Search

Joseph V Pergolizzi Jr,1 Peter Magnusson,2,3 Jo Ann LeQuang,1 Frank Breve,4 Kailyn Mitchell,1 Maninder Chopra,5 Giustino Varrassi6 1NEMA Research, Inc., Naples, FL, USA; 2Centre for Research and Development, Region Gävleborg/Uppsala University, Gävle, Sweden; 3Department of Medicine, Cardiology Research Unit, Karolinska Institutet, Stockholm, Sweden; 4Department of Pharmacy Practice, Temple University School of Pharmacy, Philadelphia, PA, USA; 5Decision Alternatives, LLC, Frederick, MD, USA; 6Paolo Procacci Foundation, Rome, ItalyCorrespondence: Jo Ann LeQuangNEMA Research, Inc., 4005 Technology Drive, Suite 1008-V, Angleton, TX, 77515, USATel +1-979-824-0251Email joannlequang@gmail.comAbstract: Transdermal buprenorphine is indicated for chronic pain management, but as its role in the clinical management of acute pain is less clear, this narrative review examines studies of the patch for acute pain, mainly in the postoperative setting. Although perhaps better known for its role in opioid rehabilitation programs, buprenorphine is also an effective analgesic that is a Schedule III controlled substance. Although buprenorphine is a partial agonist at the μ-opioid receptor, it is erroneous to think of the agent as a partial analgesic; it has full analgesic efficacy and unique attributes among opioids, such as a ceiling for respiratory depression and low “drug likeability” among those who take opioids for recreational purposes. Transdermal buprenorphine has been most thoroughly studied for acute pain control in postoperative patients. Postoperative pain follows a distinct and predictable trajectory depending on the type of surgery and patient characteristics. Overall, when the patch is applied prior to surgery and left in place for the prescribed seven days, it was associated with reduced postoperative pain, lower consumption of other analgesics, and patient satisfaction. Transdermal buprenorphine has been evaluated in clinical studies of patients undergoing gynecological surgery, hip fracture surgery, knee or hip arthroscopy/arthroplasty, shoulder surgery, and spinal surgery. Transdermal buprenorphine may also be appropriate pain medication for controlling pain during postsurgical orthopedic rehabilitation programs. Transdermal buprenorphine may result in typical opioid-associated side effects but with less frequency than other opioids. Despite clinical reservations about transdermal buprenorphine and its potential role in acute pain management in the clinical setting, clinical acceptance may be hampered by the fact that it is off-label and buprenorphine is better known as an opioid maintenance agent rather than an analgesic.Keywords: acute pain control, ceiling effect of buprenorphine, geriatric pain patients, gynecological surgery, hip arthroscopy, knee arthroscopy, opioid-associated side effects, orthopedic rehabilitation, orthopedic surgery, postoperative pain, spinal surgery, transdermal buprenorphine dosing

Summary: What is known and objective: Current analgesic pharmacotherapy—opioids, non‐steroidal anti‐inflammatory drugs (NSAIDs), acetaminophen (paracetamol) and related drugs—is effective for acute pain, but their use is limited by adverse effects on the renal, hepatic, cardiovascular or gastrointestinal systems, or they have potential for abuse. Therefore, alternative options are desired. Compounds used in traditional medicine might offer such alternatives, but the evidence must be based on pharmacologic properties and on clinical trial data. This review summarizes the evidence for one of these: the analgesic properties of turmeric and other curcumins. Methods: The PubMed database and other sources were searched using keywords related to turmeric, curcumin, antinociception and analgesia. Primary sources and reviews of preclinical and clinical studies were identified, assessed and summarized. Bibliographies within these sources provided additional information. Results: Turmeric has consistently been demonstrated to produce analgesic and anti‐inflammatory effects in animal models and in clinical trials, and appears to have less serious adverse effects than many current analgesics. What is new and conclusions: Turmeric (curcumin) appears to be a possible candidate for consideration for use as a stand‐alone analgesic, or in analgesic combinations as part of opioid‐, NSAID‐ or paracetamol (acetaminophen)‐sparing strategies. [ABSTRACT FROM AUTHOR]

