A Machine Learning Application to Classify Patients at Differing Levels of Risk of Opioid Use Disorder: Clinician-Based Validation Study.

Background: Despite restrictive opioid management guidelines, opioid use disorder (OUD) remains a major public health concern. Machine learning (ML) offers a promising avenue for identifying and alerting clinicians about OUD, thus supporting better clinical decision-making regarding treatment. Objective: This study aimed to assess the clinical validity of an ML application designed to identify and alert clinicians of different levels of OUD risk by comparing it to a structured review of medical records by clinicians. Methods: The ML application generated OUD risk alerts on outpatient data for 649,504 patients from 2 medical centers between 2010 and 2013. A random sample of 60 patients was selected from 3 OUD risk level categories (n=180). An OUD risk classification scheme and standardized data extraction tool were developed to evaluate the validity of the alerts. Clinicians independently conducted a systematic and structured review of medical records and reached a consensus on a patient's OUD risk level, which was then compared to the ML application's risk assignments. Results: A total of 78,587 patients without cancer with at least 1 opioid prescription were identified as follows: not high risk (n=50,405, 64.1%), high risk (n=16,636, 21.2%), and suspected OUD or OUD (n=11,546, 14.7%). The sample of 180 patients was representative of the total population in terms of age, sex, and race. The interrater reliability between the ML application and clinicians had a weighted kappa coefficient of 0.62 (95% CI 0.53-0.71), indicating good agreement. Combining the high risk and suspected OUD or OUD categories and using the review of medical records as a gold standard, the ML application had a corrected sensitivity of 56.6% (95% CI 48.7%-64.5%) and a corrected specificity of 94.2% (95% CI 90.3%-98.1%). The positive and negative predictive values were 93.3% (95% CI 88.2%-96.3%) and 60.0% (95% CI 50.4%-68.9%), respectively. Key themes for disagreements between the ML application and clinician reviews were identified. Conclusions: A systematic comparison was conducted between an ML application and clinicians for identifying OUD risk. The ML application generated clinically valid and useful alerts about patients' different OUD risk levels. ML applications hold promise for identifying patients at differing levels of OUD risk and will likely complement traditional rule-based approaches to generating alerts about opioid safety issues.

Research Priorities for Expansion of Opioid Use Disorder Treatment in the Community Pharmacy.

In the last decade, the U.S. opioid overdose crisis has magnified, particularly since the introduction of synthetic opioids, including fentanyl. Despite the benefits of medications for opioid use disorder (MOUD), only about a fifth of people with opioid use disorder (OUD) in the U.S. receive MOUD. The ubiquity of pharmacists, along with their extensive education and training, represents great potential for expansion of MOUD services, particularly in community pharmacies. The National Institute on Drug Abuse's National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) convened a working group to develop a research agenda to expand OUD treatment in the community pharmacy sector to support improved access to MOUD and patient outcomes. Identified settings for research include independent and chain pharmacies and co-located pharmacies within primary care settings. Specific topics for research included adaptation of pharmacy infrastructure for clinical service provision, strategies for interprofessional collaboration including health service models, drug policy and regulation, pharmacist education about OUD and OUD treatment, including didactic, experiential, and interprofessional curricula, and educational interventions to reduce stigma towards this patient population. Together, expanding these research areas can bring effective MOUD to where it is most needed.

Healthcare professionals' knowledge, confidence and perceptions of pharmacogenomics in primary care and pain management.

Aim: To assess knowledge, confidence and perceptions of healthcare professionals specializing in primary care and pain management at Brigham and Women's Hospital, related to clinical pharmacogenomics (PGx). Methods: A 25-question online survey was distributed to 328 Brigham and Women's Hospital clinicians for analysis. Results: Thirty-four clinicians completed the survey. Respondents had minimal experience with PGx and limited awareness of PGx resources. Although respondents expressed belief that PGx has utility to improve medication-related patient outcomes, many lack confidence to apply PGx results to their practice. For clinical drug-gene questions relevant to primary care and/or pain management, respondents scored poorly. Conclusion: More clinician education is needed for appropriate utilization of PGx in clinical practice as it pertains to primary care and pain management.

A comparison of registered and published primary outcomes in clinical trials of opioid use disorder: ACTTION review and recommendations.

