Identifying Risk Factors for Cardiovascular Events Among Active-Duty Service Members and Veterans Prescribed Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

Background: Oral NSAIDs are widely used analgesic medications for the treatment of musculoskeletal and inflammatory conditions. NSAIDs are associated with adverse effects that arise from COX enzyme inhibition including cardiovascular events. The combined role of patient and prescription factors associated with NSAID use on cardiovascular risk is not well characterized. Objective: The purpose of this study is to identify the risk factors with cardiovascular events among NSAID users. Methods: This study is a retrospective, nested case-control study, within the DAVINCI database, among active-duty service members and veterans with at least one NSAID pharmacy claim between fiscal year (FY) 2015-FY2020. Inclusion criteria individuals ≥18 years of age received a prescription NSAID for ≥7-day supply and a duration ≥1 month overall. Cases experienced nonfatal myocardial infarction, nonfatal stroke, or new onset heart failure. Ten controls were selected per case. Risk factors were identified through logistic regression modeling. Results: The risk factors with strongest association to the primary outcome included age starting at 45 up to 75 and older, the first 90 days of NSAID exposure, cerebrovascular disease, cardiomyopathy, and history of myocardial infarction. Cox-selectivity and dose did not appear to be clinically significant in their association with cardiovascular events. Conclusion: The results of this study indicate that age, initial NSAID exposure, and comorbidities are more predictive than NSAID-specific factors such as COX-selectivity and dose. The results provide the framework for development of a risk score to improve prediction of NSAID-associated cardiovascular events.

What's new in NSAID pharmacotherapy: oral agents to injectables.

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) represent a critically important class of medications useful in numerous musculoskeletal and inflammatory diseases. The focus of NSAID use has recently centered on gastrointestinal (GI) side effects and potential cardiovascular toxicity. Innovative new oral and intra-articular pharmaceutically engineered dosage forms are examined. We review recently developed intravenous NSAIDs and their potential advantages over oral products in the perioperative setting. DESIGN: Databases searched included PubMed, Google Scholar, Ovid, and Athens. We contacted key U.S. and Japanese manufactures who are developing new and innovative NSAID technologies for inclusion in this overview. Early attempts at mitigating GI toxicity with oral agents combined with gastroprotective additives are outlined. RESULTS: Contemporary technologies coupled with uniquely advanced pharmaceutical manipulations to improve safety and efficacy are discussed including combined vasodilating agent naproxcinod as the prototypical cyclooxygenase-inhibiting nitric oxide (NO) donor; hydrogen sulfide-releasing compounds to protect GI mucosa; glycoscience technologies combining the intra-articular hyaluronic acid SI-613 combined with NSAIDs; and nano-formulated SoluMatrix submicron technologies that include diclofenac, indomethacin, naproxen, and meloxicam. CONCLUSIONS: New NSAIDs under development are intended to address GI and cardiovascular pitfalls inherent to current therapy options across the entire NSAID drug class. NO or hydrogen sulfide donating drugs, new reliable injectables for perioperative and inpatient use, novel intra-articular extended-release NSAIDs combined with IAHA, and nano-formulations of submicron NSAIDs featuring delivery of decreased doses without diminished efficacy promise to afford innovative technologies that likely will be the future of NSAID therapy.

A review of the safety of buprenorphine in special populations.

Rates of opioid misuse and opioid use disorder have been increasing in recent years. Buprenorphine has emerged as an appealing medication for its use not only as treatment for opioid use disorder, but also as an opioid for chronic pain that has a ceiling effect on risks associated with opioid therapy. As other opioid prescribing decreases, buprenorphine prescribing continues to increase. As a result, it is imperative to understand the safety and efficacy of its use in special populations. This review article will explore the safety and efficacy of buprenorphine when used in subjects with hepatic and renal impairment, the elderly, and pregnant women. While manufacturer labeling for buprenorphine products may caution against their use in these populations, further examination of available data indicates that buprenorphine can be used safely and effectively for both chronic pain and/or opioid use disorder in all four of these populations.

Nonsteroidal Antiinflammatory Drugs for Acute and Chronic Pain.