The digital revolution has had a profound effect on American and global healthcare, which was accelerated by the pandemic and telehealth applications. Digital health also includes popular and more esoteric forms of wearable monitoring systems and interscatter and other wireless technologies that facilitate their telemetry. The rise in artificial intelligence (AI) and machine learning (ML) may serve to improve interpretation from imaging technologies to electrocardiography or electroencephalographic tracings, and new ML techniques may allow these systems to scan data to discern and contextualize patterns that may have evaded human physicians. The necessity of virtual care during the pandemic has morphed into new treatment paradigms, which have gained patient acceptance but still raise issues with respect to privacy laws and credentialing. Augmented and virtual reality tools can facilitate surgical planning and "hands-on" clinical training activities. Patients are working with new frontiers in digital health in the form of "Dr. Google" and patient support websites to learn or share medical information. Patient-facing digital health information is both a blessing and curse, in that it can be a boon to health-literate patients who seek to be more active in their own care. On the other hand, digital health information can lead to false conclusions, catastrophizing, misunderstandings, and "cyberchondria." The role of blockchain, familiar from cryptocurrency, may play a role in future healthcare information and would serve as a disruptive, decentralizing, and potentially beneficial change. These important changes are both exciting and perplexing as clinicians and their patients learn to navigate this new system and how we address the questions it raises, such as medical privacy in a digital age. The goal of this review is to explore the vast range of digital health and how it may impact the healthcare system., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Pergolizzi Jr. et al.)

Pain regimens, particularly for chronic cancer and noncancer pain, must balance the important analgesic benefits against potential risks. Many effective and frequently used pain control regimens are associated with iatrogenic adverse events. Interventional procedures can be associated with nerve injuries, vascular injuries, trauma to the spinal cord, and epidural abscesses. Although rare, these adverse events are potentially catastrophic. Pharmacologic remedies for pain must also consider potential side effects that can occur even at therapeutic doses of over-the-counter remedies such as paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs. Opioids are effective pain relievers but are associated with many side effects, some of which can be treatment limiting. A prevalent and distressing side effect of opioid therapy is constipation. Opioid-induced constipation is caused by binding to opioid receptors in the gastrointestinal system, making conventional laxatives ineffective. Peripherally acting mu-opioid receptor antagonists are a new drug class that offers the benefits of preserving opioid analgesia without side effects in the gastrointestinal system. An important safety concern, particularly among geriatric patients is the increasingly prevalent condition of polypharmacy. Many senior patients take five or more medications, including some that may be contraindicated in geriatric patients, duplicative of other drugs, have potential pharmacokinetic drug-drug interactions, or may not be the optimal choice for the patient's age and condition. Careful assessment of medications in the elderly, including possibly deprescribing with tapering of certain drugs, may be warranted but should be done systematically and under clinical supervision., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gharibo et al.)

Xylazine is an alpha-adrenergic receptor agonist approved for use only in animals with a prescription from a veterinarian. It is a powerful sedative that is slowly infiltrating the recreational street drug scene and is often used by polysubstance abusers. Known as "tranq," it can be fatal, and xylazine-induced toxicity cannot be reversed with naloxone or nalmefene. Due to its vasoconstrictive effects, chronic use of xylazine is associated with necrotic skin lesions and general deterioration of health. Since xylazine is not approved for human use and is not scheduled as a controlled substance, there are no human studies to provide evidence of drug-drug interactions, lethal doses, or reversal protocols. Xylazine is available online without a prescription. Street drug users may take xylazine knowingly or unknowingly, as it is often combined with other illicit substances such as fentanyl. There are no rapid tests for xylazine, although there are specialty tests that can be ordered. Xylazine represents a major threat to street drug users and another challenge to emergency healthcare workers, first responders, and others who care for those who have taken this "new" street drug., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Pergolizzi Jr et al.)

Nitazenes are a group of compounds developed in the 1950s as opioid analgesics, but they were never approved to market. As such, they are not well known outside of academic research laboratories. A characteristic of nitazenes is their high potency (e.g., hundreds to thousands fold more potent than morphine and other opioids and tenfold more potent than fentanyl). In the past few years, several nitazenes, including "designer analogs," have been detected in the illicit drug supply and have been implicated in overdose mortality, primarily due to their exceptionally high potency. In the street drug supply, nitazenes are often found mixed with fentanyl or other agents but their presence is not always disclosed to drug buyers, who may not even be familiar with nitazenes. These drugs pose a particular challenge since there is little experience in how to reverse a nitazene overdose or potential drug-drug or drug-alcohol interactions. Public health efforts are needed to better inform street drug consumers, first responders, healthcare professionals, and the general public about these "new old drugs" that are infiltrating the recreational drug supply., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Pergolizzi Jr et al.)

