Browsing by Subject "Opioid analgesics"
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Item A Novel Perioperative Multidose Methadone-Based Multimodal Analgesic Strategy in Children Achieved Safe and Low Analgesic Blood Methadone Levels Enabling Opioid-Sparing Sustained Analgesia With Minimal Adverse Effects(Wolters Kluwer, 2021) Sadhasivam, Senthilkumar; Aruldhas, Blessed W.; Packiasabapathy, Senthil; Overholser, Brian R.; Zhang, Pengyue; Zang, Yong; Renschler, Janelle S.; Fitzgerald, Ryan E.; Quinney, Sara K.; Anesthesia, School of MedicineBackground: Intraoperative methadone, a long-acting opioid, is increasingly used for postoperative analgesia, although the optimal methadone dosing strategy in children is still unknown. The use of a single large dose of intraoperative methadone is controversial due to inconsistent reductions in total opioid use in children and adverse effects. We recently demonstrated that small, repeated doses of methadone intraoperatively and postoperatively provided sustained analgesia and reduced opioid use without respiratory depression. The aim of this study was to characterize pharmacokinetics, efficacy, and safety of a multiple small-dose methadone strategy. Methods: Adolescents undergoing posterior spinal fusion (PSF) for idiopathic scoliosis or pectus excavatum (PE) repair received methadone intraoperatively (0.1 mg/kg, maximum 5 mg) and postoperatively every 12 hours for 3-5 doses in a multimodal analgesic protocol. Blood samples were collected up to 72 hours postoperatively and analyzed for R-methadone and S-methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP) metabolites, and alpha-1 acid glycoprotein (AAG), the primary methadone-binding protein. Peak and trough concentrations of enantiomers, total methadone, and AAG levels were correlated with clinical outcomes including pain scores, postoperative nausea and vomiting (PONV), respiratory depression, and QT interval prolongation. Results: The study population included 38 children (10.8-17.9 years): 25 PSF and 13 PE patients. Median total methadone peak plasma concentration was 24.7 (interquartile range [IQR], 19.2-40.8) ng/mL and the median trough was 4.09 (IQR, 2.74-6.4) ng/mL. AAG concentration almost doubled at 48 hours after surgery (median = 193.9, IQR = 86.3-279.5 µg/mL) from intraoperative levels (median = 87.4, IQR = 70.6-115.8 µg/mL; P < .001), and change of AAG from intraoperative period to 48 hours postoperatively correlated with R-EDDP (P < .001) levels, S-EDDP (P < .001) levels, and pain scores (P = .008). Median opioid usage was minimal, 0.66 (IQR, 0.59-0.75) mg/kg morphine equivalents/d. No respiratory depression (95% Wilson binomial confidence, 0-0.09) or clinically significant QT prolongation (median = 9, IQR = -10 to 28 milliseconds) occurred. PONV occurred in 12 patients and was correlated with morphine equivalent dose (P = .005). Conclusions: Novel multiple small perioperative methadone doses resulted in safe and lower blood methadone levels, <100 ng/mL, a threshold previously associated with respiratory depression. This methadone dosing in a multimodal regimen resulted in lower blood methadone analgesia concentrations than the historically described minimum analgesic concentrations of methadone from an era before multimodal postoperative analgesia without postoperative respiratory depression and prolonged corrected QT (QTc). Larger studies are needed to further study the safety and efficacy of this methadone dosing strategy.Item Association of a Positive Drug Screening for Cannabis With Mortality and Hospital Visits Among Veterans Affairs Enrollees Prescribed Opioids(American Medical Association, 2022-12-01) Keyhani, Salomeh; Leonard, Samuel; Byers, Amy L.; Zaman, Tauheed; Krebs, Erin; Austin, Peter C.; Moss-Vazquez, Tristan; Austin, Charles; Sandbrink, Friedhelm; Bravata, Dawn M.; Medicine, School of MedicineImportance: Cannabis has been proposed as a therapeutic with potential opioid-sparing properties in chronic pain, and its use could theoretically be associated with decreased amounts of opioids used and decreased risk of mortality among individuals prescribed opioids. Objective: To examine the risks associated with cannabis use among adults prescribed opioid analgesic medications. Design, setting, and participants: This cohort study was conducted among individuals aged 18 years and older who had urine drug screening in 2014 to 2019 and received any prescription opioid in the prior 