Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.

Worth the Risk? Standardized Screening to Identify Substance Use Among Patients Prior to Surgery.

OBJECTIVE: We sought to compare identification of unhealthy substance use before surgery using The Tobacco, Alcohol, Prescription Medication, and Other Substance Use (TAPS), a standardized 4-item instrument, versus routine clinical documentation in the electronic medical record (EHR). SUMMARY BACKGROUND DATA: Over 20% of individuals exhibit unhealthy substance use before elective surgery. Routine EHR documentation is often based on non-standard questions that may not fully capture the extent of substance use and is subject to bias. In contrast, brief standardized screening could provide a more efficient and systematic approach. METHODS: We conducted a cross-sectional study among adults (≥18 y) at a preoperative clinic from August to September, 2021. Positive screens for unhealthy substances by TAPS were compared to data from the EHR. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were reported. Receiver operating characteristic curves (ROCs) were used to assess diagnostic ability. Multivariable logistic regression was used to estimate the predictors of positive screens by TAPS. RESULTS: The cohort included 240 surgical patients. TAPS screening identified significantly more positive screens than EHR documentation (43.3% vs. 14.2%). Patients with unhealthy substance use were younger (50.8 vs. 56.7 y; P=0.003), and TAPS revealed alcohol misuse in 30.8% of cases, contrasting with 0% in clinician documentation (P<0.001). Of the 104 TAPS-positive patients, 69.2% were missed by EHR documentation. Sensitivity (31%) and accuracy (AUC=0.65) of clinician documentation for any unhealthy substance use were lower compared to TAPS. CONCLUSION: Standardized TAPS screening detected preoperative unhealthy substance use more frequently than routine clinician documentation, emphasizing the need for integrating standardized measures into surgical practice to ensure safer perioperative care and outcomes.

The Association of Cannabis Use After Discharge From Surgery With Opioid Consumption and Patient-reported Outcomes.

OBJECTIVE: To compare outcomes of patients using versus not using cannabis as a treatment for pain after discharge from surgery. BACKGROUND: Cannabis is increasingly available and is often taken by patients to relieve pain. However, it is unclear whether cannabis use for pain after surgery impacts opioid consumption and postoperative outcomes. METHODS: Using Michigan Surgical Quality Collaborative registry data at 69 hospitals, we analyzed a cohort of patients undergoing 16 procedure types between January 1, 2021, and October 31, 2021. The key exposure was cannabis use for pain after surgery. Outcomes included postdischarge opioid consumption (primary) and patient-reported outcomes of pain, satisfaction, quality of life, and regret to undergo surgery (secondary). RESULTS: Of 11,314 included patients (58% females, mean age: 55.1 years), 581 (5.1%) reported using cannabis to treat pain after surgery. In adjusted models, patients who used cannabis consumed an additional 1.0 (95% CI: 0.4-1.5) opioid pills after surgery. Patients who used cannabis were more likely to report moderate-to-severe surgical site pain at 1 week (adjusted odds ratio: 1.7, 95% CIL 1.4-2.1) and 1 month (adjusted odds ratio: 2.1, 95% CI: 1.7-2.7) after surgery. Patients who used cannabis were less likely to endorse high satisfaction (72.1% vs 82.6%), best quality of life (46.7% vs 63.0%), and no regret (87.6% vs 92.7%) (all P < 0.001). CONCLUSIONS: Patient-reported cannabis use, to treat postoperative pain, was associated with increased opioid consumption after discharge from surgery that was of clinically insignificant amounts, but worse pain and other postoperative patient-reported outcomes.

The Association of Preoperative Opioid Use with Post-Discharge Outcomes: A Cohort Study of the Michigan Surgical Quality Collaborative.