Tianeptine is often incorrectly described as a selective serotonin reuptake inhibitor, but it actually is a µ-opioid receptor agonist with anxiolytic effects. It has been approved since the last 1980s in about 24 countries as a treatment for depression, but it was never cleared to market in the United States for this purpose. Nevertheless, tianeptine joined the billion-dollar US market of nootropics as ZaZa or Tianna Red and is widely available online and in small shops without a prescription, to the point that it has been nicknamed "gas station heroin." While the therapeutic dose range is about 25 to 50 mg/day, tianeptine abusers may take 100 times that amount. Tolerance occurs rapidly and users who seek to recapture the short-lived euphoric effects of the drug have to take more and more. Social media has peer-support sites for those trying to discontinue tianeptine. Tianeptine is associated with multiple side effects at high doses along with dependence, withdrawal symptoms, toxicity, respiratory depression, and even mortality. Agitation is more often a presenting symptom of withdrawal than toxicity. Tianeptine is often used by polysubstance drug abusers who may be unaware of the drug's dangers. Few clinicians are aware of tianeptine and most urine assays do not screen for it. Greater awareness is needed for this drug and steps must be taken as tianeptine or "gas station heroin" is emerging as a new public health threat., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Wagner et al.)

The most common type of idiopathic interstitial pneumonia is idiopathic pulmonary fibrosis (IPF), an irreversible, progressive disorder that has lately come into question for possible associations with COVID-19. With few geographical exceptions, IPF is a rare disease but its prevalence has been increasing markedly since before the pandemic. Environmental exposures are frequently implicated in IPF although genetic factors play a role as well. In IPF, healthy lung tissue is progressively replaced with an abnormal extracellular matrix that impedes normal alveolar function while, at the same time, natural repair mechanisms become dysregulated. While chronic viral infections are known risk factors for IPF, acute infections are not and the link to COVID-19 has not been established. Macrophagy may be a frontline defense against any number of inflammatory pulmonary diseases, and the inflammatory cascade that may occur in patients with COVID-19 may disrupt the activity of monocytes and macrophages in clearing up fibrosis and remodeling lung tissue. It is unclear if COVID-19 infection is a risk factor for IPF, but the two can occur in the same patient with complicating effects. In light of its increasing prevalence, further study of IPF and its diagnosis and treatment is warranted., (© 2023. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

The sigma-1 and sigma-2 receptors were first discovered in the 1960s and were thought to be a form of opioid receptors initially. Over time, more was gradually learned about these receptors, which are actually protein chaperones, and many of their unique or unusual properties can contribute to a range of important new therapeutic applications. These sigma receptors translocate in the body and regulate calcium homeostasis and mitochondrial bioenergetics and they also have neuroprotective effects. The ligands to which these sigma receptors respond are several and dissimilar, including neurosteroids, neuroleptics, and cocaine. There is controversy as to their endogenous ligands. Sigma receptors are also involved in the complex processes of cholesterol homeostasis and protein folding. While previous work on this topic has been limited, research has been conducted in multiple disease states, such as addiction, aging. Alzheimer's disease, cancer, psychiatric disorders, pain and neuropathic pain, Parkinson's disease, and others. There is currently increasing interest in sigma-1 and sigma-2 receptors as they provide potential therapeutic targets for many disease indications., Competing Interests: Mark Coleman is on the Board of Directors of Axome Therapeutics. Joseph V. Perolizzi is the Executive Chairman and President of Advantx Pharmaceuticals, Inc., (Copyright © 2023, Pergolizzi et al.)

Background Patients interacting with the multiple moving parts of the healthcare system may not fully understand all the information provided to them. They find themselves misinformed or unaware of certain facts pertaining to their health. Community pharmacists, who are readily accessible, are occupationally situated in such a way that makes them the most ideal candidates to impact and improve patients' health literacy. Aims and objectives The aim of this research is to identify and examine how pharmacists can aid their patients and help them toward adequate health literacy. Methods First-year pharmacy candidates enrolled in the Doctor of Pharmacy (PharmD) program at Temple University School of Pharmacy were given an optional, essay-based assignment titled, "How can pharmacists improve the health literacy of the patients they serve?" Students were given one week to respond to the prompt, and those who completed the assignment were awarded bonus points toward the final examination. Of the 145 students given the potential to complete the assignment, only 100 students participated in the assignment. These essays were subsequently read, categorized, and analyzed. Results The essays were categorized into six main perspectives: educating patients, using simple language, providing resources, creating a trusting patient-pharmacist relationship, sending medication reminders, and providing translation services. More than 30% of the student responses emphasized that educating patients about their medication side effects and disease states will help them better understand their medical needs. About another 30% of the students suggested that using simple, everyday language and providing translators, when necessary, will help patients deal with their health problems. The remaining suggested either creating a safe relationship with patients, providing reliable resources such as pamphlets and visual aids, or sending patient-specific reminders. Conclusion Although these suggestions are not new to the world of pharmacy and have been around before, the difficulty lies in practical application in a world that seems busier now than ever before. However, within the six student perspective response categories, most can be incorporated into one patient interaction. By creating a trusting relationship with the patient and counseling them while using simple language and translators, if necessary, teaching them about their medications, and providing the necessary outside resources, pharmacists can improve the health literacy of their patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, John et al.)

