients in recovery to maintain sobriety, and guiding those not yet in recovery to seek treatment. How do these 2 serious epidemics intersect and affect oncology practice? First, oncology professionals will need to adopt practices to prevent SUDs by assessing risk and providing safe pain care. Second, oncology practices are likely to see an increased number of patients with a current or past SUD, including opioid misuse. Few guidelines exist for the direct management of pain when opioids may be indicated in these individuals. Third, modified prescribing practices along with the education of patients and families are warranted to prevent the exposure of these medications to unintended persons. Finally, advocacy on behalf of those with cancer pain is imperative to avoid losing access to essential therapies, including opioids, for those who might benefit. Cancer 2018;124:2491-7. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Aims: To evaluate the impact of physicians' adherence to guideline-recommended medications for heart failure with reduced ejection fraction (HFrEF), including ≥50% prescription of recommended doses, on clinical outcomes at 6-month follow-up., Methods and Results: In QUALIFY, an international, prospective, observational, longitudinal survey, 6669 outpatients with HFrEF were recruited 1-15 months after heart failure (HF) hospitalization from September 2013 to December 2014 in 36 countries and followed up at 6 months. A global adherence to guidelines score was developed for prescription of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and ivabradine and their dosages. Baseline global adherence score was good in 23% of patients, moderate in 55%, and poor in 22%. At 6-month follow-up, poor adherence was associated with significantly higher overall mortality [hazard ratio (HR) 2.21, 95% confidence interval (CI) 1.42-3.44, P=0.001], cardiovascular mortality (HR 2.27, 95% CI 1.36-3.77, P=0.003), HF mortality (HR 2.26, 95% CI 1.21-4.2, P=0.032), combined HF hospitalization or HF death (HR 1.26, 95% CI 1.08-1.71, P=0.024) and cardiovascular hospitalization or cardiovascular death (HR 1.35, 95% CI 1.08-1.69, P=0.013). There was a strong trend between poor adherence and HF hospitalization (HR 1.32, 95% CI 1.04-1.68, P=0.069)., Conclusion: Good adherence to pharmacologic treatment guidelines for ACEIs, ARBs, BBs, MRAs and ivabradine, with prescription of at least 50% of recommended dosages, was associated with better clinical outcomes during 6-month follow-up. Continuing global educational initiatives are needed to emphasise the importance of guideline recommendations for optimising drug therapy and prescribing evidence-based doses in clinical practice., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Changes in behavior are necessary to apply genomic discoveries to practice. We prospectively studied medication changes made by providers representing eight different medicine specialty clinics whose patients had submitted to preemptive pharmacogenomic genotyping. An institutional clinical decision support (CDS) system provided pharmacogenomic results using traffic light alerts: green = genomically favorable, yellow = genomic caution, red = high risk. The influence of pharmacogenomic alerts on prescribing behaviors was the primary endpoint. In all, 2,279 outpatient encounters were analyzed. Independent of other potential prescribing mediators, medications with high pharmacogenomic risk were changed significantly more often than prescription drugs lacking pharmacogenomic information (odds ratio (OR) = 26.2 (9.0-75.3), P < 0.0001). Medications with cautionary pharmacogenomic information were also changed more frequently (OR = 2.4 (1.7-3.5), P < 0.0001). No pharmacogenomically high-risk medications were prescribed during the entire study when physicians consulted the CDS tool. Pharmacogenomic information improved prescribing in patterns aimed at reducing patient risk, demonstrating that enhanced prescription decision-making is achievable through clinical integration of genomic medicine., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: The STOPP/START criteria are increasingly used to assess prescribing quality in elderly patients at practice level. Our aim was to test computerized algorithms for applying these criteria to a medical record database., Methods: STOPP/START criteria-based computerized algorithms were defined using Anatomical-Therapeutic-Chemical (ATC) codes for medication and International Classification of Primary Care (ICPC) codes for diagnoses. The algorithms were applied to a Dutch primary care database, including patients aged ≥65 years using ≥5 chronic drugs. We tested for associations with patient characteristics that have previously shown a relationship with the original STOPP/START criteria, using multivariate logistic regression models., Results: Included were 1187 patients with a median age of 75 years. In total, 39 of the 62 STOPP and 18 of the 26 START criteria could be converted to a computerized algorithm. The main reasons for inapplicability were lack of information on the severity of a condition and insufficient covering of ICPC-codes. We confirmed a positive association between the occurrence of both the STOPP and the START criteria and the number of chronic drugs (adjusted OR ranging from 1.37, 95% CI 1.04-1.82 to 3.19, 95% CI 2.33-4.36) as well as the patient's age (adjusted OR for STOPP 1.30, 95% CI 1.01-1.67; for START 1.73, 95% CI 1.35-2.21), and also between female gender and the occurrence of STOPP criteria (adjusted OR 1.41, 95% CI 1.09-1.82)., Conclusion: Sixty-five percent of the STOPP/START criteria could be applied with computerized algorithms to a medical record database with ATC-coded medication and ICPC-coded diagnoses., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background/objective: Direct-acting oral anticoagulants (DOACs) are increasingly used to prevent or treat thromboembolism. We conducted a study to compare how well initial DOAC prescribing for adult inpatients adhered to dosing recommendations approved by the US Food and Drug Administration (FDA)., Design: Retrospective analysis., Setting: Single academic medical center, July 1, 2014 to June 30, 2015., Patients: 508 adult inpatients., Measurements: DOAC prescriptions were evaluated to determine whether they met FDA-recommended dosing and administration according to patient age, weight, sex, race, kidney function, diagnoses, and concomitant medications., Results: DOACs were prescribed in 635 admissions (247 apixaban, 97 dabigatran, 291 rivaroxaban). The indication was atrial fibrillation/flutter in 465 admissions (8% with bioprostheses or valve repair), chronic deep vein thrombosis (DVT) in 67, acute DVT in 32, chronic pulmonary embolism in 23, acute pulmonary embolism in 19, DVT prevention after hip or knee surgery in 19, and non-FDA-approved indications in 10. Sixteen percent of orders for venous thromboembolic disease were for patients with active malignancy. Dosages not concordant with recommendations were prescribed for apixaban in 18% of admissions, for rivaroxaban in 14%, and for dabigatran in 7% (𝑃 = 0.04). Lower than recommended dosing was more common than higher than recommended dosing (𝑃 < 0.05). Half the deviations were continuations of outpatient dosing. Atrial fibrillation/flutter and post-hip or -knee surgery dosing deviations were more common than venous thromboembolic disease deviations (𝑃 < 0.001) but were not related to prescriber specialty., Conclusions: DOAC prescribing recommendation deviations that can affect clinical efficacy were identified. Education and point-of-care decision support tools for improving dosing are needed, as are outcome data for patients who receive DOACs at lower than recommended dosing or for off-label indications., (© 2017 Society of Hospital Medicine)

