Classification methods are often utilized to build toward categorical variables, however methods like neural networks are also designed for predicting continuous variables . Regression models are often used for the prediction of continuous measures or in the case of canonical approaches this can be with multiple dependent variables predicted simultaneously . Finally, in the case where there is no existent or optimal category or variable that the biomarkers seek to predict unsupervised approaches can be useful. With all these approaches variables can either be approached as linear or non-linear, although transformations and feature reduction approaches can mitigate these differences. It is important, regardless of approach, to understand the biological mechanisms being modeled by defining a model that best reflects the underlying systems to optimize prediction. Two key methods for statistical reduction of variables are selecting top ranking variables and creation of composite variables by factor or component-based analysis. Random Forest, as depicted in Figure 2, can be utilized to determine importance scores by evaluating the hierarchical functionality of a given variable as a bifurcator for optimizing classification . Random Forest is not alone in its utility to provide variable importance ranking but provides a nice mechanism for this analysis. The statistical creation of composite variables can be done through principal component analysis such that novel values are calculated for a set of variables that account for large swaths of variance with a single value vector . This can substantially increase the efficiency of a model and serve to highlight a robust latent feature. A summary of pain biomarkers discussed in this review article are provided in Table 1. Non-imaging pain biomarkers include opioid pain biomarkers: Beta-endorphin, B-cell opioid receptors, composite genetic, Mu-opioid receptor A118G polymorphisms, migraine opioid PET, and endogenous opioid function. Inflammatory pain biomarkers include cytokines, sICAM-1, cytokines related to back pain,cannabis grow racks cytokines related to peripheral neuropathy, substance P, and neuropeptides. Endocannabinoid pain biomarkers include: AEA in CRPS, 2-AG in optic neuromyelitis, AEA and 2-AG in headaches, ECB elements in multiple non-neuropathic pain conditions, ECB elements in endogenous opioid function, and ECB elements in gut-brain interactions.

There are pain biomarker genes related to neuropathic pain risk. MICRO-RNA dysregulation pain biomarkers are found in neuropathic pain, peripheral neuropathic pain, CRPS, migraine, and non-neuropathic pain conditions. Stress related pain biomarkers include allostatic load, Cortisol, DHEA, and allopregnanolone. Measuring saliva contains potentially particularly accessible pain biomarkers. Other pain biomarkers can be accessed via QST, skin conductance, pupil dilation, fatty acid pain biomarkers , neurotrophic factors, and serum neurotransmitters. Brain imaging pain biomarkers for measuring pain can be evaluated using three different MRI brain methods: gray matter structural imaging, white matter diffusion tensor imaging, and functional brain activation. Brain circuits related to pain mechanisms include an ascending brain circuit, a descending pain modulation circuit, the default mode circuit, the executive network brain circuit, and finally the salience network. Pain mechanisms in the brain can be measured via modulation in brain circuits: acute pain machine learning measures of chronic pain, pain rumination, pain mind wandering, placebo mechanisms, pain traits and states, and resilience. HIV peripheral neuropathy changes in the brain include reduced total cortical gray matter and reduced posterior cingulate cortex volume in particular, white matter degeneration, altered resting state networks, and aberrant expectation of pain relief. By focusing on a broad array of mechanisms and biomarkers, we can uncover important mechanistic connections and interactions across systems. Assessment and understanding in an appropriately comprehensive approach are challenging due to the vast and diverse literature and the complexity measurement. This review aims to facilitate navigation of this literature and the appropriate selection of biomarkers for future research. Health professional shortage areas are communities identified by the U.S. Human Resources and Services Administration in which there is a shortage of primary care health professionals.These shortages are accompanied by an absence of a consistent source of care, difficulty accessing care when needed, and a lack of outpatient preventative care, leading to increased hospitalizations.Multiple interventions have been attempted to increase access to care in HPSAs, including increased use of nonphysician providers. During the opioid epidemic, increasing access to naloxone furnishing has been viewed as critical in rural areas where opioid misuse is disproportionately high, including California’s Central Valley.

In the United States, pharmacists at community pharmacies are one of the most accessible points of care, with 90% of Americans living within 5 miles of a pharmacy.People seeking care have expressed interest in services at pharmacies not only because of ease of accessibility but also the availability of multilingual staff and extended hours that make it possible to access care on evenings and weekends.Previous studies have also shown that pharmacy-based care can extend services for patients in medically under served rural areas to reduce inappropriate prescribing, improve disease management, and enhance medication adherence and knowledge.In 2013, the California legislature passed SB 493, known as the Pharmacy Practice Bill, which expanded the role of pharmacists by giving them authority to furnish naloxone, hormonal contraception, nicotine replacement therapy, and travel medications, specifically prescription drugs and immunizations that are recommended by the Centers for Disease Control and Prevention to prevent or treat disease when travelling outside of the United States.California uses the term “furnish” to describe pharmacist-initiated prescription of medications.Expansion of pharmacist furnishing capabilities provides access to those in need, including people who use opioids.Past studies have sought to determine rates of pharmacist furnishing given its potential impact on access to care. However, these studies have focused on urban areas;previous studies of pharmacist furnishing of naloxone in California sampled primarily urban pharmacies ; previous studies on naloxone, hormonal contraception, and postexposure prophylaxis/preexposure prophylaxis furnishing were conducted in the San Francisco Bay Area only.As of the date of this study, there has been no prior research assessing furnishing rates in California’s Central Valley, a largely rural area, with a shortage of primary care physicians.However, understanding furnishing in these communities and those like it, particularly for naloxone, is critical given the disproportionate impact of the opioid epidemic in rural communities. For example, the age-adjusted rate of opioid-related overdose deaths in Fresno, one of the Central Valley’s largest counties, increased by 46%, from 48.6 per 100,000 residents in 2019 to 71 per 100,000 residents in 2020.This study sought to address this existing gap in research by assessing the extent of pharmacist furnishing, with a focus on naloxone, in the Central Valley. Research focused on the Central Valley due to the high potential impact of furnishing to increase access to care. It first assessed the extent of naloxone furnishing through a phone survey, then identified barriers and facilitators to implementation through interviews with a subset of furnishing pharmacists identified in the phone survey. We expected that rates of naloxone furnishing would be lower in disproportionately rural Central Valley pharmacies than in urban pharmacies evaluated in previous research, given the effects of high out-of-pocket costs in an area where people have lower incomes and social stigma surrounding opioid use disorders in more politically conservative communities.