Introduction: The numerous drugs in the NSAID class are often used to treat acute postoperative pain associated with oral surgery such as impacted third-molar extractions. These drugs are effective in this setting and dental pain studies often serve as models for acute pain relief and for registration of analgesics. With numerous cyclooxygenase (COX) inhibitors available as monotherapy, for use in combination with analgesic regimens, and in different doses and formulations, it was our aim to determine if there were clear-cut distinctions among these products and dosing regimens., Areas Covered: This is a literature review of recent randomized controlled clinical trials evaluating NSAIDs for use in postoperative pain management following oral surgery. Of particular interest were head-to-head studies, which might offer some insight into comparative effectiveness., Expert Opinion: Postoperative oral surgery pain is largely managed in real-world clinical practice using NSAIDs, either alone or in combination, and there is good evidence supporting their use especially in multimodal therapy. Head-to-head and comparative studies do not show a clear-cut 'optimal NSAID' in this setting, although ibuprofen, ketoprofen, dexketoprofen, and naproxen have gained most acceptance. Combination therapy with other analgesics or adjuvants is largely accepted.

Combinations of drugs may be fixed (two or more entities in a single product) or loose (two or more agents taken together but as individual agents) to help address multimechanistic pain. The use of opioids plus nonopioids can result in lower opioid consumption without sacrificing analgesic benefits. Drug combinations may offer additive or synergistic benefits. A variety of fixed-dose combination products are available on the market such as diclofenac plus thiocolchicoside, acetaminophen and caffeine, acetaminophen and opioid, ibuprofen and acetaminophen, tramadol and acetaminophen, and others. Fixed-dose combination products offer predictable pharmacokinetics and pharmacodynamics, known adverse events, and can reduce the pill burden. However, they are limited to certain drug combinations and doses; loose dosing allows prescribers the versatility to meet individual patient requirements as well as the ability to titrate as needed. Not all drug combinations offer synergistic benefits, which depend on the drugs and their doses. Certain drugs offer dual mechanisms of action in a single molecule, such as tapentadol, and these may further be used in combination with other analgesics. New technology allows for co-crystal productions of analgesic agents which may further improve drug characteristics, such as bioavailability. Combination analgesics are important additions to the analgesic armamentarium and may offer important benefits at lower doses than monotherapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Pergolizzi et al.)

Post-viral new-onset diabetes has been an important feature of the COVID-19 pandemic. It is not always clear if new-onset diabetes is the unmasking of a previously undiagnosed condition, the acceleration of prediabetes, or new-onset diabetes that would not have otherwise occurred. Even asymptomatic cases of COVID-19 have been associated with new-onset diabetes. Diabetes that emerges during acute COVID-19 infection tends to have an atypical presentation, characterized by hyperglycemia and potentially life-threatening diabetic ketoacidosis. It is not always clear if new-onset diabetes is type 1 or type 2 diabetes mellitus. Many cases of COVID-associated diabetes appear to be type 1 diabetes, which is actually an autoimmune disorder. The clinical course varies temporally and with respect to outcomes; in some cases, diabetes resolves completely or improves incrementally after recovery from COVID-19. Disruptions in macrophagy caused by COVID-19 infection along with an exaggerated inflammatory response that can occur in COVID-19 also play a role. Those who survive COVID-19 remain at a 40% elevated risk for diabetes in the first year, even if their case of COVID-19 was not particularly severe. A subsequent post-pandemic wave of new diabetes patients may be expected., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Pergolizzi et al.)

Introduction: Guidelines recommend a number of pharmacotherapeutic options used as monotherapy or in combination with others for treating the pain of trigeminal neuropathy., Areas Covered: The authors examine the pharmacotherapeutic options for treating trigeminal neuralgia and supporting evidence in the literature. Guidelines reported the most effective treatment for trigeminal neuropathy, in particular trigeminal neuralgia, appears to be carbamazepine or oxcabazepine, but side effects can be treatment limiting. Lamotrigine and gabapentin are also recommended in guidance. In real-world clinical practice, baclofen, cannabinoids, eslicarbazepine, levetiracetam, brivaracetam, lidocaine, misoprostol, opioids, phenytoin, fosphenytoin, pimozide, sodium valproate, sumatriptan, tizanidine, tocainide, tricyclic antidepressants, and vixotrigine are sometimes used, either as monotherapy or in combination. The relatively small patient population has limited the number of large-scale studies and there is limited evidence on which to base prescribing choices., Expert Opinion: While there is no optimal pharmacotherapy for treating trigeminal neuropathy, advancements in our understanding of the underlying mechanisms of this condition and drug development indicate promise for NaV inhibitors, despite the fact that not all patients respond to them and they may have potentially treatment-limiting side effects. Nevertheless, better understanding of NaV channels may be important avenues for future drug development for trigeminal neuropathy.