Purpose: Products containing the sedative/hypnotic zolpidem were subject to Drug Safety Communications (DSCs) in January and May 2013 describing the risk of next-morning impairment and recommending lower starting doses particularly for women. This study aimed to assess whether zolpidem DSCs were associated with prescribing-pattern changes between January 2011 and December 2013., Methods: We assessed overall dispensings of zolpidem-containing products between January 2011 and December 2013 by conducting a time-series analysis. Analyses were stratified by gender because the DSC contained gender-specific information. Participants were patients drawn from the Optum Clinformatics data source of commercially insured people in the USA. We evaluated changes in mean prescribed dose of the two drugs and health care utilization metrics., Results: Each month of the study, more than 80 000 patients received a zolpidem-containing product and approximately one-tenth as many received eszopiclone. The two DSCs did not affect the downward trajectory of new zolpidem prescriptions. However, there was an increase in use of lower-dose forms of zolpidem (30% increase, p < 0.001), coupled with a reduction in higher-dose forms (13% decrease, p = 0.03), so that the average dose decreased after the DSCs (from 9.7 mg to 9.4 mg, p < 0.001), a change that was not seen with eszopiclone (from 2.74 mg to 2.74 mg, p = 0.45)., Conclusion: The DSCs related to zolpidem-containing products shifted prescribing toward the lower-dose formulations, consistent with the recommendations in the DSCs. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

European medical students should have acquired adequate prescribing competencies before graduation, but it is not known whether this is the case. In this international multicenter study, we evaluated the essential knowledge, skills, and attitudes in clinical pharmacology and therapeutics (CPT) of final-year medical students across Europe. In a cross-sectional design, 26 medical schools from 17 European countries were asked to administer a standardized assessment and questionnaire to 50 final-year students. Although there were differences between schools, our results show an overall lack of essential prescribing competencies among final-year students in Europe. Students had a poor knowledge of drug interactions and contraindications, and chose inappropriate therapies for common diseases or made prescribing errors. Our results suggest that undergraduate teaching in CPT is inadequate in many European schools, leading to incompetent prescribers and potentially unsafe patient care. A European core curriculum with clear learning outcomes and assessments should be urgently developed., (© 2016 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of The American Society for Clinical Pharmacology and Therapeutics.)