90 days or long-term opioid therapy (LTOT), defined as more than 84 days of the prior 90 days, through the Veterans Affairs health system. Data were analyzed from November 2020 through March 2022. Exposures: Biologically verified cannabis use from a urine drug screen. Main outcomes and measures: The main outcomes were 90-day and 180-day all-cause mortality. A composite outcome of all-cause emergency department (ED) visits, all-cause hospitalization, or all-cause mortality was a secondary outcome. Weights based on the propensity score were used to reduce confounding, and hazard ratios [HRs] were estimated using Cox proportional hazards regression models. Analyses were conducted among the overall sample of patients who received any prescription opioid in the prior 90 days and were repeated among those who received LTOT. Analyses were repeated among adults aged 65 years and older. Results: Among 297 620 adults treated with opioids, 30 514 individuals used cannabis (mean [SE] age, 57.8 [10.5] years; 28 784 [94.3%] men) and 267 106 adults did not (mean [SE] age, 62.3 [12.3] years; P < .001; 247 684 [92.7%] men; P < .001). Among all patients, cannabis use was not associated with increased all-cause mortality at 90 days (HR, 1.07; 95% CI, 0.92-1.22) or 180 days (HR, 1.00; 95% CI, 0.90-1.10) but was associated with an increased hazard of the composite outcome at 90 days (HR, 1.05; 95% CI, 1.01-1.07) and 180 days (HR, 1.04; 95% CI, 1.01-1.06). Among 181 096 adults receiving LTOT, cannabis use was not associated with increased risk of all-cause mortality at 90 or 180 days but was associated with an increased hazard of the composite outcome at 90 days (HR, 1.05; 95% CI, 1.02-1.09) and 180 days (HR, 1.05; 95% CI, 1.02-1.09). Among 77 791 adults aged 65 years and older receiving LTOT, cannabis use was associated with increased 90-day mortality (HR, 1.55; 95% CI, 1.17-2.04). Conclusions and relevance: This study found that cannabis use among adults receiving opioid analgesic medications was not associated with any change in mortality risk but was associated with a small increased risk of adverse outcomes and that short-term risks were higher among older adults receiving LTOT.Item Association of Individual and Community Factors With Hepatitis C Infections Among Pregnant People and Newborns(American Medical Association, 2021-10-29) Patrick, Stephen W.; Dupont, William D.; McNeer, Elizabeth; McPheeters, Melissa; Cooper, William O.; Aronoff, David M.; Osmundson, Sarah; Stein, Bradley D.; Medicine, School of MedicineImportance: The opioid crisis has increasingly affected pregnant people and infants. Hepatitis C virus (HCV) infections, a known complication of opioid use, grew in parallel with opioid-related complications; however, the literature informing individual and community risks associated with maternal HCV infection is sparse. Objectives: To determine (1) individual and county-level factors associated with HCV among pregnant people and their newborn infants, and (2) how county-level factors influence individual risk among the highest risk individuals. Design setting and participants: This time-series analysis of retrospective, repeated cross-sectional data included pregnant people in all US counties from 2009 to 2019. We constructed mixed-effects logistic regression models to explore the association between HCV infection and individual and county-level covariates. Analyses were conducted between June 2019 and September 2021. Exposures: Individual-level: race and ethnicity, education, marital status, insurance type; county-level: rurality, employment, density of obstetricians. Main outcomes and measures: Hepatitis C virus as indicated on the newborn's birth certificate. Results: Between 2009 and 2019, there were 39 380 122 pregnant people who met inclusion criteria, among whom 138 343 (0.4%) were diagnosed with HCV. People with HCV were more likely to be White (79.9% vs 53.5%), American Indian or Alaska Native (AI/AN) (2.9% vs 0.9%), be without a 4-year degree (93.2% vs 68.6%), and be unmarried (73.7% vs 38.8%). The rate (per 1000 live births) of HCV among pregnant people increased from 1.8 to 5.1. In adjusted analyses, the following factors were associated with higher rates of HCV: individuals identified as White (adjusted odds ratio [aOR], 7.37; 95% CI, 7.20-7.55) and AI/AN (aOR, 7.94; 95% CI, 7.58-8.31) compared with Black individuals, those without a 4-year degree (aOR, 3.19; 95% CI, 3.11-3.28), those with