Efficacy and Safety of Low Dose Naltrexone for Chronic Pain.

Naltrexone is a mu-opioid receptor antagonist increasingly used as an analgesic for chronic pain at low doses. This retrospective, observational cohort study was conducted at an academic medical center to evaluate low-dose naltrexone (LDN) efficacy and describe its use in routine clinical practice. Adults receiving LDN, doses <10 mg for ≥1 month, seen at an outpatient pain clinic from January 1, 2014 to April 1, 2022 were included. The primary outcome was change in the Pain, Enjoyment of Life, and General Activity (PEG) score after LDN. Thirty-one patients were included. Median age was 50 years and 71% were female. Median duration of pain at baseline was 5 years. Mean PEG scores were 7.27 ± 1.39 and 6.62 ± 2.04 at baseline and follow-up, respectively. Mean difference was 0.66 (95% CI [0.10-1.21], p = 0.022). Eighty-seven percent (27) of patients discontinued LDN, 52% (16) for lack of benefit, 23% (7) for loss of benefit, 10% (3) for side effects, and 3% (1) for other reasons. Seven (23%) reported side effects. LDN was associated with a statistically significant reduction in PEG in adult chronic pain patients, however the clinical significance is unclear as over 75% of patients discontinued LDN due to lack of benefit.

Identifying the prevalence of clinically actionable drug-gene interactions in a health system biorepository to guide pharmacogenetics implementation services.

Understanding patterns of drug-gene interactions (DGIs) is important for advancing the clinical implementation of pharmacogenetics (PGx) into routine practice. Prior studies have estimated the prevalence of DGIs, but few have confirmed DGIs in patients with known genotypes and prescriptions, nor have they evaluated clinician characteristics associated with DGI-prescribing. This retrospective chart review assessed prevalence of DGI, defined as a medication prescription in a patient with a PGx phenotype that has a clinical practice guideline recommendation to adjust therapy or monitor drug response, for patients enrolled in a research genetic biorepository linked to electronic health records (EHRs). The prevalence of prescriptions for medications with pharmacogenetic (PGx) guidelines, proportion of prescriptions with DGI, location of DGI prescription, and clinical service of the prescriber were evaluated descriptively. Seventy-five percent (57,058/75,337) of patients had a prescription for a medication with a PGx guideline. Up to 60% (n = 26,067/43,647) of patients had at least one DGI when considering recommendations to adjust or monitor therapy based on genotype. The majority (61%) of DGIs occurred in outpatient prescriptions. Proton pump inhibitors were the most common DGI medication for 11 of 12 clinical services. Almost 25% of patients (n = 10,706/43,647) had more than one unique DGI, and, among this group of patients, 61% had a DGI with more than one gene. These findings can inform future clinical implementation by identifying key stakeholders for initial DGI prescriptions, helping to inform workflows. The high prevalence of multigene interactions identified also support the use of panel PGx testing as an implementation strategy.

Validation of ICD-9 Codes for Identification of Chronic Overlapping Pain Conditions.

Chronic overlapping pain conditions (COPCs) are a collection of chronic pain syndromes that often co-occur and are thought to share underlying nociplastic pathophysiology. Since they can manifest as seemingly unrelated syndromes they have historically been studied in isolation. Use of International Classification of Diseases (ICD) codes in medical records has been proposed as a means to identify and study trends in COPCs at the population level, however validated code sets are needed. Recently, a code set comprising ICD-10 codes as proxies for 11 COPCs was validated. The goal of this project was to validate a code set composed of ICD-9 codes for the identification of COPCs in administrative datasets. Data was extracted using the Electronic Medical Record Search Engine at the University of Michigan Health System from January 1st, 2011 to January 1st, 2015. The source population were patients with one of the candidate ICD-9 codes corresponding to various COPCs. Natural language searches were used as a reference standard. If code sets met a pre-specified threshold of agreement between ICD-9 codes and natural language searches (≥ 70%), they were retained and diagnostic accuracy statistics were calculated for each code set. Validated ICD-9 code sets were generated for 10 of the 11 COPCs evaluated. The majority had high levels of diagnostic accuracy, with all but one code set achieving ≥ 80% specificity, sensitivity, and predictive values. This code set may be used by pain researchers to identify COPCs using ICD-9 codes in administrative datasets.