BACKGROUND AND AIMS: Prospective trial registration can increase research integrity. This Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) review was designed to compare the primary outcomes (PO) reported in registries with associated publications for opioid use disorder (OUD) clinical trials. DESIGN: The World Health Organization's International Clinical Trials Registry Platform (ICTRP) was searched for completed trials (2010 through 2019). Associated publications were identified and paired with trial registry data based on the publication date. MEASUREMENTS: Reviewers independently rated the occurrence of discrepancies between the POs in the registry compared to the publication. An analysis of prospective versus retrospective registration was also completed. FINDINGS: One-hundred and forty trials were identified in the search, and 43 registry-publication pairs evaluated. Only 34 of the 43 pairs could be examined for discrepancies because nine did not report a PO in registry and publication. Of the 34 pairs, only four met rigorous criteria for prospective trial registration and had an exact match of POs. In contrast, the majority of the 34 trials, or 80%, had inconsistent POs (e.g., registered secondary outcomes published as primary; the timing of PO not specified) and/or were retrospectively registered. CONCLUSIONS: Many clinical trials focused on OUD have not met the standards of trial registration, such as consistent reporting of POs and prospective registration. Failure to properly register trial characteristics undermines the validity of research findings and can delay the development of life-saving treatments. Recommendations for improving prospective trial reporting practices are provided.

Results of a Team Objective Structured Clinical Examination (OSCE) in a Patient with Pain.

PURPOSE: As rates of chronic pain and opioid use disorder continue to rise, improved pain education is essential. Using an interprofessional team objective structured clinical examination (OSCE) simulation, this study evaluates whether prior exposure to a case-based learning module improves students' assessment and treatment planning of a standardized patient prescribed chronic opioids presenting with acute pain. METHODS: A quasi-experimental mixed method approach using convenience sampling was employed to evaluate student performance and the impact of the educational intervention. RESULTS: Fourteen (intervention) and 16 (control) nurse practitioner, physician assistant, medical, pharmacy, and dental students in the final pre-licensure program years completed the team OSCE. Demographics, OSCE learning scores, Interprofessional Attitudes Scale scores, and pain management plans did not differ between groups. All students evaluated the activity highly. Qualitative analysis did not demonstrate differences between groups, but did identify similar themes: students missed opportunities to establish patient-provider rapport and educate across disciplines; opioid use disorder was assumed with chronic opioid therapy; team discussions improved treatment plans; moderators variably influenced team discussion. CONCLUSIONS: This novel approach to interprofessional training in pain management using a team OSCE is promising, with modifications suggested. A case-based learning module without structured education prior to the OSCE did not improve students' assessment and pain management skills compared to a control group. Nonetheless, important themes emerged including biases towards the standardized patient. Additional research is needed to develop effective curricular initiatives to foster and improve interprofessional collaboration in assessing and managing a standardized patient with acute and chronic pain.

Invasive pulmonary mucormycosis and aspergillosis in a patient with decompensated hepatic cirrhosis.

Invasive pulmonary mucormycosis and aspergillosis are rare, life-threatening fungal infections. Most documented cases have been reported in non-cirrhotic patients with diabetes mellitus, neutropenia, or treatment with corticosteroids. The prevalence of each infection is low among patients with hepatic cirrhosis. We report the first likely case of combined invasive pulmonary mucormycosis and aspergillosis in a male with decompensated hepatic cirrhosis. This report also highlights the first non-diabetic case of invasive pulmonary mucormycosis with decompensated hepatic cirrhosis.

Langerhans cell histiocytosis masquerading as acute appendicitis: Case report and review.

Langerhans cell histiocytosis (LCH) is a rare syndrome characterized by unifocal, multifocal unisystem, or disseminated/multi-system disease that commonly involves the bone, skin, lymph nodes, pituitary, or sometimes lung (almost exclusively in smokers) causing a variety of symptoms from rashes and bone lesions to diabetes insipidus or pulmonary infiltrates. We present a previously unreported case of gastrointestinal LCH as well as a novel characteristic lesion affecting the colon of a young woman who presented with signs and symptoms mimicking acute on chronic appendicitis. Immunohistochemical analysis of appendectomy specimen and nodular specimens on colonoscopy demonstrated S-100, CD1a, and langerin reactivity. The patient underwent systemic chemotherapy with cytarabine and demonstrated excellent response to therapy.

Attitudes of Primary Care Practitioners in Managing Chronic Pain Patients Prescribed Opioids for Pain: A Prospective Longitudinal Controlled Trial.