OBJECTIVE: To examine the association of prescription opioid fills over the year prior to surgery with postoperative outcomes. BACKGROUND: Nearly one third of patients report opioid use in the year preceding surgery, yet an understanding of how opioid exposure influences patient-reported outcomes after surgery remains incomplete. Therefore, this study was designed to test the hypothesis that preoperative opioid exposure may impede recovery in the postoperative period. METHODS: This retrospective cohort study used a statewide clinical registry from 70 hospitals linked to opioid fulfillment data from the state's prescription drug monitoring program to categorize patients' preoperative opioid exposure as none (naïve), minimal, intermittent, or chronic. Outcomes were patient-reported pain intensity (primary), as well as 30-day clinical and patient-reported outcomes (secondary). RESULTS: Compared to opioid-naïve patients, opioid exposure was associated with higher reported pain scores at 30 days after surgery. Predicted probabilities was higher among the opioid exposed versus naive group for reporting moderate pain (43.5% [95% CI 42.6 - 44.4%] vs 39.3% [95% CI 38.5 - 40.1%]) and severe pain (13.% [95% CI 12.5 - 14.0%] vs 10.0% [95% CI 9.5 - 10.5%]), and increasing probability was associated increased opioid exposure for both outcomes. Clinical outcomes (incidence of ED visits, readmissions, and reoperation within 30-days) and patient-reported outcomes (reported satisfaction, regret, and quality of life) were also worse with increasing preoperative opioid exposure for most outcomes. CONCLUSIONS: This study is the first to examine the effect of presurgical opioid exposure on both clinical and non-clinical outcomes in a broad cohort of patients, and shows that exposure is associated with worse postsurgical outcomes. A key question to be addressed is whether and to what extent opioid tapering before surgery mitigates these risks after surgery.

Association Between Prescription Drug Monitoring Program Use Mandate and Opioid Prescribing and Patient-Reported Outcomes After Surgery.

OBJECTIVE: To evaluate changes in opioid prescribing and patient-reported outcomes after surgery following implementation of Michigan's prescription drug monitoring program (PDMP) use mandate in June 2018. BACKGROUND: Most states mandate clinicians to query prescription drug monitoring program (PDMP) databases before prescribing controlled substances. Whether these PDMP use mandates affect opioid prescribing and patient-reported outcomes after surgery is unclear, especially among patients with elevated "Narx" scores, a risk score for overdose death used in most PDMPs. METHODS: We conducted an interrupted time series analysis of a statewide surgical registry linked to Michigan's PDMP database. Analyses included adults undergoing general surgical procedures during January 2017-October 2019. Outcomes included monthly mean days supplied in dispensed opioid prescriptions (those filled within 3 days of discharge) and monthly mean scores for 3 patient-reported outcomes (pain in the week after surgery, care satisfaction, regret undergoing surgery). Segmented regression models were used to assess for level and slope changes in outcomes in June 2018. Analyses were repeated among patients with Narx scores ≥200, a threshold that defines the top quartile. RESULTS: Analyses included 21,897 patients. The mandate was associated with a -0.5 (95% CI: -0.8, -0.2) level decrease in mean days supplied in dispensed opioid prescriptions, but not with worsened patient-reported outcomes. Findings were similar among patients with Narx scores ≥200. CONCLUSIONS: Following implementation of Michigan's PDMP use mandate, the duration of opioid prescriptions decreased, but patient-reported outcomes did not worsen. Findings suggest PDMP use mandates may not be associated with worsened experience among general surgical patients.

Medicaid Insurance Predicts Increased Postoperative Care Encounters Among Patients on Long-Term Opioid Therapy.

OBJECTIVE: This study examined the association between insurance type and postoperative unplanned care encounters among patients on long-term opioid therapy prior to surgery. SUMMARY BACKGROUND DATA: Preoperative long-term opioid therapy is associated with unique risks and poorer outcomes following surgery. To date, the extent to which insurance coverage influences postoperative outcomes in this population remains unclear. METHODS: Among individuals receiving a supply of greater than 120 total days or at least 10 opioid prescriptions in the year prior to surgery, we examined patients with Medicaid or private insurance who underwent abdominopelvic surgery from 2017 to 2021 across 70 hospitals in the state of Michigan. The primary outcome was unplanned care encounters, defined as an emergency department visit or unplanned readmission within 30 days of discharge from surgery. Multivariable logistic regression was used to assess the likelihood of acute care events with insurance type as the primary covariate of interest. RESULTS: Among 1212 patients on long-term opioid therapy prior to surgery, 45.6% (n = 553) had Medicaid insurance. Overall, one in eight (n=151) patients met criteria for a postoperative unplanned care encounter within 30 days. The probability of an unplanned encounter was 4.5 percentage points higher among patients with Medicaid insurance compared to private insurance (95% CI: 0.5%, 8.4%). CONCLUSIONS: Among patients on preoperative long-term opioid therapy, unplanned care encounters were higher among patients with Medicaid when compared to private insurance. While this is likely multifactorial, differences by insurance status may point to disparities in underlying social determinants of health and suggest the need for postoperative care pathways that address these gaps.