Medicaid vs private insurance (aOR, 3.27; 95% CI, 3.21-3.33), and those who were unmarried (aOR, 2.80; 95% CI, 2.76-2.84); whereas, rural residence, higher rates of employment, and greater density of obstetricians was associated with lower risk of HCV. Among individuals at the highest risk of HCV, higher levels of county employment, accounting for other factors, were associated with less of a rise in HCV infections over time. Conclusions and relevance: In this cross-sectional study, maternal and newborn HCV infections increased substantially between 2009 and 2019, disproportionately among White and AI/AN people without a 4-year degree. County-level factors, including higher levels of employment, were associated with lower individual risks of acquiring the virus.Item Associations of opioid prescription dose and discontinuation with risk of substance-related morbidity in long-term opioid therapy(Wolters Kluwer, 2022) Quinn, Patrick D.; Chang, Zheng; Bair, Matthew J.; Rickert, Martin E.; Gibbons, Robert D.; Kroenke, Kurt; D’Onofrio, Brian M.; Medicine, School of MedicineEfforts to reduce opioid-related harms have decreased opioid prescription but have provoked concerns about unintended consequences, particularly for long-term opioid therapy (LtOT) recipients. Research is needed to address the knowledge gap regarding how risk of substance-related morbidity changes across LtOT and its discontinuation. This study used nationwide commercial insurance claims data and a within-individual design to examine associations of LtOT dose and discontinuation with substance-related morbidity. We identified 194,839 adolescents and adults who initiated opioid prescription in 2010 to 2018 and subsequently received LtOT. The cohort was followed for a median of 965 days (interquartile range, 525-1550), of which a median of 176 days (119-332) were covered by opioid prescription. During follow-up, there were 17,582 acute substance-related morbidity events, defined as claims for emergency visits, inpatient hospitalizations, and ambulance transportation with substance use disorder or overdose diagnoses. Relative to initial treatment, risk was greater within individual during subsequent periods of >60 to 120 (adjusted odds ratio [OR], 1.29; 95% CI, 1.12 to 1.49) and >120 (OR, 1.48; 95% CI, 1.24-1.76) daily morphine milligram equivalents. Risk was also greater during days 1 to 30 after discontinuations than during initial treatment (OR, 1.19; 95% CI, 1.05-1.35). However, it was no greater than during the 30 days before discontinuations, indicating that the risk may not be wholly attributable to discontinuation itself. Results were supported by a negative control pharmacotherapy analysis and additional sensitivity analyses. They suggest that LtOT recipients may experience increased substance-related morbidity risk during treatment subsequent to initial opioid prescription, particularly in periods involving higher doses.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Codeine Therapy in the Context of Cytochrome P450 2D6 (CYP2D6) Genotype(Wiley, 2012-02) Crews, K.R.; Gaedigk, A.; Dunnenberger, H.M.; Klein, T.E.; Shen, D.D.; Callaghan, J.T.; Kharasch, E.D.; Skaar, Todd C.Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.Item Clinician Willingness to Prescribe Medications for Opioid Use Disorder to Adolescents in Indiana(American Medical Association, 2024-09-03) Aalsma, Matthew C.; Bell, Lauren A.; Schwartz, Katherine; Ouyang, Fangqian; Kolak, Marynia; Monahan, Patrick O.; Mermelstein, Sharon P.; Carson, Ian; Hulvershorn, Leslie A.; Adams, Zachary W.; Psychiatry, School of MedicineImportance: Prescribing medications for opioid use disorders (MOUD), including buprenorphine, naltrexone, and methadone, to adolescents remains an underused evidence-based strategy for reducing harms associated with opioid use. Objective: To identify potential associations between clinician- and community-level characteristics regarding clinicians' self-reported willingness to prescribe MOUD to adolescents. Design, setting, and participants: This cross-sectional study included a phone survey of Indiana clinicians and spatial analysis of community-level characteristics. Clinicians were eligible for inclusion in analyses if actively providing health care and listed on the Buprenorphine Practitioner Locator website, a publicly available national registry of clinicians possessing a waiver to legally prescribe buprenorphine (ie, waivered clinicians). Exposures: Community-level characteristics, including total population, rurality or urbanicity, percentage with incomes below the federal poverty line, and racial or ethnic makeup. Main outcomes and measures: Clinicians were asked about their willingness to prescribe MOUD to adolescents younger than 18 years if clinically indicated. Responses were recorded as no, yes, or yes with conditions. Results: Among the 871 clinicians listed on the website as of July 2022, 832 were eligible for inclusion and contacted by phone. Among waivered clinicians, 759 (91.2%) reported being unwilling to prescribe MOUD to adolescents, 73 clinicians (8.8%) reported willingness to prescribe MOUD to adolescents, and only 24 (2.9%) would do so without conditions. A multivariable logistic regression model including spatially lagged community-level variables showed that, among areas with waivered clinicians, clinicians practicing in more populated areas were significantly less likely to prescribe to adolescents (β = 0.65; 95% CI, 0.49-0.87; P = .003). Similarly, those in more rural areas were significantly more likely to prescribe to adolescents (β = 1.27; 95% CI, 1.02-1.58; P = .03). Variation in clinician willingness to prescribe was not explained by other community-level characteristics. Among all waivered clinicians, advanced practice clinicians were less likely than physicians to report willingness to prescribe (β = 0.58; 95% CI, 0.35-0.97; P = .04), as were physicians without any specialty training relevant to MOUD prescribing when compared with family medicine clinicians (β = 0.40; 95% CI, 0.18-0.89; P = .03). A small subgroup of waivered clinicians had training in pediatrics (13 clinicians [1.6%]), and none were willing to prescribe MOUD to adolescents. Conclusions and relevance: From this cross-sectional study, it appears that Indiana adolescents continued to face gaps in access to MOUD treatment, despite its well-established efficacy. Programs that support primary care practitioners, including family medicine clinicians and pediatricians, in safe and appropriate use of MOUD in adolescents may bridge these gaps.Item Correction to: Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS)(Springer Nature, 2021) Pizzagalli, Diego A.; Smoski, Moria; Ang, Yuen-Siang; Whitton, Alexis E.; Sanacora, Gerard; Mathew, Sanjay J.; Nurnberger, John, Jr.; Lisanby, Sarah H.; Iosifescu, Dan V.; Murrough, James W.; Yang, Hongqiu; Weiner, Richard D.; Calabrese, Joseph R.; Goodman, Wayne; Potter, William Z.; Krystal, Andrew D.; Psychiatry, School of MedicineCorrection to: Neuropsychopharmacology 10.1038/s41386-020-0738-4, published online 16 June 2020 In this article a conflict of interest was missing. The co-author Sanjay J. Mathew served as a consultant to Alkermes. The original article has been corrected. The original article can be found online at 10.1038/s41386-020-0738-4.Item Effect of Medication Optimization vs Cognitive Behavioral Therapy Among US Veterans With Chronic Low Back Pain Receiving Long-term Opioid Therapy: A Randomized Clinical Trial(American Medical Association, 2022-11-01) Bushey, Michael A.; Slaven, James E.; Outcalt, Samantha D.; Kroenke, Kurt; Kempf, Carol; Froman, Amanda; Sargent, Christy; Baecher, Brad; Zillich, Alan J.; Damush, Teresa M.; Saha, Chandan; French, Dustin D.; Bair, Matthew J.; Psychiatry, School of MedicineImportance: Medication management and cognitive behavioral therapy (CBT) are commonly used treatments for chronic low back pain (CLBP). However, little evidence is available comparing the effectiveness of these approaches. Objective: To compare collaborative care medication optimization vs CBT on pain intensity, interference, and other pain-related outcomes. Design, setting, and participants: The Care Management for the Effective Use of Opioids (CAMEO) trial was a 12-month, comparative effectiveness randomized clinical trial with blinded outcome assessment. Recruitment of veterans with CLBP prescribed long-term opioids occurred at 7 Veterans Affairs primary care clinics from September 1, 2011, to December 31, 2014, and follow-up was completed December 31, 2015. Analyses were based on intention to treat in all randomized participants and were performed from March 22, 2015, to November 1, 2021. Interventions: Patients were randomized to receive either collaborative care with nurse care manager-delivered medication optimization (MED group) (n = 131) or psychologist-delivered CBT (CBT group) (n = 130) for 6 