OBJECTIVE: There is increasing concern among primary care practitioners (PCPs) regarding medication misuse and noncompliance among chronic pain patients prescribed opioids for pain. This study investigated the benefits of interventions designed to track potential opioid misuse and to improve practitioner confidence in managing patients with chronic pain through the use of risk assessment, monthly monitoring of compliance, and specialty support. METHODS: Fifty-six PCPs and 253 chronic pain patients were recruited into the study. All patients were assessed for risk and called once a month for 6 months to monitor pain and opioid compliance. Practitioner knowledge about opioids, concerns about analgesic prescriptions, practice behavior, and attitudes of managing chronic pain patients were assessed and questionnaires were repeated after 1 year. Practitioners in the experimental group received monthly patient summary reports that consisted of pain, mood, activity levels, healthcare utilization, and results of the Opioid Compliance Checklist, while practitioners in the control group did not receive the monthly reports. RESULTS: After 1 year all the PCPs reported improvement in identifying patients at risk for misuse (P < 0.05), perceived confidence in prescribing opioids for pain (P < 0.05) and increased satisfaction with communication with pain specialists (P < 0.05). The patients reported greater compliance with their opioid medication and felt that the monthly monitoring was beneficial. Despite modest improvements, many PCPs still lacked confidence in managing pain patients and reported reluctance to prescribe opioids for chronic noncancer pain, especially among younger practitioners. This study demonstrates the benefits of careful monitoring of chronic pain patients and need for pain management support within primary care.

Beliefs and attitudes about opioid prescribing and chronic pain management: survey of primary care providers.

OBJECTIVE: There is growing concern of medication misuse and noncompliance among patients with chronic pain prescribed opioids for pain. The aim of this survey was to obtain information from primary care providers (PCPs) about their perception of prescribing opioids for patients with chronic pain. METHODS: PCPs were invited to complete a packet of questionnaires about attitudes and concerns about opioids for chronic pain. These questionnaires included 1) General Health Questionnaire, 2) Test of Opioid Knowledge (TOK), 3) Opioid Therapy Provider Survey, and 4) Concerns About Analgesic Prescription Questionnaire. RESULTS: Fifty-six (N = 56) PCPs from eight centers participated in this study. In general, the PCPs showed adequate opioid knowledge on the KOT and their general health was unrelated to prescription attitudes. Most expressed concern about medication misuse (89 percent) and felt that managing patients with chronic pain was stressful (84 percent). Most were worried about addiction (82 percent) and less than half felt that they were sufficiently trained in prescribing opioids (46 percent). Younger providers felt more reluctant to prescribe opioids, experienced more stress in managing patients with pain, had less overall confidence in managing patients with pain, and worried more about opioid dependence than older providers (p < 0.05). Younger providers were also less knowledgeable about opioids, but opioid knowledge was not found to be related to concerns about analgesic prescriptions. CONCLUSION: This study indicates a general concern and reluctance of primary care physicians to manage the prescribing of opioids among their patients with chronic pain and younger providers expressed more concern about opioids than older providers.

Implementation of a collaborative care management program with buprenorphine in primary care: a comparison between opioid-dependent patients and patients with chronic pain using opioids nonmedically.

OBJECTIVE: To implement a collaborative care management program with buprenorphine in a primary care clinic. DESIGN: Prospective observational study. SETTING: A busy urban academic primary care clinic affiliated with a tertiary care hospital. PARTICIPANTS: Opioid-dependent patients or patients with chronic pain using opioids nonmedically were recruited for the study. A total of 45 participants enrolled. INTERVENTIONS: Patients were treated with buprenorphine and managed by a supervising psychiatrist, pharmacist care manager, and health coaches. The care manager conducted buprenorphine inductions and all follow-up visits. Health coaches offered telephonic support. The psychiatrist supervised both the care manager and health coaches. MAIN OUTCOME MEASURES: Primary outcomes were treatment retention at 6 months, and change in the proportion of aberrant toxicology results and opioid craving scores from baseline to 6 months. After data collection, clinical outcomes were compared between opioid-dependent patients and patients with chronic pain using opioids nonmedically. Overall, 55.0 percent of participants (25/45) remained in treatment at 6 months. Primary care physicians (PCPs)' attitudes about opioid dependence treatment were surveyed at baseline and at 18 months. RESULTS: Forty-three patients (95.6 percent) accepted treatment and 25 (55.0 percent) remained in treatment at 6 months. The proportion of aberrant urine toxicology results decreased significantly from baseline to 6 months (p < 0.01). Craving scores significantly decreased from baseline to 6 months (p < 0.01). Opioid-dependent patients, as opposed to patients with chronic pain using opioids nonmedically, were significantly more likely to complete 6 months of treatment (p < 0.05). PCPs' confidence in treating opioid dependence in primary care increased significantly from baseline to 18 months postimplementation (p < 0.01). CONCLUSION: Collaborative care management for opioid dependence with buprenorphine may be feasible in a primary care clinic. More research is needed to understand the role of buprenorphine in managing patients with chronic pain using opioids nonmedically.