Association Between State Limits on Opioid Prescribing and the Incidence of Persistent Postoperative Opioid Use Among Surgical Patients.

OBJECTIVE: To examine whether laws limiting opioid prescribing have been associated with reductions in the incidence of persistent postoperative opioid use. SUMMARY OF BACKGROUND DATA: In an effort to address the opioid epidemic, 26 states (as of 2018) have passed laws limiting opioid prescribing for acute pain. However, it is unknown whether these laws have achieved their reduced the risk of persistent postoperative opioid use. METHODS: We identified 957,639 privately insured patients undergoing one of 10 procedures between January 1, 2004 and September 30, 2018. We then estimated the association between persistent postoperative opioid use, defined as having filled ≥10 prescriptions or ≥120 days supply of opioids during postoperative days 91-365, and whether opioid prescribing limits were in effect on the day of surgery. States were classified as having: no limits, a limit of ≤7 days supply, or a limit of >7 days supply. The regression models adjusted for observable confounders such as patient comorbidities and also utilized a difference-in-differences approach, which relied on variation in state laws over time, to further minimize confounding. RESULTS: The adjusted incidence of persistent postoperative opioid use was 3.5% (95%CI 3.3%-3.7%) for patients facing a limit of ≤7 days supply, compared with 3.3% (95%CI 3.3%-3.3%) for patients facing no prescribing limits ( P = 0.13 for difference compared to no prescribing limits) and 3.4%, (95%CI 3.2%-3.6%) for patients facing a limit of >7 days supply ( P = 0.43 for difference compared to no prescribing limits). CONCLUSIONS: Laws limiting opioid prescriptions were not associated with subsequent reductions in persistent postoperative opioid use.

Identifying Persistent Opioid Use After Surgery: The Reliability of Pharmacy Dispensation Databases.

OBJECTIVE: The present study assessed concordance in perioperative opioid fulfillment data between Michigan's prescription drug monitoring program (PDMP) and a national pharmacy prescription database. BACKGROUND: PDMPs and pharmacy dispensation databases are widely utilized, yet no research has compared their opioid fulfilment data postoperatively. METHODS: This retrospective study included participants (N=19,823) from 2 registry studies at Michigan Medicine between July 1, 2016, and February 7, 2019. We assessed the concordance of opioid prescription fulfilment between the Michigan PDMP and a national pharmacy prescription database (Surescripts). The primary outcome was concordance of opioid fill data in the 91 to 180 days after surgical discharge, a time period frequently used to define persistent opioid use. Secondary outcomes included concordance of opioid dose and number of prescriptions fulfilled. Multinomial logistic regression analysis examined concordance across key subgroups. RESULTS: In total, 3076 participants had ≥1 opioid fulfillments 91 to 180 days after discharge, with 1489 (49%) documented in PDMP only, 243 (8%) in Surescripts only, and 1332 (43%) in both databases. Among participants with fulfillments in both databases, there were differences in the number (n=239; 18%) and dose (n=227; 17%). The PDMP database was more likely to capture fulfillment among younger and publicly insured participants, while Surescripts was more likely to capture fulfillment from counties bordering neighboring states. The prevalence of persistent opioid use was 10.7% using PDMP data, 5.5% using Surescripts data only, and 11.7% using both data resources. CONCLUSIONS: The state PDMP appears reliable for detecting opioid fulfillment after surgery, detecting 2 times more patients with persistent opioid use compared with Surescripts.