Background: A range of health workforce strategies are needed to address health service demands in low-, middle- and high-income countries. Non-medical prescribing involves nurses, pharmacists, allied health professionals, and physician assistants substituting for doctors in a prescribing role, and this is one approach to improve access to medicines., Objectives: To assess clinical, patient-reported, and resource use outcomes of non-medical prescribing for managing acute and chronic health conditions in primary and secondary care settings compared with medical prescribing (usual care)., Search Methods: We searched databases including CENTRAL, MEDLINE, Embase, and five other databases on 19 July 2016. We also searched the grey literature and handsearched bibliographies of relevant papers and publications., Selection Criteria: Randomised controlled trials (RCTs), cluster-RCTs, controlled before-and-after (CBA) studies (with at least two intervention and two control sites) and interrupted time series analysis (with at least three observations before and after the intervention) comparing: 1. non-medical prescribing versus medical prescribing in acute care; 2. non-medical prescribing versus medical prescribing in chronic care; 3. non-medical prescribing versus medical prescribing in secondary care; 4 non-medical prescribing versus medical prescribing in primary care; 5. comparisons between different non-medical prescriber groups; and 6. non-medical healthcare providers with formal prescribing training versus those without formal prescribing training., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. Two review authors independently reviewed studies for inclusion, extracted data, and assessed study quality with discrepancies resolved by discussion. Two review authors independently assessed risk of bias for the included studies according to EPOC criteria. We undertook meta-analyses using the fixed-effect model where studies were examining the same treatment effect and to account for small sample sizes. We compared outcomes to a random-effects model where clinical or statistical heterogeneity existed., Main Results: We included 46 studies (37,337 participants); non-medical prescribing was undertaken by nurses in 26 studies and pharmacists in 20 studies. In 45 studies non-medical prescribing as a component of care was compared with usual care medical prescribing. A further study compared nurse prescribing supported by guidelines with usual nurse prescribing care. No studies were found with non-medical prescribing being undertaken by other health professionals. The education requirement for non-medical prescribing varied with country and location.A meta-analysis of surrogate markers of chronic disease (systolic blood pressure, glycated haemoglobin, and low-density lipoprotein) showed positive intervention group effects. There was a moderate-certainty of evidence for studies of blood pressure at 12 months (mean difference (MD) -5.31 mmHg, 95% confidence interval (CI) -6.46 to -4.16; 12 studies, 4229 participants) and low-density lipoprotein (MD -0.21, 95% CI -0.29 to -0.14; 7 studies, 1469 participants); we downgraded the certainty of evidence from high due to considerations of serious inconsistency (considerable heterogeneity), multifaceted interventions, and variable prescribing autonomy. A high-certainty of evidence existed for comparative studies of glycated haemoglobin management at 12 months (MD -0.62, 95% CI -0.85 to -0.38; 6 studies, 775 participants). While there appeared little difference in medication adherence across studies, a meta-analysis of continuous outcome data from four studies showed an effect favouring patient adherence in the non-medical prescribing group (MD 0.15, 95% CI 0.00 to 0.30; 4 studies, 700 participants). We downgraded the certainty of evidence for adherence to moderate due to the serious risk of performance bias. While little difference was seen in patient-related adverse events between treatment groups, we downgraded the certainty of evidence to low due to indirectness, as the range of adverse events may not be related to the intervention and selective reporting failed to adequately report adverse events in many studies.Patients were generally satisfied with non-medical prescriber care (14 studies, 7514 participants). We downgraded the certainty of evidence from high to moderate due to indirectness, in that satisfaction with the prescribing component of care was only addressed in one study, and there was variability of satisfaction measures with little use of validated tools. A meta-analysis of health-related quality of life scores (SF-12 and SF-36) found a difference favouring usual care for the physical component score (MD 1.17, 95% CI 0.16 to 2.17), but not the mental component score (MD 0.58, 95% CI -0.40 to 1.55). However, the quality of life measurement may more appropriately reflect composite care rather than the prescribing component of care, and for this reason we downgraded the certainty of evidence to moderate due to indirectness of the measure of effect. A wide variety of resource use measures were reported across studies with little difference between groups for hospitalisations, emergency department visits, and outpatient visits. In the majority of studies reporting medication use, non-medical prescribers prescribed more drugs, intensified drug doses, and used a greater variety of drugs compared to usual care medical prescribers.The risk of bias across studies was generally low for selection bias (random sequence generation), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), and reporting bias (selective reporting). There was an unclear risk of selection bias (allocation concealment) and for other biases. A high risk of performance bias (blinding of participants and personnel) existed., Authors' Conclusions: The findings suggest that non-medical prescribers, practising with varying but high levels of prescribing autonomy, in a range of settings, were as effective as usual care medical prescribers. Non-medical prescribers can deliver comparable outcomes for systolic blood pressure, glycated haemoglobin, low-density lipoprotein, medication adherence, patient satisfaction, and health-related quality of life. It was difficult to determine the impact of non-medical prescribing compared to medical prescribing for adverse events and resource use outcomes due to the inconsistency and variability in reporting across studies. Future efforts should be directed towards more rigorous studies that can clearly identify the clinical, patient-reported, resource use, and economic outcomes of non-medical prescribing, in both high-income and low-income countries.