Class-wide REMS for extended-release and long-acting opioids: potential impact on pharmacies.

OBJECTIVES: To provide an update on the recently approved class-wide risk evaluation and mitigation strategy (REMS) for extended-release (ER) and long-acting (LA) opioids and to discuss the potential impact on pharmacy practice. DATA SOURCES: In mid-2011, the Food and Drug Administration notified drug manufacturers that a single, class-wide REMS would be required for ER and LA opioids. This regulation was the result of a multiyear process that incorporated input from government, drug manufacturers, medical associations, and other stakeholders. SUMMARY: The goal of the class-wide REMS for ER/LA opioids is to reduce addiction, unintentional overdose, and death resulting from inappropriate prescribing, misuse, and abuse. To accomplish these goals, this REMS focuses on physician education on safe and appropriate prescribing and patient counseling on the risks of opioids. Although voluntary, a movement to require physician education to obtain or renew Drug Enforcement Administration licensing is occurring. Pharmacists are not included in the class-wide REMS per se. Pharmacists play an important role in overall risk reduction and are critical to the success of the class-wide REMS. CONCLUSION: Although the changing requirements for prescribing ER/LA opioids will not have a direct effect on pharmacist workflow, the pharmacist-patient interaction remains critical for overall risk reduction with this class of medication.

Abuse-deterrent and tamper-resistant opioids: how valuable are novel formulations in thwarting non-medical use?

INTRODUCTION: In recent years, attention has been given to the development of abuse-deterrent and tamper-resistant opioid formulations in light of concern over the growing misuse and abuse of opioids prescribed for the treatment of chronic pain. AREAS COVERED: This critical review discusses abuse-deterrent and tamper-resistant formulations, which may help to overcome concerns of misuse in using opioids for pain management. The role and utility of these novel formulations in clinical practice are outlined, as well as the risks and benefits associated with formulations that are currently available or under development. EXPERT OPINION: Numerous concerns with the integration of these formulations into clinical practice remain, as no product is intended or capable of addressing all types of misuse or abuse. As a result, these formulations should not necessarily be considered preferred agents once available in clinical practice. Moreover, before initiating therapy with abuse-deterrent and tamper-resistant formulations, proper patient assessment to identify risk factors for misuse and abuse should be implemented and optimized. With screening and monitoring in place, it would then be sensible to consider these formulations in patients who appear to be at high risk of misuse, abuse and/or diversion.

The role of dose reduction with NSAID use.

Effective pain relief with use of nonsteroidal anti-inflammatory drugs (NSAIDs) may come at the cost of an increased risk for serious cardiovascular (CV), gastrointestinal (GI), and renal complications. Research has shown that these adverse events are more likely to occur with higher NSAID dosing and in individuals with a preexisting risk for CV and GI complications. To minimize the potential risk for an adverse event, numerous regulatory bodies and medical societies recommend using the lowest effective NSAID dose for the shortest time necessary. One potential strategy is to offer patients lower doses of standard NSAID formulations. However, efforts to modify physician prescribing behavior may be challenging because of concerns regarding the potential for suboptimal pain management. Another strategy has emerged through use of new technology that produces submicron NSAID formulations. This new technology is also an approach that could provide effective pain relief at low doses. This article reviews the role of dose and duration in the risk for NSAID-associated adverse events, and discusses the potential benefits associated with new low-dose submicron NSAID formulations.

Abuse-deterrent and tamper-resistant opioid formulations: what is their role in addressing prescription opioid abuse?

About one in every three individuals will experience chronic pain in their lifetime, and opioids are known to be an effective means to treat this condition. Much attention, however, has been given to the fact that prescription opioid analgesics are some of the most frequently abused drugs, and misuse is prominent in patients with chronic pain. Several new opioid formulations that are designed to prevent or deter the abuse of opioids are currently in development, and two have been approved for marketing (morphine sulphate co-formulated with naltrexone hydrochloride [Embeda®] and a new formulation of the extended-release oxycodone [OxyContin®]). In this article, we review the various types of abuse-deterrent and tamper-resistant formulations in clinical development. We believe that continued advances in opioid formulations can help mitigate risk for those with legitimate need for pain control, but only if used rationally in the context of good clinical practice.