Safety and Distribution of Opioid Prescribing by U.S. Surgeons.

OBJECTIVE: To estimate high-risk prescribing patterns among opioid prescriptions from U.S. surgeons; to characterize the distribution of high-risk prescribing among surgeons. BACKGROUND: National data on the prevalence of opioid prescribing and high-risk opioid prescribing by U.S. surgeons are lacking. METHODS: Using the IQVIA Prescription Database, which reports dispensing from 92% of U.S. pharmacies, we identified opioid prescriptions from surgeons dispensed in 2019 to patients ages ≥12 years. "High-risk" prescriptions were characterized by: days supplied >7, daily dosage ≥50 oral morphine equivalents (OMEs), opioid-benzodiazepine overlap, and extended-release/long-acting opioid. We determined the proportion of opioid prescriptions, total OMEs, and high-risk prescriptions accounted for by "high-volume surgeons" (those in the ≥95th percentile for prescription counts). We used linear regression to identify characteristics associated with being a high-volume surgeon. RESULTS: Among 15,493,018 opioid prescriptions included, 7,036,481 (45.4%) were high-risk. Among 114,610 surgeons, 5753 were in the 95th percentile or above for prescription count, with ≥520 prescriptions dispensed in 2019. High-volume surgeons accounted for 33.5% of opioid prescriptions, 52.8% of total OMEs, and 44.2% of high-risk prescriptions. Among high-volume surgeons, 73.9% were orthopedic surgeons and 60.6% practiced in the South. Older age, male sex, specialty, region, and lack of affiliation with academic institutions or health systems were correlated with high-risk prescribing. CONCLUSIONS: The top 5% of surgeons account for 33.5% of opioid prescriptions and 45.4% of high-risk prescriptions. Quality improvement initiatives targeting these surgeons may have the greatest yield given their outsized role in high-risk prescribing.

Prevalence of Unhealthy Substance Use and Associated Characteristics Among Patients Presenting for Surgery.

OBJECTIVE: To assess the prevalence of and identify characteristics associated with unhealthy use before surgery. BACKGROUND: Although the escalation in US drug overdose deaths is apparent, the unhealthy use of substances among patients presenting for surgery is unclear. METHODS: We conducted a retrospective study of patients presenting for elective surgical procedures between December 2018 and July 2021 and prospectively recruited to 1 of 2 clinical research studies (Michigan Genomics Initiative, Prevention of Iatrogenic Opioid Dependence after Surgery Study). The primary outcome was unhealthy substance use in the past 12 months as determined using the Tobacco, Alcohol, Prescription medication, and other Substance use tool. RESULTS: Among 1912 patients, unhealthy substance use was reported in 768 (40.2%). The most common substances with unhealthy use were illicit drugs [385 (20.1%)], followed by alcohol 358 (18.7%)], tobacco [262 (13.7%)], and prescription medications [86 (4.5%)]. Patients reporting unhealthy substance use were significantly more likely to be younger, male [aOR: 1.95 (95% CI, 1.58-2.42)], and have higher scores for pain [aOR: 1.07 (95% CI, 1.02-1.13)], and anxiety [aOR: 1.03 (95% CI, 1.01-1.04)]. Unhealthy substance use was more common among surgical procedures of the forearm, wrist, and hand [aOR: 2.58 (95% CI, 1.01-6.55)]. CONCLUSIONS: As many as 2 in 5 patients in the preoperative period may present with unhealthy substance use before elective surgery. Given the potential impact of substance use on surgical outcomes, increased recognition of the problem by screening patients is a critical next step for surgeons and perioperative care teams.

Association Between Payer Type and Risk of Persistent Opioid Use After Surgery.