Pharmacogenomic (PGx) information is increasingly being incorporated into US Food and Drug Administration-approved drug labels. We reviewed the data source (adults vs. pediatrics) of PGx information in approved drug labels and assessed the suitability of applying adult-derived PGx information and related prescribing recommendations to the care of pediatric patients. We identified 65 drugs with labels containing PGx information and that have also been evaluated in children and found that in the majority of cases (56/65, 86%), the PGx information described was derived from adult studies. The application of PGx information from adults to pediatrics was deemed suitable for 71.4% (n = 40) of the drugs and unclear for 28.6% (n = 16). An ontogeny effect, limited or conflicting data regarding ontogeny of the genetic biomarker, or a difference in the pathophysiology or progression of the adult vs. pediatric disease were the primary reasons for deeming direct application from adults to pediatrics unclear., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

Background: There is a substantial body of evidence that prescribing for care home residents is suboptimal and requires improvement. Consequently, there is a need to identify effective interventions to optimise prescribing and resident outcomes in this context. This is an update of a previously published review (Alldred 2013)., Objectives: The objective of the review was to determine the effect of interventions to optimise overall prescribing for older people living in care homes., Search Methods: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (including the Cochrane Effective Practice and Organisation of Care (EPOC) Specialised Register), MEDLINE, EMBASE and CINAHL to May 2015. We also searched clinical trial registries for relevant studies., Selection Criteria: We included randomised controlled trials evaluating interventions aimed at optimising prescribing for older people (aged 65 years or older) living in institutionalised care facilities. Studies were included if they measured one or more of the following primary outcomes: adverse drug events; hospital admissions; mortality; or secondary outcomes, quality of life (using validated instrument); medication-related problems; medication appropriateness (using validated instrument); medicine costs., Data Collection and Analysis: Two authors independently screened titles and abstracts, assessed studies for eligibility, assessed risk of bias and extracted data. We presented a narrative summary of results., Main Results: The 12 included studies involved 10,953 residents in 355 (range 1 to 85) care homes in ten countries. Nine studies were cluster-randomised controlled trials and three studies were patient-randomised controlled trials. The interventions evaluated were diverse and often multifaceted. Medication review was a component of ten studies. Four studies involved multidisciplinary case-conferencing, five studies involved an educational element for health and care professionals and one study evaluated the use of clinical decision support technology. We did not combine the results in a meta-analysis due to heterogeneity across studies. Interventions to optimise prescribing may lead to fewer days in hospital (one study out of eight; low certainty evidence), a slower decline in health-related quality of life (one study out of two; low certainty evidence), the identification and resolution of medication-related problems (seven studies; low certainty evidence), and may lead to improved medication appropriateness (five studies out of five studies; low certainty evidence). We are uncertain whether the intervention improves/reduces medicine costs (five studies; very low certainty evidence) and it may make little or no difference on adverse drug events (two studies; low certainty evidence) or mortality (six studies; low certainty evidence). The risk of bias across studies was heterogeneous., Authors' Conclusions: We could not draw robust conclusions from the evidence due to variability in design, interventions, outcomes and results. The interventions implemented in the studies in this review led to the identification and resolution of medication-related problems and improvements in medication appropriateness, however evidence of a consistent effect on resident-related outcomes was not found. There is a need for high-quality cluster-randomised controlled trials testing clinical decision support systems and multidisciplinary interventions that measure well-defined, important resident-related outcomes.

