Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant.

Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have an extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLIs) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), -15, and -18 to generate memory-like (ML) NK cells with enhanced antileukemia responses. We treated 9 pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells in a phase 1 trial. Patients received fludarabine, cytarabine, and filgrastim followed 2 weeks later by infusion of donor lymphocytes and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical and matched-related and -unrelated donors. After infusion, donor-derived ML NK cells expanded and maintained an ML multidimensional mass cytometry phenotype for >3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered interferon-γ production. After DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for >3 months, with 1 patient in remission for >2 years. No significant toxicity was experienced. This study demonstrates that, in a compatible post-HCT immune environment, donor ML NK cells robustly expand and persist with potent antileukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://clinicaltrials.gov as #NCT03068819.

Utility of the Pain Medication Questionnaire to predict aberrant urine drug tests: Results from a longitudinal cohort study.

Identifying patients at risk of misusing prescription opioids is a priority. Standardized risk measures exist, but prior research has been limited in an assessment of their utility by a reliance on cross-sectional or retrospective analyses. In this study, the Pain Medication Questionnaire (PMQ), a standardized self-report measure of risk for prescription opioid misuse, was used to predict aberrant urine drug test (UDT) results over the subsequent 24 months. At baseline, participants who were prescribed long-term opioid therapy completed self-report measures assessing pain, function, and quality of life; this also included the PMQ. Medical record data were abstracted for 24 months postbaseline to collect results of UDTs administered during clinical care. Among participants, 12.9% had a UDT result that was positive for a nonprescribed or illicit substance, 18.9% had an aberrant negative UDT result, 3.6% had aberrant positive and negative UDT results, and the remaining 64.6% had expected UDT results. Average PMQ score at baseline did not significantly differ based on participants' type of UDT result over 24 months of follow-up. Participant variables that were significantly associated with a subsequent aberrant positive UDT were higher prescription opioid dose and hazardous alcohol use; those associated with an aberrant negative UDT were lower prescription opioid dose and hazardous alcohol use; no variable was associated with combined positive and negative UDT results. In conclusion, total PMQ score was not predictive of aberrant positive or negative UDT results. More work is needed to identify optimal strategies of screening for risk of aberrant UDT results. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Prospective Investigation of Factors Associated with Prescription Opioid Dose Escalation among Patients in Integrated Health Systems.

BACKGROUND: Prior research has identified factors associated with prescription opioid initiation, but little is known about the prevalence or predictors of dose escalation among patients already prescribed long-term opioid therapy (LTOT). OBJECTIVE: This was a 2-year prospective cohort study to examine patient and clinician factors associated with opioid dose escalation. DESIGN: A prospective cohort study. Participants were seen at baseline and every 6 months for a total of 2 years. PARTICIPANTS: Patients prescribed a stable dose of LTOT for musculoskeletal pain were recruited from two integrated health systems (Kaiser Permanente and the Department of Veterans Affairs, respectively). MAIN MEASURES: The prescription opioid dose was based on pharmacy records and self-report. Administrative data were gathered on characteristics of the opioid-prescribing clinician and healthcare utilization. Participants completed measures of pain, functioning, and quality of life. KEY RESULTS: Of enrolled participants (n = 517), 19.5% had an opioid dose increase. In multivariate analyses, patient variables associated with dose escalation were lower opioid dose (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.79-0.94, for every 10-mg increase in baseline dose) and greater pain catastrophizing (HR = 1.03, 95% CI = 1.01-1.05). Other variables associated with dose escalation were as follows: receiving medications from a nurse practitioner primary care provider (HR = 2.10, 95% CI = 1.12-3.96) or specialty physician (HR = 3.18, 95% CI = 1.22-8.34), relative to a physician primary care provider, and having undergone surgery within the past 6 months (HR = 1.80, 95% CI = 1.10-2.94). Other variables, including pain intensity, pain disability, or depression, were not associated with dose escalation. CONCLUSIONS: In this 2-year prospective cohort study, variables associated with opioid dose escalation were lower opioid dose, higher pain catastrophizing, receiving opioids from a medical specialist (rather than primary care clinician) or nurse practitioner, and having recently undergone surgery. Study findings highlight intervention points that may be helpful for reducing the likelihood of future prescription opioid dose escalation.

Outcomes of prescription opioid dose escalation for chronic pain: results from a prospective cohort study.

The use of long-term opioid therapy for chronic pain remains common, yet data on long-term outcomes, especially after dose escalation, are sparse. This study examined potential benefits and harms associated with prescription opioid dose escalation. Participants from 2 institutions were enrolled in a 2-year prospective cohort study. All participants (n = 517) had a musculoskeletal pain diagnosis and were receiving a stable dose of long-term opioid therapy at baseline. Participants completed self-report measures of pain, disability, depression, and potential adverse effects at baseline and every 6 months for 2 years. We reviewed electronic health record data weekly to identify episodes of prescription opioid dose escalation; participants who had increases in their dose were seen for additional research visits within 1 month of dose escalation. Over 2 years, 19.5% of participants had prescription opioid dose increases. After controlling for covariates, there were no significant changes on any variable after dose escalation. Of those with a dose increase, 3% experienced a clinically meaningful improvement in pain after dose escalation. Participants in the entire sample had small improvements in pain intensity, depressive symptoms, medication-related side effects, and lower risk for prescription opioid misuse during the study period. Sexual functioning worsened over time. There were no significant changes in the full sample on pain disability, sleep functioning, or experiencing a fall. In summary, patients prescribed stable doses of long-term opioid therapy may demonstrate small changes in key pain-related outcomes over time, but prescription opioid dose escalation status is unrelated to clinical outcomes.