OBJECTIVE: To assess whether the risk of persistent opioid use after surgery varies by payer type. BACKGROUND: Persistent opioid use is associated with increased health care utilization and risk of opioid use disorder, opioid overdose, and mortality. Most research assessing the risk of persistent opioid use has focused on privately insured patients. Whether this risk varies by payer type is poorly understood. METHODS: This cross-sectional analysis of the Michigan Surgical Quality Collaborative database examined adults aged 18 to 64 years undergoing surgical procedures across 70 hospitals between January 1, 2017 and October 31, 2019. The primary outcome was persistent opioid use, defined a priori as 1+ opioid prescription fulfillment at (1) an additional opioid prescription fulfillment after an initial postoperative fulfillment in the perioperative period or at least 1 fulfillment in the 4 to 90 days after discharge and (2) at least 1 opioid prescription fulfillment in the 91 to 180 days after discharge. The association between this outcome and payer type was evaluated using logistic regression, adjusting for patient and procedure characteristics. RESULTS: Among 40,071 patients included, the mean age was 45.3 years (SD 12.3), 24,853 (62%) were female, 9430 (23.5%) were Medicaid-insured, 26,760 (66.8%) were privately insured, and 3889 (9.7%) were covered by other payer types. The rate of POU was 11.5% and 5.6% for Medicaid-insured and privately insured patients, respectively (average marginal effect for Medicaid: 2.9% (95% CI 2.3%-3.6%)). CONCLUSIONS: Persistent opioid use remains common among individuals undergoing surgery and higher among patients with Medicaid insurance. Strategies to optimize postoperative recovery should focus on adequate pain management for all patients and consider tailored pathways for those at risk.

High-risk Prescribing Following Surgery Among Payer Types for Patients on Chronic Opioids.

OBJECTIVE: Among those on chronic opioids, to determine whether patients with Medicaid coverage have higher rates of high-risk opioid prescribing following surgery compared with patients on private insurance. BACKGROUND: Following surgery, patients on chronic opioids experience gaps in transitions of care back to their usual opioid prescriber, but differences by payer type are not well understood. This study aimed to analyze how new high-risk opioid prescribing following surgery compares between Medicaid and private insurance. METHODS: In this retrospective cohort study through the Michigan Surgical Quality Collaborative, perioperative data from 70 hospitals across Michigan were linked to prescription drug monitoring program data. Patients with either Medicaid or private insurance were compared. The outcome of interest was new high-risk prescribing, defined as a new occurrence of: overlapping opioids or benzodiazepines, multiple prescribers, high daily doses, or long-acting opioids. Data were analyzed using multivariable regressions and a Cox regression model for return to usual prescriber. RESULTS: Among 1435 patients, 23.6% (95% CI: 20.3%-26.8%) with Medicaid and 22.7% (95% CI: 19.8%-25.6%) with private insurance experienced new, postoperative high-risk prescribing. New multiple prescribers was the greatest contributing factor for both payer types. Medicaid insurance was not associated with higher odds of high-risk prescribing (odds ratio: 1.067, 95% CI: 0.813-1.402). CONCLUSIONS: Among patients on chronic opioids, new high-risk prescribing following surgery was high across payer types. This highlights the need for future policies to curb high-risk prescribing patterns, particularly in vulnerable populations that are at risk of greater morbidity and mortality.

Postoperative Opioid Prescribing and New Persistent Opioid Use: The Risk of Excessive Prescribing.

