Drug-drug-gene interaction risk among opioid users in the U.S. Department of Veterans Affairs.

ABSTRACT: Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol). A retrospective analysis was performed within the Veterans Health Administration evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012 to 2017. Among 2,436,654 Veterans Health Administration pharmacy users with at least 1 opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days-supply). Opioids were commonly coprescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n = 526,905) of these patients are at an elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizers at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers coprescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of coprescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%), and chart review suggests that test results were used to optimize antidepressant treatments rather than pain medications. Using PGx testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans.

Phase 2 study of sodium phenylbutyrate in ALS.

The objective of the study was to establish the safety and pharmacodynamics of escalating dosages of sodium phenylbutyrate (NaPB) in participants with ALS. Transcription dysregulation may play a role in the pathogenesis of ALS. Sodium phenylbutyrate, a histone deacetylase inhibitor, improves transcription and post-transcriptional pathways, promoting cell survival in a mouse model of motor neuron disease. Forty research participants at eight sites enrolled in an open-label study. Study medication was increased from 9 to 21 g/day. The primary outcome measure was tolerability. Secondary outcome measures included adverse events, blood histone acetylation levels, and NaPB blood levels at each dosage. Twenty-six participants completed the 20-week treatment phase. NaPB was safe and tolerable. No study deaths or clinically relevant laboratory changes occurred with NaPB treatment. Histone acetylation was decreased by approximately 50% in blood buffy-coat specimens at screening and was significantly increased after NaPB administration. Blood levels of NaPB and the primary metabolite, phenylacetate, increased with dosage. While the majority of subjects tolerated higher dosages of NaPB, the lowest dose (9 g/day), was therapeutically efficient in improving histone acetylation levels.

A pain assessment tool for people with advanced Alzheimer's and other progressive dementias.

Appropriate pain management can only be achieved through accurate pain assessment that is individualized, ongoing, and well documented. Assessment tools must focus on the patient as the authority on pain's existence and severity; however, self-reports are not feasible when patients lose their ability to verbally communicate. This article describes a scientifically proven pain assessment tool that can be used for patients with advanced dementia and Alzheimer's Disease.

Detecting adverse events in surgery: comparing events detected by the Veterans Health Administration Surgical Quality Improvement Program and the Patient Safety Indicators.

BACKGROUND: The Patient Safety Indicators (PSIs) use administrative data to screen for select adverse events (AEs). In this study, VA Surgical Quality Improvement Program (VASQIP) chart review data were used as the gold standard to measure the criterion validity of 5 surgical PSIs. Independent chart review was also used to determine reasons for PSI errors. METHODS: The sensitivity, specificity, and positive predictive value of PSI software version 4.1a were calculated among Veterans Health Administration hospitalizations (2003-2007) reviewed by VASQIP (n = 268,771). Nurses re-reviewed a sample of hospitalizations for which PSI and VASQIP AE detection disagreed. RESULTS: Sensitivities ranged from 31% to 68%, specificities from 99.1% to 99.8%, and positive predictive values from 31% to 72%. Reviewers found that coding errors accounted for some PSI-VASQIP disagreement; some disagreement was also the result of differences in AE definitions. CONCLUSIONS: These results suggest that the PSIs have moderate criterion validity; however, some surgical PSIs detect different AEs than VASQIP. Future research should explore using both methods to evaluate surgical quality.

How valid is the AHRQ Patient Safety Indicator "postoperative hemorrhage or hematoma"?

BACKGROUND: Postoperative hemorrhage or hematoma (PHH), an Agency for Healthcare Research and Quality Patient Safety Indicator, uses administrative data to detect cases of potentially preventable postsurgical bleeding requiring a reparative procedure. How accurately it identifies true events is unknown. We therefore determined PHH's positive predictive value. STUDY DESIGN: Using Patient Safety Indicator software (v.3.1a) and fiscal year 2003-2007 discharge data from 28 Veterans Health Administration hospitals, we identified 112 possible cases of PHH. Based on medical record abstraction, we characterized cases as true (TPs) or false positives (FPs), calculated positive predictive value, and analyzed FPs to ascertain reasons for incorrect identification and TPs to determine PHH-associated clinical consequences and risk factors. RESULTS: Eighty-four cases were TPs (positive predictive value, 75%; 95% CI, 66-83%); 63% had a hematoma diagnosis, 30% had a hemorrhage diagnosis, 7% had both. Reasons for FPs included events present on admission (29%); hemorrhage/hematoma identified and controlled during the original procedure rather than postoperatively (21%); or postoperative hemorrhage/hematoma that did not require a procedure (18%). Most TPs (82%) returned to the operating room for hemorrhage/hematoma management; 64% required blood products and 7% died in-hospital. The most common index procedures resulting in postoperative hemorrhage/hematoma were vascular (38%); 56% were performed by a physician-in-training (under supervision). We found no substantial association between physician training status or perioperative anticoagulant use and bleeding risk. CONCLUSIONS: PHH's accuracy could be improved by coding enhancements, such as adopting present on admission codes or associating a timing factor with codes dealing with bleeding control. The ability of PHH to identify events representing quality of care problems requires additional evaluation.

Validity of selected Patient Safety Indicators: opportunities and concerns.

BACKGROUND: The Agency for Healthcare Research and Quality (AHRQ) recently designed the Patient Safety Indicators (PSIs) to detect potential safety-related adverse events. The National Quality Forum has endorsed several of these ICD-9-CM-based indicators as quality-of-care measures. We examined the positive predictive value (PPV) of 3 surgical PSIs: postoperative pulmonary embolus and deep vein thrombosis (pPE/DVT), iatrogenic pneumothorax (iPTX), and accidental puncture and laceration (APL). STUDY DESIGN: We applied the AHRQ PSI software (v.3.1a) to fiscal year 2003 to 2007 Veterans Health Administration (VA) administrative data to identify (flag) patients suspected of having a pPE/DVT, iPTX, or APL. Two trained nurse abstractors reviewed a sample of 336 flagged medical records (112 records per PSI) using a standardized instrument. Inter-rater reliability was assessed. RESULTS: Of 2,343,088 admissions, 6,080 were flagged for pPE/DVT (0.26%), 1,402 for iPTX (0.06%), and 7,203 for APL (0.31%). For pPE/DVT, the PPV was 43% (95% CI, 34% to 53%); 21% of cases had inaccurate coding (eg, arterial not venous thrombosis); and 36% featured thromboembolism present on admission or preoperatively. For iPTX, the PPV was 73% (95% CI, 64% to 81%); 18% had inaccurate coding (eg, spontaneous pneumothorax), and 9% were pneumothoraces present on admission. For APL, the PPV was 85% (95% CI, 77% to 91%); 10% of cases had coding inaccuracies and 5% indicated injuries present on admission. However, 27% of true APLs were minor injuries requiring no surgical repair (eg, small serosal bowel tear). Inter-rater reliability was >90% for all 3 PSIs. CONCLUSIONS: Until coding revisions are implemented, these PSIs, especially pPE/DVT, should be used primarily for screening and case-finding. Their utility for public reporting and pay-for-performance needs to be reassessed.