Exploratory study examining associations between prescription opioid dose and delay discounting in patients with chronic pain.

OBJECTIVE: Although some research has identified correlates of high-dose opioid prescriptions, relatively little is known about factors that lead to higher doses. Delay discounting (DD), defined as the subjective value of a reward declining as a function of the delay to that reward, is an objective measure of impulsivity. DD is commonly studied in the context of addictive behaviors, and findings consistently demonstrate greater DD among individuals with opioid use disorders. The authors conducted a preliminary investigation to examine the extent to which DD is associated with prescription opioid dose among patients with musculoskeletal pain. DESIGN: Cross-sectional study. SETTING: A single veterans affairs medical center located in the Pacific Northwest. SUBJECTS: Participants with chronic musculoskeletal pain. The authors identified patients prescribed with high doses of opioids (100 mg morphine equivalent per day [MED] or more; n = 17), traditional doses of opioids (5-99 mg MED; n = 34), and patients with pain who were not prescribed opioids (n = 24). METHODS: All participants completed a battery of self-report measures assessing demographic characteristics, pain-related variables, and psychiatric symptoms. Participants also completed a computerized DD task. RESULTS: DD was negatively correlated with average daily opioid dose (p = 0.003) and positively correlated with anxiety (p = 0.013). In a multivariable regression analysis, after controlling for the effects of demographic and clinical factors, DD was significantly associated with prescription opioid dose. CONCLUSIONS: Contrary to study expectations, higher opioid dose was associated with less DD. These findings call for prospective research to further elucidate the relationships between DD and other measures of impulsivity and prescription opioid doses.

Clinician Response to Aberrant Urine Drug Test Results of Patients Prescribed Opioid Therapy for Chronic Pain.

OBJECTIVE: Urine drug testing (UDT) is recommended for patients who are prescribed opioid medications, but little is known about the various strategies clinicians use to respond to aberrant UDT results. We sought to examine changes in opioid prescribing and implementation of other risk reduction activities following an aberrant UDT. METHODS: In a national cohort of Veterans Affairs patients with new initiations of opioid therapy through 2013, we identified a random sample of 100 patients who had aberrant positive UDTs (results positive for nonprescribed/illicit substance), 100 who had aberrant negative UDTs (results negative for prescribed opioid), and 100 who had expected UDT results. We examined medical record data for opioid prescribing changes and risk reduction strategies in the 12 months following UDT. RESULTS: Following an aberrant UDT, 17.5% of clinicians documented planning to discontinue or change the opioid dose and 52.5% initiated another strategy to reduce opioid-related risk. In multivariate analyses, variables associated with a planned change in opioid prescription status were having an aberrant positive UDT (odds ratio [OR], 30.77; 95% confidence interval [CI], 5.92-160.10) and higher prescription opioid dose (OR, 1.01; 95% CI, 1.01-1.02). The only variable associated with implementation of other risk reduction activities was having an aberrant positive UDT (OR, 0.29; 95% CI, 0.16-0.55). DISCUSSION: The majority of clinicians enacted some type of opioid prescribing or other change to reduce risk following an aberrant UDT, and the action depended on whether the result was an aberrant positive or aberrant negative UDT. Experimental studies are needed to develop and test strategies for managing aberrant UDT results.

Treatment changes following aberrant urine drug test results for patients prescribed chronic opioid therapy.

BACKGROUND/OBJECTIVE: Urine drug testing (UDT) may be used to help screen for prescription opioid misuse. There are little data available describing usual pain care practices for patients who have aberrant UDT results. The goal of this research was to evaluate the clinical care for patients prescribed chronic opioid therapy (COT) and have an aberrant UDT. DESIGN: Retrospective cohort study. SETTING: VA Medical Center in the Pacific Northwest. PARTICIPANTS: Patients with chronic pain who were prescribed COT and had a UDT result that was positive for an illicit or nonprescribed substance. MAIN OUTCOME MEASURES: This was an exploratory study designed to document usual care practices. RESULTS: Participants' (n = 83) mean age was 49.5 (SD = 9.6) and 81.5 percent were male. The most common substances detected on UDT were marijuana (69 percent) or a nonprescribed opioid (25 percent); 18 percent had a UDT positive for two or more substances. Plans to modify treatment were documented in 69 percent of cases. The most common treatment change after aberrant UDT results was instituting more frequent UDTs, which occurred in 43 percent of cases. Clinicians documented plans to alter their opioid prescribing (eg, terminating opioids, requiring more frequent fills, changing opioid dose, or transitioning to another opioid) in 52 percent of cases, but implemented these changes in only 24 percent. DISCUSSION: Current methods for optimizing treatment after obtaining aberrant UDT results should be enhanced. To improve the utility of UDT to reduce prescription opioid misuse, additional interventions and support for clinicians need to be developed and tested.