OBJECTIVE: Evaluate the association between postoperative opioid prescribing and new persistent opioid use. SUMMARY BACKGROUND DATA: Opioid-nave patients who develop new persistent opioid use after surgery are at increased risk of opioid-related morbidity and mortality. However, the extent to which postoperative opioid prescribing is associated with persistent postoperative opioid use is unclear. METHODS: Retrospective study of opioid-naïve adults undergoing surgery in Michigan from 1/1/2017 to 10/31/2019. Postoperative opioid prescriptions were identified using a statewide clinical registry and prescription fills were identified using Michigan's prescription drug monitoring program. The primary outcome was new persistent opioid use, defined as filling at least 1 opioid prescription between post-discharge days 4 to 90 and filling at least 1 opioid prescription between post-discharge days 91 to 180. RESULTS: A total of 37,654 patients underwent surgery with a mean age of 52.2 (16.7) years and 20,923 (55.6%) female patients. A total of 31,920 (84.8%) patients were prescribed opioids at discharge. Six hundred twenty-two (1.7%) patients developed new persistent opioid use after surgery. Being prescribed an opioid at discharge was not associated with new persistent opioid use [adjusted odds ratio (aOR) 0.88 (95% confidence interval (CI) 0.71-1.09)]. However, among patients prescribed an opioid, patients prescribed the second largest [12 (interquartile range (IQR) 3) pills] and largest [20 (IQR 7) pills] quartiles of prescription size had higher odds of new persistent opioid use compared to patients prescribed the smallest quartile [7 (IQR 1) pills] of prescription size [aOR 1.39 (95% CI 1.04-1.86) andaOR 1.97 (95% CI 1.442.70), respectively]. CONCLUSIONS: In a cohort of opioid-naïve patients undergoing common surgical procedures, the risk of new persistent opioid use increased with the size of the prescription. This suggests that while opioid prescriptions in and of themselves may not place patients at risk of long-term opioid use, excessive prescribing does. Consequently, these findings support ongoing efforts to mitigate excessive opioid prescribing after surgery to reduce opioid-related harms.

Evidence-Based Opioid Prescribing Guidelines and New Persistent Opioid Use After Surgery.

OBJECTIVE: Evaluate the association of evidence-based opioid prescribing guidelines with new persistent opioid use after surgery. SUMMARY BACKGROUND DATA: Patients exposed to opioids after surgery are at risk of new persistent opioid use, which is associated with opioid use disorder and overdose. It is unknown whether evidence-based opioid prescribing guidelines mitigate this risk. METHODS: Using Medicare claims, we performed a difference-in-differences study of opioid-naive patients who underwent 1 of 6 common surgical procedures for which evidence-based postoperative opioid prescribing guidelines were released and disseminated through a statewide quality collaborative in Michigan in October 2017. The primary outcome was the incidence of new persistent opioid use, and the secondary outcome was total postoperative opioid prescription quantity in oral morphine equivalents (OME). RESULTS: We identified 24,908 patients who underwent surgery in Michigan and 118,665 patients who underwent surgery outside of Michigan. Following the release of prescribing guidelines in Michigan, the adjusted incidence of new persistent opioid use decreased from 3.29% (95% CI 3.15-3.43%) to 2.51% (95% CI 2.35-2.67%) in Michigan, which was an additional 0.53 (95% CI 0.36-0.69) percentage point decrease compared with patients outside of Michigan. Simultaneously, adjusted opioid prescription quantity decreased from 199.5 (95% CI 198.3-200.6) mg OME to 88.6 (95% CI 78.7-98.5) mg OME in Michigan, which was an additional 55.7 (95% CI 46.5-65.4) mg OME decrease compared with patients outside of Michigan. CONCLUSIONS: Evidence-based opioid prescribing guidelines were associated with a significant reduction in the incidence of new persistent opioid use and the quantity of opioids prescribed after surgery.

Long-term Health Outcomes of New Persistent Opioid Use After Surgery Among Medicare Beneficiaries.

OBJECTIVE: We examined long-term health outcomes associated with new persistent opioid use after surgery and hypothesized that patients with new persistent opioid use would have poorer overall health outcomes compared with those who did not develop new persistent opioid use after surgery. BACKGROUND: New persistent opioid use is a common surgical complication. Long-term opioid use increases risk of mortality, fractures, and falls; however, less is known about health care utilization among older adults with new persistent opioid use after surgical care. METHODS: We analyzed claims from a 20% national sample of Medicare beneficiaries ≥65 years undergoing surgery between January 1, 2009, and June 30, 2019. We estimated associations between new persistent use and subsequent health events between 6 and 12 months after surgery, including mortality, serious fall/fall-related injury, and respiratory or opioid/pain-related readmission/emergency department (ED) visits using a Cox proportional hazards model to estimate mortality and multivariable logistic regression for the remaining outcomes, adjusting for demographic/clinical characteristics. Our primary outcome was mortality within 6 to 12 months after surgery. Secondary outcomes included falls and readmissions or ED visits (respiratory, pain related/opioid related) within 6 to 12 months after surgery. RESULTS: Of 229,898 patients, 6874 (3.0%) developed new persistent opioid use. Compared with patients who did not develop new persistent opioid use, patients with new persistent opioid use had a higher risk of mortality (hazard ratio 3.44, CI, 2.99-3.96), falls [adjusted odds ratio (aOR): 1.21, 95% CI, 1.05-1.39], and respiratory-related (aOR: 1.67, 95% CI, 1.49-1.86) or pain-related/opioid-related (aOR: 1.68, 95% CI, 1.55-1.82) readmissions/ED visits. CONCLUSIONS: New persistent opioid use after surgery is associated with increased mortality and poorer health outcomes after surgery. Although the mechanisms that underlie this risk are not clear, persistent opioid use may also be a marker for greater morbidity requiring more care in the late postoperative period. Increased awareness of individuals at risk for new persistent use after surgery and close follow-up in the late postoperative period is critical to mitigate the harms associated with new persistent use.