months, with check-in visits at 9 months and final outcome assessment at 12 months. Main outcomes and measures: The primary outcome was change in Brief Pain Inventory (BPI) total score, a composite of the pain intensity and interference subscales at 6 (treatment completion) and 12 (follow-up completion) months. Scores on the BPI range from 0 to 10, with higher scores representing greater pain impact and a 30% improvement considered a clinically meaningful treatment response. Secondary outcomes included pain-related disability, pain catastrophizing, self-reported substance misuse, health-related quality of life, depression, and anxiety. Results: A total of 261 patients (241 [92.3%] men; mean [SD] age, 57.9 [9.5] years) were randomized and included in the analysis. Baseline mean (SD) BPI scores in the MED and CBT groups were 6.45 (1.79) and 6.49 (1.67), respectively. Improvements in BPI scores were significantly greater in the MED group at 12 months (between-group difference, -0.54 [95% CI, -1.18 to -0.31]; P = .04) but not at 6 months (between-group difference, -0.46 [95% CI, -0.94 to 0.11]; P = .07). Secondary outcomes did not differ significantly between treatment groups. Conclusions and relevance: In this randomized clinical trial among US veterans with CLBP who were prescribed long-term opioid therapy, collaborative care medication optimization was modestly more effective than CBT in reducing pain impact during the 12-month study. However, this difference may not be clinically meaningful or generalize to nonveteran populations.Item Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators(Wiley, 2024) Skaar, Todd C.; Myers, Rachel A.; Fillingim, Roger B.; Callaghan, John T.; Cicali, Emily; Eadon, Michael T.; Elwood, Erica N.; Ginsburg, Geoffrey S.; Lynch, Sheryl; Nguyen, Khoa A.; Obeng, Aniwaa Owusu; Park, Haesuk; Pratt, Victoria M.; Rosenman, Marc; Sadeghpour, Azita; Shuman, Saskia; Singh, Rajbir; Tillman, Emma M.; Volpi, Simona; Wiisanen, Kristin; Winterstein, Almut G.; Horowitz, Carol R.; Voora, Deepak; Orlando, Lori; Chakraborty, Hrishikesh; Van Driest, Sara; Peterson, Josh F.; Cavallari, Larisa A.; Johnson, Julie A.; Dexter, Paul R.; IGNITE Pragmatic Trials Network; Medicine, School of MedicineChronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.Item Individual factors predict substance use treatment course patterns among patients in community-based substance use disorder treatment(Public Library of Science, 2023-01-12) Argyriou, Evangelia; Bakoyannis, Giorgos; Wu, Wei; Rattermann, Mary Jo; Cyders, Melissa A.; Psychology, School of ScienceBackground and objectives: Substance use disorders (SUDs) usually involve a complex natural trajectory of recovery alternating with symptom reoccurrence. This study examined treatment course patterns over time in a community SUD clinic. We examined depressive symptoms level, primary SUD assigned at each admission, and lifetime misuse of multiple substances as potential risk factors for premature treatment termination and subsequent treatment readmission. Methods: De-identified longitudinal data were extracted from charts of 542 patients from an SUD treatment center. Survival analysis methods were applied to predict two time-to-event outcomes: premature treatment termination and treatment readmission. Results: Primary opioid (vs alcohol) use disorder diagnosis at admission was associated with higher hazard of premature termination (HR = 1.91, p<0.001). The interaction between depressive symptoms level and substance use status (multiple vs single use) on treatment readmission was significant (p = 0.024), such that higher depressive symptoms level was predictive of readmission only among those with a history of single substance use (marginally significant effect). Lifetime use of multiple (vs single) substances (HR = 1.55, p = 0.002) and age (HR = 1.01, p = 0.019) predicted increased hazard of readmission. Conclusions: Findings did not support a universal role for depressive symptoms level in treatment course patterns. Primary SUD diagnosis, age, and history of substance misuse can be easily assessed and incorporated into treatment planning to support SUD patients and families. This study is the first to our knowledge that afforded a stringent test of these relationships and their interactions in a time-dependent, recurrent event, competing risks survival analysis examining both termination and readmission patterns utilizing a real-world clinic-based sample.