For decades, medical practice has increasingly relied on prescription medicines to treat, cure, or prevent illness but their net benefit is reduced by prescribing errors that result in adverse drug reactions (ADRs) and tens of thousands of deaths each year. Optimal prescribing requires effective management of massive amounts of data. Clinical decision support systems (CDSS) can help manage information and support optimal therapeutic decisions before errors are made by operating as the prescribers' "autopilot.", (© 2015 ASCPT.)

Background: In the United Kingdom, nurses and pharmacists who have undertaken additional post-registration training can prescribe medicines for any medical condition within their competence (non-medical prescribers, NMPs), but little is known about patients' experiences and perceptions of this service., Objective: to obtain feedback from primary care patients on the impact of prescribing by nurse independent prescribers (NIPs) and pharmacist independent prescribers (PIPs) on experiences of the consultation, the patient-professional relationship, access to medicines, quality of care, choice, knowledge, patient-reported adherence and control of their condition., Design: Two cross-sectional postal surveys., Setting and Participants: Patients prescribed for by either NIPs or PIPs in six general practices from different regions in England., Results: 30% of patients responded (294/975; 149/525 NIPs; 145/450 PIPs). Most said they were very satisfied with their last visit (94%; 87%), they were told as much as they wanted to know about their medicines (88%; 80%), and felt the independent prescriber really understood their point of view (87%; 75%). They had a good relationship with (89%; 79%) and confidence in (84%; 77%) their NMP. When comparing NMP and doctor prescribing services, most patients reported no difference in their experience of care provided, including access to it, control of condition, support for adherence, quality and safety of care., Discussion and Conclusions: Patients had positive perceptions and experience from their NMP visit. NMPs were well received, and patients' responses indicated the establishment of rapport. They did not express a strong preference for care provided by either their non-medical or medical prescriber., (© 2013 John Wiley & Sons Ltd.)

Purpose: To evaluate the concurrent validity of three European sets of drug-specific indicators of prescribing quality, Methods: In 200 hip fracture patients (≥65 years), consecutively recruited to a randomized controlled study in Sahlgrenska University Hospital in 2009, quality of drug treatment at study entry was assessed according to a gold standard as well as to three drug-specific indicator sets (Swedish National Board of Health and Welfare, French consensus panel list, and German PRISCUS list). As gold standard, two specialist physicians independently assessed and then agreed on the quality for each patient, after initial screening with STOPP (Screening Tool of Older Persons' potentially inappropriate Prescriptions) and START (Screening Tool to Alert to Right Treatment)., Results: According to the Swedish, French, and German indicator sets, 82 (41%), 54 (27%), and 43 (22%) patients had potentially inappropriate drug treatment. A total of 141 (71%) patients had suboptimal drug treatment according to the gold standard. The sensitivity for the indicator sets was 0.51 (95% confidence interval: 0.43; 0.59), 0.33 (0.26; 0.41), and 0.29 (0.22; 0.37), respectively. The specificity was 0.83 (0.72; 0.91), 0.88 (0.77; 0.94), and 0.97 (0.88; 0.99). Suboptimal drug treatment was 2.0 (0.8; 5.3), 1.9 (0.7; 5.1), and 6.1 (1.3; 28.6) times as common in patients with potentially inappropriate drug treatment according to the indicator sets, after adjustments for age, sex, cognition, residence, multi-dose drug dispensing, and number of drugs., Conclusions: In this setting, the indicator sets had high specificity and low sensitivity. This needs to be considered upon use and interpretation., (© 2015 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons, Ltd.)

Background: Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings., Methods: Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method., Results: A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47-4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62-0.93) and 0.98 (95%CI 0.85-1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively., Conclusion: Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events., (© 2015 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.)