Association between nociplastic pain and premature endocrine therapy discontinuation in breast cancer patients.

PURPOSE: At least 5 years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation. METHODS: This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and Chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models. RESULTS: Six hundred eighty-one patients diagnosed between 2012 and 2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation. CONCLUSION: Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain.

Association of Genetic Variants with Postsurgical Pain: A Systematic Review and Meta-analyses.

BACKGROUND: Postsurgical pain is a key component of surgical recovery. However, the genetic drivers of postsurgical pain remain unclear. A broad review and meta-analyses of variants of interest will help investigators understand the potential effects of genetic variation. METHODS: This article is a systematic review of genetic variants associated with postsurgical pain in humans, assessing association with postsurgical pain scores and opioid use in both acute (0 to 48 h postoperatively) and chronic (at least 3 months postoperatively) settings. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from 2000 to 2022 for studies using search terms related to genetic variants and postsurgical pain in humans. English-language studies in adult patients examining associations of one or more genetic variants with postsurgical pain were included. The primary outcome was association of genetic variants with either acute or chronic postsurgical pain. Pain was measured by patient-reported pain score or analgesic or opioid consumption. RESULTS: A total of 163 studies were included, evaluating 129 unique genes and 594 unique genetic variants. Many of the reported significant associations fail to be replicated in other studies. Meta-analyses were performed for seven variants for which there was sufficient data (OPRM1 rs1799971; COMT rs4680, rs4818, rs4633, and rs6269; and ABCB1 rs1045642 and rs2032582). Only two variants were associated with small differences in postsurgical pain: OPRM1 rs1799971 (for acute postsurgical opioid use standard mean difference = 0.25; 95% CI, 0.16 to 0.35; cohort size, 8,227; acute postsurgical pain score standard mean difference = 0.20; 95% CI, 0.09 to 0.31; cohort size, 4,619) and COMT rs4680 (chronic postsurgical pain score standard mean difference = 0.26; 95% CI, 0.08 to 0.44; cohort size, 1,726). CONCLUSIONS: Despite much published data, only two alleles have a small association with postsurgical pain. Small sample sizes, potential confounding variables, and inconsistent findings underscore the need to examine larger cohorts with consistent outcome measures.

Prolonged Opioid Use and Pain Outcome and Associated Factors after Surgery under General Anesthesia: A Prospective Cohort Association Multicenter Study.