Understanding nonsteroidal antiinflammatory drug (NSAID) use and impact on common rheumatic and arthritic conditions is critical to reconciling their appropriate use with their potentially serious adverse effects. NSAIDs have a profound impact on the treatment of connective tissue disorders because of their ability to address the underlying cause with specific benefits of decreasing stiffness and inflammation, and improving mobility. NSAID use is twice as common as opioid use, and inappropriate use of NSAIDs is widespread. NSAID use should be monitored and the impact understood to mitigate the risks. NSAID discontinuation should be evidence based and individualized to specific requirements.

A review of the role of benzene metabolites and mechanisms in malignant transformation: summative evidence for a lack of research in nonmyelogenous cancer types.

The aromatic hydrocarbon benzene is a well-recognised haematotoxin and carcinogen associated with malignancy in occupational environments. Primary benzene metabolites phenol, catechol, and hydroquinone are implicated in the progression from cytotoxicity to carcinogenicity, and malignant transformation in myelogenous cell lineage is hypothesised to encompass a complex multistep process involving gene mutations in cell signalling and mitosis, oncogene activation, downregulated immune-mediated tumour surveillance, anti-apoptotic activities, and genetic susceptibility. Several mechanisms of carcinogenicity are proposed but none are accepted widely as causative. Involvement of covariables such as duration and frequency of benzene exposure, metabolite concentration, and degree of biological interactions provides a theoretical framework for a multiple mechanistic model to explain cytotoxic-malignant transformation. Despite significant research in myeloid leukaemias, limited biological and epidemiological studies on benzene and its metabolites in nonhaematopoietic malignancies suggests more research is needed to determine its role in contributing to other cancer types.

Common elements in opioid use disorder guidelines for buprenorphine prescribing.

OBJECTIVES: This study sought to formulate a consolidation of guidelines representing best practices related to office-based opioid treatment (OBOT) of opioid use disorder (OUD) using buprenorphine. It also demonstrates how a set of evidence-based guidelines may be linked with claims data to leverage analytic techniques that drive cost-effective, positive health outcomes. STUDY DESIGN: Literature review of US and international guidelines for OBOT using buprenorphine for OUD. METHODS: The study conducted a review of currently available US and several international guidelines from 2009 to 2018 published on OUD and the use of buprenorphine in OBOT. Guidelines were consolidated based on common elements. The process of correlating common elements with available commercial and state Medicaid claims data is described, including which elements are amenable to analysis along with relative complexity. RESULTS: Seven guidelines met inclusion criteria and are presented as 3 tables, organized by clinical themes and phase of care related to OBOT use of buprenorphine for OUD. Themes included establishing care, monitoring treatment stability and engagement, and nonpharmacologic treatment to improve outcomes. Areas of agreement and divergence between guidelines are highlighted. Specific components are identified as they relate to metrics of interest to public and private payers. CONCLUSIONS: Among US and international guidelines for treatment of OUD, common themes are readily identified and may indicate agreement in regard to interventions. Linking pharmacy and medical billing claims data to evidence-supported best practices provides public and private payers the ability to track individual patients, facilitate high-quality care, and monitor outcomes.

Cystic fibrosis, vector-mediated gene therapy, and relevance of toll-like receptors: a review of problems, progress, and possibilities.

Gene delivery in cystic fibrosis is hampered by extracellular and intracellular biological barriers and inefficient vectors. Although progress is evident, continued bioengineering of DNA, vectors, and delivery technologies will be critical to ensure biocompatibility, safety, and therapeutic effectiveness. Both viral and nonviral vectors demonstrate insufficient gene expression to adequately correct chloride ion and respiratory homeostasis, but vector modifications and novel vector types continue to advance understanding of transfection processes, immunobiological responses, and cystic fibrosis pathology. Interactions of toll-like receptors and other coreceptors may be critical components of cystic fibrosis immunobiology but additional research will be needed before causative associations are widely established; however, receptor modulation provides a theoretical framework to develop new therapeutic approaches. Clinical-phase pharmacotherapies offer short-term promise to restore electrolyte imbalance and/or symptomatology, but it may be many years before gene therapy offers a curative solution for the disease.

Old Friends With New Faces: Are Sodium Channel Blockers the Future of Adjunct Pain Medication Management?