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a mu-opioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappa-opioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or 'serotonin syndrome' may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Pergolizzi et al.)

In this review, we evaluated several studies in the literature to analyze the benefits and deleterious effects of the use of monoclonal antibodies (MABs)-based proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in patients with hypercholesterolemia. Increased low-density lipoprotein cholesterol (LDL-C) levels lead to an increase in the risk of cardiovascular (CV) disease. Statins are the cornerstones of hypercholesterolemia treatment, but the patient response may often vary, and additional therapies may be needed to control the increased LDL-C levels. MABs bind to PCSK9 receptors, causing a reduction in LDL-C levels. MAB-based PCSK9 inhibitors such as alirocumab and evolocumab have been approved for use in hypercholesterolemia in combination with statins. Studies have suggested that both alirocumab and evolocumab are effective in lowering LDL-C levels, have favorable side effect profiles, and can be administered at convenient dosing intervals; however, further double-blind, randomized trials evaluating the long-term safety and efficacy of both the agents could assist with clinical decision-making., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Parikh et al.)

Neurological manifestations are increasingly reported in a subset of COVID-19 patients. Previous infections related to coronaviruses, namely Severe Acute Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome (MERS) also appeared to have neurological effects on some patients. The viruses associated with COVID-19 like that of SARS enters the body via the ACE-2 receptors in the central nervous system, which causes the body to balance an immune response against potential damage to nonrenewable cells. A few rare cases of neurological sequelae of SARS and MERS have been reported. A growing body of evidence is accumulating that COVID-19, particularly in severe cases, may have neurological consequences although respiratory symptoms nearly always develop prior to neurological ones. Patients with preexisting neurological conditions may be at elevated risk for COVID-19-associated neurological symptoms. Neurological reports in COVID-19 patients have described encephalopathy, Guillain-Barré syndrome, myopathy, neuromuscular disorders, encephalitis, cephalgia, delirium, critical illness polyneuropathy, and others. Treating neurological symptoms can pose clinical challenges as drugs that suppress immune response may be contraindicated in COVID-19 patients. It is possible that in some COVID-19 patients, neurological symptoms are being overlooked or misinterpreted. To date, neurological manifestations of COVID-19 have been described largely within the disease trajectory and the long-term effects of such manifestations remain unknown.

Many Americans with opioid use disorder (OUD), do not have access to treatment. Mobile narcotic treatment programs are now under new regulations that may make treatment more accessible to more people. These mobile programs can help expand the reach of opioid agonist treatment for OUD, help reduce human immunodeficiency viruses (HIV) and hepatitis C in the OUD population, and have retention rates that are often better than those at fixed-site clinics. Mobile services can also help reach marginalized individuals, the homeless, rural communities, and other underserved communities. They may offer methadone or buprenorphine treatment. Such mobile services have been used inside and outside the United States with promising results. In particular, mobile programs can make treatment available to people who do not have insurance, who lack reliable transportation, live in chaotic situations, or may be undomiciled. The potential pairing of mobile programs together with technology, such as smartphone apps or online resources, may allow mobile patients to benefit from counseling as well. Mobile clinics must be attached to a fixed-site narcotic treatment program and may have limitations with respect to the geographic area served. Mobile programs must have policies and procedures to store, transport, deliver, account for, reconcile, and dispose of opioid waste and would be subject to audit. Mobile opioid agonist therapy is an important and innovative service of particular value to underserved communities., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Breve et al.)

In this review, we evaluated the literature on the benefits and deleterious effects of digoxin in heart failure (HF) with reduced ejection fraction (EF). Although digoxin was considered an effective treatment for HF, the supporting evidence is conflicting. Before the conventional use of modern HF therapies, digoxin was widely used for symptomatic relief on these patients. Further randomized trials are required to reach a definite conclusion about its efficacy and safety in patients experiencing HF with a reduced EF (HFrEF)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Parikh et al.)