BACKGROUND: There is insufficient prospective evidence regarding the relationship between surgical experience and prolonged opioid use and pain. The authors investigated the association of patient characteristics, surgical procedure, and perioperative anesthetic course with postoperative opioid consumption and pain 3 months postsurgery. The authors hypothesized that patient characteristics and intraoperative factors predict opioid consumption and pain 3 months postsurgery. METHODS: Eleven U.S. and one European institution enrolled patients scheduled for spine, open thoracic, knee, hip, or abdominal surgery, or mastectomy, in this multicenter, prospective observational study. Preoperative and postoperative data were collected using patient surveys and electronic medical records. Intraoperative data were collected from the Multicenter Perioperative Outcomes Group database. The association between postoperative opioid consumption and surgical site pain at 3 months, elicited from a telephone survey conducted at 3 months postoperatively, and demographics, psychosocial scores, pain scores, pain management, and case characteristics, was analyzed. RESULTS: Between September and October 2017, 3,505 surgical procedures met inclusion criteria. A total of 1,093 cases were included; 413 patients were lost to follow-up, leaving 680 (64%) for outcome analysis. Preoperatively, 135 (20%) patients were taking opioids. Three months postsurgery, 96 (14%) patients were taking opioids, including 23 patients (4%) who had not taken opioids preoperatively. A total of 177 patients (27%) reported surgical site pain, including 45 (13%) patients who had not reported pain preoperatively. The adjusted odds ratio for 3-month opioid use was 18.6 (credible interval, 10.3 to 34.5) for patients who had taken opioids preoperatively. The adjusted odds ratio for 3-month surgical site pain was 2.58 (1.45 to 4.4), 4.1 (1.73 to 8.9), and 2.75 (1.39 to 5.0) for patients who had site pain preoperatively, knee replacement, or spine surgery, respectively. CONCLUSIONS: Preoperative opioid use was the strongest predictor of opioid use 3 months postsurgery. None of the other variables showed clinically significant association with opioid use at 3 months after surgery.

An Interventional Response Phenotyping Study in Chronic Low Back Pain: Protocol for a Mechanistic Randomized Controlled Trial.

Evidence-based treatments for chronic low back pain (cLBP) typically work well in only a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients. Our central hypothesis is that an interventional response phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based treatments for cLBP. Thus, we will conduct a randomized controlled Sequential, Multiple Assessment, Randomized Trial (SMART) design study in cLBP with the following three aims. Aim 1: Perform an interventional response phenotyping study in a cohort of cLBP patients (n = 400), who will receive a sequence of interventions known to be effective in cLBP. For 4 weeks, all cLBP participants will receive a web-based pain self-management program as part of a run-in period, then individuals who report no or minimal improvement will be randomized to: a) mindfulness-based stress reduction, b) physical therapy and exercise, c) acupressure self-management, and d) duloxetine. After 8 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 8 weeks. Using those data, we will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically derived measures, can predict differential responsiveness to the treatments. In Aim 3, a subset of participants will receive deeper phenotyping (n = 160), to identify new experimental measures that predict differential responsiveness to the treatments, as well as to infer mechanisms of action. Deep phenotyping will include functional neuroimaging, quantitative sensory testing, measures of inflammation, and measures of autonomic tone.

LabWAS: Novel findings and study design recommendations from a meta-analysis of clinical labs in two independent biobanks.

Phenotypes extracted from Electronic Health Records (EHRs) are increasingly prevalent in genetic studies. EHRs contain hundreds of distinct clinical laboratory test results, providing a trove of health data beyond diagnoses. Such lab data is complex and lacks a ubiquitous coding scheme, making it more challenging than diagnosis data. Here we describe the first large-scale cross-health system genome-wide association study (GWAS) of EHR-based quantitative laboratory-derived phenotypes. We meta-analyzed 70 lab traits matched between the BioVU cohort from the Vanderbilt University Health System and the Michigan Genomics Initiative (MGI) cohort from Michigan Medicine. We show high replication of known association for these traits, validating EHR-based measurements as high-quality phenotypes for genetic analysis. Notably, our analysis provides the first replication for 699 previous GWAS associations across 46 different traits. We discovered 31 novel associations at genome-wide significance for 22 distinct traits, including the first reported associations for two lab-based traits. We replicated 22 of these novel associations in an independent tranche of BioVU samples. The summary statistics for all association tests are freely available to benefit other researchers. Finally, we performed mirrored analyses in BioVU and MGI to assess competing analytic practices for EHR lab traits. We find that using the mean of all available lab measurements provides a robust summary value, but alternate summarizations can improve power in certain circumstances. This study provides a proof-of-principle for cross health system GWAS and is a framework for future studies of quantitative EHR lab traits.