Providers are being asked to decrease the emphasis and overutilization of long-term opioid therapy, but many are left without proper guidance on appropriate utilization of nonopioid therapies. Furthermore, therapeutic options are quite limited and many providers lack confidence in distinguishing available alternatives. When first-line therapy has failed in a patient, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose among alternative agents, an understanding of pharmacology, pharmacokinetics, and efficacy in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine) for adjunct pain medication management including research updates in pharmacology, pharmacokinetics, and current evidence for pain along with promising areas of research. It is an evidence update for clinical use of sodium channel blockers, clarifies misconceptions regarding their use, and highlights emerging research for improved pain targets that justifies additional study. We performed a complete review of the literature using the search terms, "oxcarbazepine," "carbamazepine," and "eslicarbazepine" in conjunction with "pharmacokinetics," "adverse effects," "pharmacology," "voltage-gated sodium channel subtype," "neuropathic pain," "inflammatory pain," "metabolism," "epoxide metabolite formation," "drug interactions," "CYP450 interactions," "pain phenotype," and "chronic pain management." Databases searched included PubMed and Google Scholar. Package inserts were used for drug structure illustration, adverse reactions, and bioavailability. Pharmacology and pharmacokinetic data were taken from randomized controlled trials evaluating this area as well as in vitro published results. For validity, only peer-reviewed literature was included. Evidence for sodium channel blockers in chronic pain management was limited. This review focuses on highlighting the data available for the use of sodium channel blockers for certain pain syndromes as well as underutilized potential. Emerging literature on sodium channel subtypes and their connection to neuropathic, inflammatory, and mechanical pain transmission is elucidated. The authors also scrutinize literature surrounding the pharmacokinetics of oxcarbazepine and eslicarbazepine to provide clearer guidance to the significance of any drug interactions and refute assumptions made on the basis of structural similarity to carbamazepine and its known undesirable drug interactions. Side effect profiles are outlined and compared, emphasizing the differences between agents. Sodium channel blocker doses used in certain pain syndromes are outlined with a call for further research to better understand their place in chronic pain management. Identification of sodium channel subtypes with links to specific pain conditions and the ability to target them hints at the potential for truly individualized therapy. Sodium channel inhibitors are underutilized on the basis of available evidence, and emerging research has identified this area as promising for additional clinical trials to better guide clinical practice. PERSPECTIVE: This article provides a review of the pharmacology, evidence for pain management, and pharmacokinetics of oxcarbazepine, carbamazepine, and eslicarbazepine. There is a disparity in evidence using sodium channel blockers for pain and this article highlights the potential that is currently underutilized. The authors believe this will catalyze interest for further studies.

Emerging Trends in Pain Medication Management: Back to the Future: A Focus on Ketamine.

Providers face many challenges when faced with pain management. Pain is complex, difficult to understand and diagnose, and especially enigmatic to manage. The discovery of nonopioid agents for pain management has become particularly important considering the ongoing opioid epidemic. This review is focused on revisiting ketamine, an agent that has historically been used for anesthesia, in new ways to manage pain. Ketamine has unique pharmacologic properties that may prevent the development of pain as well as reduce chronic pain. This has led to the use of ketamine for perioperative analgesia as well as chronic pain syndromes. In select patients with pain refractory to other treatment modalities, ketamine may provide much needed relief.

The future of pain pharmacy: driven by need.

BACKGROUND: Opioid prescribing has increased by ~400% over the past 20 years in the US and has been correlated with dramatic increases in accidental overdose-related deaths. Emerging evidence of serious dose-dependent side effects of opioid analgesics has led to recommendations from multinational pain societies and governments to decrease opioid doses and increase referrals to pain specialists. Demand for pain specialists of all types has increased; however, training programs for health care professionals struggle to satisfy this need. OBJECTIVE: The purpose of this article is to highlight the role of clinical pharmacy specialists in pain management and to discuss available residency training programs and subspecialties within each program. METHODS: We surveyed all eleven accredited pharmacy postgraduate year two (PGY-2) Pain and Palliative Care Residency programs in the US. Program information was derived from interviews with residency directors, current residents, program brochures, and residency Web sites. Data collected included core, elective, and longitudinal rotations, with the time frame dedicated to each experience. Primary practice areas, as well as inpatient vs outpatient focus, were also documented. Additionally, a review of the available literature was completed to determine the areas in greatest need for future pain specialists. RESULTS: Pharmacy pain specialists have been referenced as highly effective additions to interdisciplinary pain management teams. Pharmacists provide expertise in complex pain medication management, which remains the primary focus of most chronic pain encounters. The PGY-2 programs surveyed differ considerably, with the majority providing significant emphasis to either acute pain management or palliative care with brief or limited exposure to chronic pain management. Four of the eleven programs require 2 months of chronic pain management; however, only two of the eleven programs identify chronic pain management as a primary practice setting. DISCUSSION: Pain specialists in all fields are in high demand; however, the need for health care professionals specialized in chronic pain management probably exceeds that for professionals specialized in acute pain management and palliative care combined. This disparity between disease prevalence and specialty training programs is not reflected in the current residency training structure, nor have additional training programs arisen to fill this critical need. CONCLUSION: Health care systems will continue to struggle to meet the demands of patients with chronic pain until significant emphasis is placed on the education and training of health care professionals in this area. Clinical pharmacy should aim to meet this demand through the expansion of PGY-2 training programs and improved didactic education in pharmacy school that reflects the increased need for chronic pain specialists.