Hospitals, clinics, and organizations using controlled substances must have policies and procedures in place for disposing of these substances and to avoid potential drug diversion as well as environmental pollution. Challenging, particularly to hospitals, is the ability to dispose of the waste of any number of hundreds of products every day, some of which require specific handling and protocols for safety. Incineration might be appropriate but many hospitals and certainly smaller clinics lack the appropriate facilities. Clinics and facilities that use controlled substances must maintain adequate and detailed records, but individual healthcare systems impose their own specific requirements. Some, for example, require drug disposal to be witnessed. However, recordkeeping systems must be robust and frequently audited to prevent diversion. Most healthcare systems want to dispose of controlled substances in an environmentally responsible way but in addition to federal laws in the United States, most states have their own environmental agencies and may have local regulations. Navigating this system can be complex, and since all regulations are subject to change, it requires vigilance and expertise., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Breve et al.)

Cocaine is taken frequently together with ethanol and this combination produces a psychoactive metabolite called cocaethylene which has similar properties to the parent drug and may be more cardiotoxic. Cocaethylene has a longer half-life than cocaine, so that people who combine cocaine and ethanol may experience a longer-lasting, as well as more intense, psychoactive effect. Cocaethylene is the only known instance where a new psychoactive substance is formed entirely within the body. Although known to science for decades, cocaethylene has not been extensively studied and even its metabolic pathways are not entirely elucidated. Like its parent drug, cocaethylene blocks the reuptake of dopamine and increases post-synaptic neuronal activity; the parent drug may also block reuptake of serotonin as well. Cocaethylene has been studied in animal models in terms of its pharmacology and its potential neurological effects. Since the combination of cocaine and alcohol is commonly used, it is important for clinicians to be aware of cocaethylene, its role in prolonging or intensifying cocaine intoxication, and how it may exacerbate cocaine-induced cardiovascular disorders. Most cardiac-related risk assessment tools do not ask about cocaine use, which can prevent clinicians from making optimal therapeutic choices. Greater awareness of cocaethylene is needed for clinicians, and those who use cocaine should also be aware of the potential for polysubstance use of cocaine and ethanol to produce a potentially potent and long-lasting psychoactive metabolite., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Pergolizzi et al.)

Premature babies often suffer apnea of prematurity as a physiological consequence of an immature respiratory system. Hypercapnia may develop, and neonates with apnea of prematurity are at an increased risk of morbidity and mortality. The long-term effects of apnea of prematurity or their treatments are less clear. While a number of treatment options exist for apnea of prematurity, there is no clear-cut "first-line" approach or gold standard of care. Effective treatments, such as caffeine citrate, carbon dioxide inhalation, nasal continuous positive airway pressure, nasal intermittent positive pressure ventilation, and others, may be associated with safety concerns. More conservative treatments are available, such as kangaroo care, postural changes, and sensory stimulation, but they may not be effective. While apnea of prematurity resolves spontaneously as the respiratory system matures, it can complicate neonatal care and may have both short-term and long-term consequences. The role, if any, that apnea of prematurity may play in mortality of preterm neonates is not clear., Competing Interests: Joseph Pergolizzi is a consultant/speaker, owner, and researcher for Spirify, US World Meds, BDSI, Salix, Enalare, Scilex, Pfizer, Lilly, Teva, Regeneron, Redhill, Grunenthal, and Neumentum., (Copyright © 2022, Pergolizzi et al.)

Introduction: The definition of nociplastic pain in 2016 has changed the way maladaptive chronic pain is viewed in that it may emerge without neural lesions or neural disease. Many endogenous and pharmacologic substances are being investigated for their role in treating the pain associated with neuronal plasticity., Areas Covered: The authors review promising pharmacologic agents for the treatment of pain associated with maladaptive neuronal plasticity. The authors then provide the reader with their expert opinion and provide their perspectives for the future., Expert Opinion: An imbalance between the amplification of ascending pain signals and the poor activation of descending inhibitory signals may be at the root of many chronic pain syndromes. The inhibitory activity of noradrenaline reuptake may play a role in neuropathic and nociplastic analgesia. A better understanding of the brain's pain matrix, its signaling cascades, and the complex bidirectional communication between the immune system and the nervous system may help meet the urgent and unmet medical need for safe, effective chronic pain treatment, particularly for pain with a neuropathic and/or nociplastic component.