Promotion of articular cartilage matrix vesicle mineralization by type I collagen.

OBJECTIVE: Calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals occur in up to 60% of osteoarthritic joints and predict an increased severity of arthritis. Articular cartilage vesicles (ACVs) generate CPPD crystals in the presence of ATP and BCP crystals with added beta-glycerophosphate. While ACVs are present in normal articular cartilage, they mineralize primarily in cartilage from osteoarthritic joints. The aim of this study was to explore the hypothesis that ACV mineralization is regulated by components of the surrounding extracellular matrix. METHODS: Porcine ACVs were embedded in agarose gels containing type II and/or type I collagen and/or proteoglycans. Mineralization was measured as (45)Ca accumulation stimulated by ATP or beta-glycerophosphate and reflects both nucleation and growth. Synthetic CPPD and BCP crystals were embedded in similar gels to isolate the effect of matrix components on crystal growth. RESULTS: After establishing baseline responsiveness of ACVs to ATP and beta-glycerophosphate in agarose gels, we examined the ability of ATP and beta-glycerophosphate to stimulate mineral formation in gels containing various matrix components. Type II collagen suppressed the ability of ATP to stimulate mineralization, while a combination of type II plus type I collagen increased the effect of ATP and beta-glycerophosphate on mineralization. Type I collagen affected ACV mineralization in a dose-responsive manner. Neither type of collagen significantly affected crystal growth or levels of mineralization-regulating enzymes. Proteoglycans suppressed mineral formation by ACVs in gels containing both type I and type II collagen. CONCLUSION: Cartilage matrix changes that occur with osteoarthritis, such as increased quantities of type I collagen and reduced proteoglycan levels, may promote ACV mineralization.

Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy.

BACKGROUND: Randomized trials evaluating intensive dose statin therapy have found enhanced protection against cardiovascular (CV) events compared with moderate-dose statin therapy in patients with acute coronary syndromes (ACS) or stable coronary artery disease (CAD). However, the potential for an increase in the risk of drug-induced adverse events with such therapy has not been quantified. OBJECTIVE: This meta-analysis was performed to compare the incremental risks associated with intensive- and moderate-dose statin therapy. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1995 to 2006 using the following terms: acute, coronary syndrome, stable coronary artery disease, atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, and fluvastatin. Prospective, randomized controlled trials evaluating intensive- and moderate-dose statin therapy for the reduction of CV events were included in the review. The safety end points examined were elevations in creatine kinase (CK) >or= 10 times the upper limit of normal (ULN), elevations in alanine or aspartate aminotransferase >or=3 times the ULN, rhabdomyolysis, drug-induced adverse events requiring discontinuation of therapy, and any drug-induced events. The efficacy end points examined were all-cause mortality, CV death, nonfatal myocardial infarction (MI), and stroke. Each analysis compared the effect of intensive- or moderate-dose statin therapy on statin-induced adverse events and clinical efficacy outcomes. Simple absolute risk, the number needed to treat, and the number needed to harm were also calculated to quantify the incremental benefit or harm associated with intensive-dose statin therapy. RESULTS: Four trials were included in the analysis.Together, they included 27,548 patients with ACS or stable CAD followed for a mean of 3.4 years, representing 108,049 patient-years of clinical-trial experience. Intensive-dose therapy with atorvastatin or simvastatin 80 mg was associated with a significant increase in the risk for any adverse event (odds ratio [OR] = 1.44; 95% CI, 1.33-1.55; P < 0.001) and adverse events requiring discontinuation of therapy (OR = 1.28; 95% CI, 1.18-1.39; P < 0.001). Intensive-dose therapy also was associated with an increased risk for abnormalities on liver function testing (OR = 4.48; 95% Cl, 3.27-6.16; P < 0.001) and elevations in CK (OR = 9.97; 95% CI, 1.28-77.92; P = 0.028). The benefits of intensive-dose statin therapy included reductions in CV death (OR = 0.86; 95% CI, 0.75-0.99; P = 0.031), MI (OR = 0.84; 95% CI, 0.76-0.93; P < 0.001), and stroke (OR = 0.82; 95% CI, 0.72-0.94; P = 0.004). CONCLUSIONS: Although intensive-dose statin therapy was associated with a reduced risk for important CV events, it was also associated with an increased risk for statin-induced adverse events. Therefore, moderate-dose statin therapy may be the most appropriate choice for achieving CV risk reduction in the majority of individuals, whereas intensive-dose statin therapy may be reserved for those at highest risk.