COPCs share underlying nociplastic etiology; it is important to distinguish these from other pain etiologies to better understand their prevalence, identify comorbid conditions, and understand trends in their pharmacologic management.COPCs have historically been under-recognized and -studied due to challenges with identifying them in administrative datasets.A validated code set for identifying COPCs in administrative datasets using ICD-10 codes exists, however this limits any longitudinal studies as ICD-10 coding was not fully implemented until 2015.This study used natural language searches to validate a set of ICD-9 codes for identifying COPCs.Code sets were able to be validated for 10 of 11 COPCs with high specificity, sensitivity, and predictive values.

Warfarin Dose Requirements in Adults Hospitalized With COVID-19 Infection: A Retrospective Case Series.

PURPOSE: To describe the impact of hospitalization with COVID-19 infection on warfarin dose requirements in adult inpatients. SUMMARY: A retrospective chart review of 8 adults on warfarin admitted to Michigan Medicine with COVID-19 infection was conducted and reported as a case series. Outcomes of interest were difference in average daily dose of warfarin prior to admission (PTA) and while inpatient (IP), warfarin sensitivity, time in therapeutic range (TTR), confirmed or suspected thromboembolic event, any major or clinically significant bleeding episodes, and in-hospital mortality. IP average daily warfarin doses were lower when compared to PTA average daily doses [1.3 mg (1.3) vs. 6.2 mg (4.1)]. The mean percentage decrease in dose was 68.8% (23) and the mean absolute dose difference was 4.8 mg (4.3). Mean IP percentage tests in range was 30.8% (24.6) and mean IP warfarin sensitivity was 4.2 (3.8), both of which differed from PTA TTR and warfarin sensitivity for those with data available (n = 3, n = 6, respectively). One patient was treated for suspected acute pulmonary embolism while on warfarin and one patient experienced clinically relevant bleeding. In-hospital mortality was zero, mean length of stay (LOS) was 17 days (14.4), and mean intensive care unit (ICU) LOS for the 3 patients requiring ICU level care was 14.3 days (4.5). CONCLUSION: Decreased warfarin dose requirements were evident in this group of adults hospitalized with COVID-19 infection. These findings suggest lower doses of warfarin may be needed to achieve therapeutic anticoagulation while inpatient.

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action.

INTRODUCTION: MDD represents a significant burden worldwide, and while a number of approved treatments exist, there are high rates of treatment resistance and refractoriness. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, is a novel, rapid-acting antidepressant, however the mechanisms underlying the efficacy of ketamine are not well understood and many other mechanisms outside of NMDAR antagonism have been postulated based on preclinical data. This focused review aims to present a summary of the proposed mechanisms of action by which ketamine functions in depressive disorders supported by preclinical data and clinical studies in humans. METHODS: A literature search was completed using the PubMed and Google Scholar databases. Results were limited to clinical trials and case studies in humans that were published in English. The findings were used to compile this article. RESULTS: The antidepressant effects associated with ketamine are mediated via a complex interplay of mechanisms; key steps include NMDAR blockade on γ-aminobutyric acid interneurons, glutamate surge, and subsequent activation and upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. DISCUSSION: Coadministration of ketamine for MDD with other psychotropic agents, for example benzodiazepines, may attenuate antidepressant effects. Limited evidence exists for these effects and should be evaluated on a case-by-case basis.

Strategies for Rotation between Gabapentinoids in the Inpatient Setting.