The first step of data collection was a telephone survey of all pharmacies with the potential to furnish naloxone in the Central Valley,cannabis drying racks to identify overall furnishing rates. Four authors who were PharmD students, in collaboration with undergraduate researchers at the University of California Merced Nicotine & Cannabis Policy Center , first contacted all pharmacies that met inclusion criteria using the telephone number listed in the Board of Pharmacy license database. Using an existing screening question from previously published research on naloxone furnishing, upon initial contact an interviewer posed the question, “I heard that you can get naloxone from a pharmacy without a prescription from your doctor. Can I do that at your pharmacy?” Contact with each pharmacy was attempted up to 3 times. To identify potential interview contacts in the second step of data collection, interviews of furnishing pharmacists, each person at a pharmacy who that indicated it furnished naloxone was asked whether a furnishing pharmacist at the store would be interested in being interviewed for the study. If a pharmacist expressed interest, they received a cover letter, consent forms to sign by email or fax, and a list of interview questions. Researchers scheduled a time to interview after receiving this written consent. Pharmacies that did not furnish naloxone were not asked for interviews on the grounds that they would be unable to identify facilitators to furnishing naloxone at their store.Participants were interviewed in a semi-structured manner using an interview instrument used in previously published research to study furnishing of other medications and modified to address naloxone .This instrument included a list of questions, however each interview was conducted in a semi-structured format that allowed for a natural flow of discussion and gave participants opportunities provide additional information that may not have been specifically addressed in the prepared questions.Topics included the following: characteristics of the pharmacy and staff ; description of the furnishing process; perceptions regarding the effectiveness, advantages, disadvantages, facilitators, and barriers to furnishing; whether respondents also furnished other medications; and recommendations for reproducibility or improvement. Participants were interviewed via video or audio call except in one case, where responses were collected by e-mail. With permission, calls were recorded and transcribed. The interviewers took additional notes during and after the interview.The analysis began with calculation of descriptive statistics, including the percentage of pharmacies that furnished naloxone identified in the telephone survey. For interviews with the subset of naloxone furnishing pharmacists, descriptive analysis summarized the extent of furnishing for medications other than naloxone. Transcripts of each interview conducted, as well e-mail responses, were uploaded to Atlas.ti software for qualitative data analysis and deidentified by numbering each interview. Beginning with codes developed from past research on furnishing practices as a preliminary guide, as well as inductive methods to identify potential novel concepts, the investigators developed a code book classifying statements as referring to barriers or facilitators, then further subdivided them by type in Atlas.ti. Complete sentences were the minimum unit of analysis coded in the transcripts to identify common themes.To ensure validity and consistency across interviews and coding, each interview was conducted by a minimum of 2 researchers, and coding was completed simultaneously by all of the researchers who had conducted interviews. Disagreements were resolved by discussion until the group reached consensus. Transcripts, findings, and key quotations used to illustrate them were summarized in drafts circulated to the entire research team. Findings were triangulated based on reviews of previous studies of furnishing. Only findings identified as relevant by the group were included in the final analysis.The second step of data collection was interviewing furnishing pharmacists in the region for interviews about barriers and facilitators to furnishing. Among the contacted pharmacies that furnished naloxone, 8 furnishing pharmacists agreed to be interviewed. The stores where these pharmacists worked represented 5 of the 11 counties in the Central Valley . Of these, 5 were associated with a chain pharmacy, while the remaining 3 were independent. Although previous research on furnishing rates is limited, it suggests that naloxone furnishing is more common than furnishing of other medications. Interview participants were asked whether they also furnished other medications; as some of the factors that discourage or encourage furnishing may be consistent across medications. Six respondents indicated that the stores where they worked also furnished hormonal contraception, 3 respondents that their stores also furnished nicotine replacement therapy , and 1 that their store also furnished preexposure prophylaxis/post exposure prophylaxis. Respondents indicated that the pharmacies where they worked filled between 250 and 1000 prescriptions per day, averaging approximately 500. The time that respondents had held their positions ranged from 5 months to 20 years, and none had completed a residency. Results are provided in Table 2. With respect to barriers to furnishing, all interview participants listed cost to patients as the primary barrier. They noted that insurance did not necessarily cover naloxone, and when it did not, patients would not purchase it. As one stated, “The biggest barrier to this is first of all money. If it’s zero copay, they probably will take it. If there’s any copay, they’re just normally not going to pay for it.” . Other barriers to furnishing included time, cost, stigma, and lack of a shared language.