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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. Fixeddose 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.

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.

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.

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.

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.

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.

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-Barre 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.

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 muopioid-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 kappaopioid 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.

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.

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.

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.

Pharmacists around the world are playing an active role in educating the public about COVID-19. First-year pharmacy students taking a healthcare course at Temple University in Philadelphia were asked to write papers based on the nature of a pharmacist’s contributions during the pandemic. 90% of the essays outlined the importance of community pharmacists, as they are the most accessible healthcare professional, providing immediate social interaction and drug expertise. They help minimize the need for hospital visits, limiting their time in public, therefore reducing their risk of becoming infected. For the pharmacies that have a drive-thru window, over-the-counter medications and other necessities can be sold to decrease the likelihood of transmission. Many students also proposed the opportunity for more leniency in prescribing power. Unless pharmacists are within a collaborative practice agreement, they cannot prescribe even maintenance medication. Due to the pandemic, it has become increasingly hard to reach the doctor or see them in person, as most offices have switched to telehealth. Clinical pharmacists operating out of hospitals have the opportunity to oversee proposed treatment options or experimental drugs, such as remdesivir. Retail pharmacies are emerging as key resources in this pandemic, and it is important that students see this as a vibrant and important form of pharmacy practice.

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).

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.

Introduction: COVID-19 (or COVID) is a highly virulent viral disease which more frequently presents severe infection in specific populations, such as the elderly, patients with hypertension, patients with respiratory disease, and patients who smoke. The effects vaping (i.e., an electronic cigarette or JUUL device) has on COVID progression remains unclear, because there is an information paucity correlating e-cigarette use and COVID. This review sought to identify links between vape use and COVID severity via literature review. Additionally, because there is more widespread information about cigarette smoking than about vaping, this review sought to illustrate commonalities between smoking and vaping. If smoking and vaping are deemed near-identical practices, then it is possible the effects of smoking on human health and on COVID disease could be comparable in vaping. Methods: Several searches were performed on PubMed with MeSH headings and JSTOR between 17 December 2020 and 22 December 2020. Search results were excluded if they were not trials or controlled clinical trials, if the articles were not about COVID, if the articles were about smoking behaviors or habits, or if the articles were not related to vaping or smoking. Key findings were summarized and tabled based on relevance, substantiability, and applicability to COVID. Results: Multiple sources viewed smoking and vaping as equal risk factors for COVID disease, whereas other sources viewed the two as unique risk factors. Because of this controversy, it is challenging to view the two practices as similar enough to pose equivalent risks for COVID. Both practices pose significant health risks to its users, but these health risks are unique to each practice. Discussion: There are several limitations which exacerbate ambiguity-(1) it is unclear how harmful smoking is for COVID patients, because several publications found smoking may have protective effects; (2) few older patients vape, but yet most severe COVID ca

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.

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.

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, singlecenter, 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.

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 mu-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.