A clinical conundrum can occur when a patient with active opioid use disorder (OUD) or at elevated risk for the condition presents with cancer and related painful symptoms. Despite earlier beliefs that cancer patients were relatively unaffected by opioid misuse, it appears that cancer patients have similar risks as the general population for OUD but are more likely to need and take opioids. Treating such patients requires an individualized approach, informed consent, and a shared decision-making model. Tools exist to help stratify patients for risk of OUD. While improved clinician education in pain control is needed, patients too need to be better informed about the risks and benefits of opioids. Patients may fear pain more than OUD, but opioids are not always the most effective pain reliever for a given patient and some patients do not tolerate or want to take opioids. The association of OUD with mental health disorders (dual diagnosis) can also complicate delivery of care as patients with mental health issues may be less adherent to treatment and may use opioids for "chemical coping" as much as for pain control., Competing Interests: JP and KM were employed by company NEMA Research, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pergolizzi, Magnusson, Christo, LeQuang, Breve, Mitchell and Varrassi.)

Opioid toxicity can result in life-threatening respiratory depression. Opioid-overdose mortality in the United States is high and increasing, but it is difficult to determine what proportion of those deaths might actually be suicides. The exact number of Americans who died of an opioid overdose but whose deaths might be classified as suicide remains unknown. It is important to differentiate between those who take opioids with the deliberate and unequivocal objective of committing suicide, that is, those with active intent, from those with passive intent. The passive-intent group understands the risks of opioid consumption and takes dangerous amounts, but with a more ambiguous attitude toward suicide. Thus, among decedents of opioid overdose, a large population dies by accident, whereas a small population dies intending to commit suicide; but between them exists a sub-population with equivocal intentions, waxing and waning between their desire to live and the carelessness about death. There may be a passive as well as active intent to commit suicide, but less is known about the passive motivation. It is important for public health efforts aimed at reducing both suicides and opioid-use disorder to better understand the range of motivations behind opioid-related suicides and how to combat them., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Pergolizzi et al.)

The 'third wave' of the ongoing opioid overdose crisis in the United States (US) is driven in large measure by illicitly manufactured fentanyl (IMF), a highly potent synthetic opioid or an analog developed in clandestine laboratories primarily in China and Mexico. It is smuggled into this country either as IMF or as precursors. The southern border of the US is a frequent point of entry for smuggled IMF and the amounts are increasing year over year. IMF is also sometimes mixed in with other substances to produce counterfeit drugs and dealers as well as end-users may not be aware of IMF in their products. IMF is inexpensive to produce and when mixed with filler materials can be used to cut heroin, vastly expanding profitability. It is an attractive product for smuggling as very tiny amounts can be extremely potent and highly profitable. Drug trafficking over the border also involves the tandem epidemic of money laundering as drugs enter the country and cash payments exit. While drug smuggling in and out of the US (and other nations) has been going on for decades, the patterns are changing. Highly potent and potentially lethal IMF is a dangerous new addition to the illicit drug landscape and one with disastrous consequences., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Pergolizzi et al.)

Introduction: Opioid analgesia for acute painful conditions has come under increasing scrutiny with the public health crisis of opioid overdose, leading clinicians to seek nonopioid alternatives, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol)., Areas Covered: This perspective evaluates recent clinical trials of nonopioids, opioids, and combination therapy for use in acute pain. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) often provide adequate analgesia, although these agents are not without risks. Combination therapy using a small amount of opioid together with a nonopioid pain reliever has been shown effective and reduces opioid consumption., Expert Opinion: The short-term use of opioids under close clinical supervision, such as in-hospital use of opioid analgesics for postoperative pain, may be appropriate, but even here, combination therapy or nonopioid therapy may be preferred. The use of opioids even for acute pain of short duration has been questioned. The ideal analgesic has yet to be developed, but effective pain control pharmacological regimens for acute pain are available.

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, single-center, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Pergolizzi et al.)

Concern about the appropriate role of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 speculate that NSAIDs, in particular ibuprofen, may upregulate the entry point for the virus, the angiotensin-converting enzyme (ACE) 2 receptors and increase susceptibility to the virus or worsen symptoms in existing disease. Adverse outcomes with COVID-19 have been linked to cytokine storm but the most effective way to address exaggerated inflammatory response is complex and unclear. The Expert Working Group on the Commission of Human Medicines in the UK and other organizations have stated that there is insufficient evidence to establish a link between ibuprofen and susceptibility to or exacerbation of COVID-19. NSAID use must also be categorized by whether the drugs are relatively low-dose over-the-counter oral products taken occasionally versus higher-dose or parenteral NSAIDs. Even if evidence emerged arguing for or against NSAIDs in this setting, it is unclear if this evidence would apply to all NSAIDs at all doses in all dosing regimens. Paracetamol (acetaminophen) has been proposed as an alternative to NSAIDs but there are issues with liver toxicity at high doses. There are clearly COVID-19 cases where NSAIDs should not be used, but there is no strong evidence that NSAIDs must be avoided in all patients with COVID-19; clinicians must weigh these choices on an individual basis.