Guidance and evidence to support best practices in rotating between gabapentinoids is lacking. This retrospective cohort study was performed to describe and evaluate strategies for rotation. Patients rotated while admitted from June 1st, 2014 to April 25th, 2020 at a large, academic medical center were included. The primary outcome was the proportion of rotations using a direct switch strategy compared to a cross-taper strategy. Secondary outcomes were successful rotation, defined as stable or improved pain scores pre- to post-rotation, dose ratios, and adverse effects. A total of 67 patients were included. Median age was 50 years (35 - 59) and 58% (38) were male. The majority used a direct switch strategy (87%). Ninety-five percent of patients using the direct switch strategy and 78% of patients using the cross-taper strategy were successful. There was no difference in strategies between those who were successful and those who were not. Post hoc analysis of patients with normal renal function (eGFR ≥ 50 mL/min/1.73 m2) found that those who were successful were more likely to have used a direct switch strategy (p = 0.048). There were no differences in adverse effects. These findings suggest that either strategy is reasonable for gabapentinoid rotation in the inpatient setting.

Rapid Buprenorphine Induction for Cancer Pain in Pregnancy.

Most patients with cancer-related pain are managed using opioids; cancer-related pain in the setting of pregnancy can be challenging to address owing to risk to the fetus associated with in utero opioid exposure. Buprenorphine is a unique opioid with potential benefits over other opioids for use in pregnancy and is often used for management of cancer-related pain in nonpregnant adults. There are limited data on cancer-related pain management in pregnant patients and no data supporting the use of buprenorphine for cancer-related pain in pregnant patients. This case describes a rapid buprenorphine induction using a microdosing regimen in a pregnant patient and highlights the potential of buprenorphine for cancer-related pain in this population.

A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration.

Alzheimer's disease (AD, OMIM: 104300) is an age-related disorder that affects millions of people. One of the underlying causes of AD is generation of hydrophobic amyloid-beta 42 (Aß42) peptides that accumulate to form amyloid plaques. These plaques induce oxidative stress and aberrant signaling, which result in the death of neurons and other pathologies linked to neurodegeneration. We have developed a Drosophila eye model of AD by targeted misexpression of human Aß42 in the differentiating retinal neurons, where an accumulation of Aß42 triggers a characteristic neurodegenerative phenotype. In a forward deficiency screen to look for genetic modifiers, we identified a molecularly defined deficiency, which suppresses Aß42-mediated neurodegeneration. This deficiency uncovers hippo (hpo) gene, a member of evolutionarily conserved Hippo signaling pathway that regulates growth. Activation of Hippo signaling causes cell death, whereas downregulation of Hippo signaling triggers cell proliferation. We found that Hippo signaling is activated in Aß42-mediated neurodegeneration. Downregulation of Hippo signaling rescues the Aß42-mediated neurodegeneration, whereas upregulation of Hippo signaling enhances the Aß42-mediated neurodegeneration phenotypes. It is known that c-Jun-amino-terminal kinase (JNK) signaling pathway is upregulated in AD. We found that activation of JNK signaling enhances the Aß42-mediated neurodegeneration, whereas downregulation of JNK signaling rescues the Aß42-mediated neurodegeneration. We tested the nature of interactions between Hippo signaling and JNK signaling in Aß42-mediated neurodegeneration using genetic epistasis approach. Our data suggest that Hippo signaling and JNK signaling, two independent signaling pathways, act synergistically upon accumulation of Aß42 plaques to trigger cell death. Our studies demonstrate a novel role of Hippo signaling pathway in Aß42-mediated neurodegeneration.

Alzheimer's disease: the silver tsunami of the 21(st) century.

Alzheimer's disease (AD), a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42 (Aß42) plaques, which result in the onset of neurodegeneration. It is not known how these plaques trigger the onset of neurodegeneration. There are several animal models developed to (i) study etiology of disease, (ii) look for genetic modifiers, and (iii) identify chemical inhibitors that can block neurodegeneration and help to find cure for this disease. An insect model of Drosophila melanogaster has also provided new insights into the disease. Here we will discuss the utility of the Drosophila eye model to study Alzheimer's disease.