Medication pain management in the elderly: unique and underutilized analgesic treatment options.

BACKGROUND: By 2030, the US population of adults aged ≥65 years will increase by >80%, and these adults will account for nearly 20% of the US population. In this population, the decline of multiple physiologic processes and diseases collectively influence treatment options. Physiologic changes, drug-drug interactions resulting from polypharmacy, and drug-disease interactions combine to make elderly patients more sensitive to the adverse events (AEs) associated with medications, all of which must be considered in drug selection. OBJECTIVE: This article focuses on select underutilized medication options for analgesia that may provide significant advantages in the elderly population above and beyond commonly prescribed conventional choices. METHODS: We performed a complete review of the literature using the search terms pain management, elderly, opioids, NSAIDs, topical NSAIDs, levorphanol, buprenorphine transdermal, and tapentadol. Databases searched included PubMed, Google Scholar, Ovid, and Athens. Package inserts were utilized for approval dates, indications, and formulations available. We looked at reviews of agents to identify important studies for consideration that searches may have missed. Pharmacology and pharmacokinetic data were taken from randomized trials focusing in this area. Pivotal Phase III trials were utilized for discussion of clinical trial experience and to summarize efficacy and AEs. For purposes of validity, only peer-reviewed literature was included. RESULTS: There were limited data that specifically outlined analgesic drug selection and highlighted safer alternatives for the elderly patient based on polypharmacy risks, end-organ deterioration, and/or drug choices that presented less risk. We focused on unique opioid alternatives: levorphanol, which offers several therapeutic advantages similar to methadone but without the pharmacokinetic and drug-interaction pitfalls associated with methadone; tapentadol, associated with significantly less gastrointestinal distress and constipation; and transdermal buprenorphine, an agonist/antagonist with less risk for the toxicities associated with conventional opioids and with compliance benefits. Topical NSAIDs are discussed as a viable therapeutic option. Specific attention to a more desirable tolerability profile, including avoidance of drug interactions, end-organ dysfunction, and gastrointestinal bleed with topical NSAID agents versus their oral counterparts is discussed, including the ability to achieve superior tissue levels for appropriately selected inflammatory conditions. CONCLUSION: It is incumbent that providers consider these options as part of an analgesic armamentarium in an effort to maximize therapeutic benefit and minimize risks in the increasing elderly patient population.

Toll-like receptors, transduction-effector pathways, and disease diversity: evidence of an immunobiological paradigm explaining all human illness?

Membrane-bound Toll-like receptors (TLRs) are frontline guardians in the mammalian innate immune system. They primarily function to recognize pathogen-associated molecular patterns (PAMPs) of invading microorganisms and on activation mount rapid, nonspecific innate responses and trigger sequential delayed specific adaptive cellular responses, which are mediated by complex signal transduction pathways involving adaptor molecules, costimulatory ligands and receptors, kinases, transcription factors, and modulated gene expression. Increasing evidence of multiple functionality and diversity suggests TLRs play critical roles in noninfective medical conditions such as cardiovascular, gastrointestinal, neurologic, musculoskeletal, obstetric, renal, liver, and dermatologic diseases, allergy, autoimmunity, and tissue regeneration. The significance of TLR heterogeneity underscores the possibility for establishing a universal immunobiological model to explain all human disease. Novel immunomodulatory therapies targeting specific or multiple TLRs may in the future offer new tools to combat or eradicate pathogenesis potentially transforming the landscape of current medical treatments.