Cluster headache is a rare form of headache associated with sleep and even speculated to be a manifestation of a sleep disorder rather than a primary headache. Cluster headache exhibits both circadian and circannual rhythmicity. While attacks often occur during sleep, the implication that cluster headaches might be involved with rapid eye movement (REM) sleep phases has neither been fully established nor refuted. The regulatory mechanisms governing sleep including hypothalamic activity and the autonomic nervous system response may play a role. Hypothalamic activation has been observed in cluster headache patients during positron emission tomography testing, but only during attacks. While sleep apnea is associated with morning headaches in general, the link between sleep-disordered respiration and cluster headache remains elusive. Hypoarousal during sleep and periods of hypoxia are associated with cluster headache, the latter likely involving inflammatory processes rather than apnea. Further study is needed, as cluster headaches represent a serious primary cephalgia that is incompletely understood.

In the light of the COVID-19 pandemic, anti-vaccine sentiments have been on the rise, with a recent seminal study on the development of anti-vaccine views in social media even making its way into Nature Communications. Yet, with the current scientific consensus being in overwhelming agreement over the safety and efficacy of vaccines, many scientists lose their grasp on the fears, concerns, and arguments that the opposition may hold. This paper discusses and evaluates vaccine-hesitant individuals on a socioeconomic, historical, and philosophical landscape. It also provides an analysis of common argumentative patterns and the psychological impact that these arguments may have on undecided individuals. The discussion also explores why anti-vaccine sentiments are on the rise, and how members of the scientific and medical community require a more structured approach to communicating key arguments. This is particularly important if vaccination rates and herd immunity are to be sustained. No longer is it sufficient to win arguments based on a factual and scientific basis, but rather scientists and medical practitioners have to focus on conveying confidence and reassurance on both an informative and emotional level to those with doubts and fears.

Concern about coronavirus 2019 (COVID-19) morbidity and mortality has drawn attention to the potential role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) because the SARS-CoV-2 uses the ACE2 receptor as its point of entry into the body. It is not clear if and to what degree the SARS-CoV-2 virus affects the renin-angoiotensin system. Early studies from China which speculated on the role of ACE inhibition and ARBs did not evaluate the drug regimens. A vast body of evidence supports the use of ACE inhibitors and ARBs in hypertensive patients and patients with heart failure, and very little evidence has been acquired about their role in COVID-19. There is good evidence in support of the use of ACE inhibitors and ARBs in indicated patients with hypertension and heart failure, and clinicians should be reticent about abruptly withdrawing these drugs based on a paucity of evidence., (Copyright © 2020. Published by Elsevier Inc.)

The emergence of a novel coronavirus and coronavirus disease 2019 (COVID-19) represents a challenge to global healthcare. In the past 20 years, this is the third coronavirus that jumped the species barrier and infected humans. It is highly contagious but associated with low pathogenicity. First identified in Wuhan, China, a city of over 11 million, the disease has since spread to every continent except Antarctica. About 15% to 20% of all cases may be called severe, and it is believed many cases are asymptomatic. The average age of a person with COVID has been reported as 49 years. Worse outcomes are associated with geriatric populations and those with underlying diseases such as cardiovascular, respiratory disorders, and/or diabetes. The coronavirus, like other coronaviruses, is highly contagious and has a latency period of about 14 days. Most patients present with fever and a dry cough, but fever may be absent. Differential diagnosis can be challenging since influenza may present with similar symptoms. Chest radiography or computed tomography may be used to find evidence of secondary pneumonia. Nosocomial infection is of concern, and it has been reported that 3.8% of all cases with COVID-19 in that country involve healthcare workers in China. Most patients have mild disease, and supportive care suffices. A variety of repurposed and investigational drugs are being evaluated. There are currently no antiviral therapies or vaccines, even if many therapies are proposed. Hand hygiene, social distancing, and scientifically sound information are the best strategies at the moment to combat this epidemic., Competing Interests: Conflict of Interests: None of the authors declared conflict of interest., (Copyright © 2020, Author(s).)

Tapentadol is the newest centrally acting analgesic to be approved by the US FDA and regulatory bodies in other countries. It has been called the first-in-class of a novel-acting analgesic mechanism of action that combines µ-opioid receptor agonist activity with neuronal norepinephrine-reuptake inhibition in a single molecule. This duality of action should combine inhibition of ascending (afferent) pain-transmitting signals with activation of descending (efferent) pain-attenuating systems (e.g., diffuse noxious inhibitory controls). However, not all novel mechanisms of action impart the characteristics needed for an analgesic to be considered for first-line therapy. These key questions may help inform clinical decision making.