The Challenges in Clinical Diagnosis of Trigeminal Neuralgia: A Review.

The lack of established laboratory tests or biomarkers for trigeminal neuralgia (TN) makes diagnosing this relatively rare condition extremely challenging. Trigeminal nerve compression observable on magnetic resonance imaging may indicate TN, but many patients do not have visible lesions or compression. In particular, TN may be confused with migraine, cluster headache, temporomandibular disorder, and other types of headache. An accurate diagnosis is imperative for proper treatment since these conditions do not respond to the same treatment. Many symptoms of these headaches can be vague or overlap, and clinicians depend in large measure on the subjective reports of their patients. Nevertheless, it is imperative to diagnose TN better, which can cause excruciating pain, reduce the quality of life, and even result in disability. It is possible that TN is underestimated.

An update on pharmacotherapy for trigeminal neuralgia.

INTRODUCTION: Trigeminal neuralgia is a rare condition that can be effectively treated by carbamazepine or oxcarbazepine but these older drugs are associated with dose-dependent and potentially treatment-limiting adverse effects. Third-generation anticonvulsants, new calcitonin gene-related peptide blockers for migraine, and older drugs such as ketamine and cannabinoids may be promising adjuvants or monotherapeutic options. AREAS COVERED: The new drugs, their presumed mechanisms of action, safety and efficacy are discussed herein. There is a paucity of robust clinical evidence in support of these drugs for trigeminal neuralgia. New migraine agents are considered as well although migraines and trigeminal neuralgia are distinct, albeit similar, conditions. No new drugs have been released to market in recent years with the specific indication of trigeminal neuralgia. EXPERT OPINION: In real-world clinical practice, about half of trigeminal neuralgia patients take more than one agent for prevention and combination therapy may be the optimal approach. Combination therapy might allow for lower doses of carbamazepine or oxcarbazepine, thus reducing the number and severity of potential adverse events but the potential for pharmacokinetic drug-drug interactions must be considered. Drug therapy for trigeminal neuralgia involves acute or abortive treatments, often administered in hospital versus long-term preventive therapy, usually involving oral agents.

Trigeminal neuralgia is a relatively rare condition that usually affects one side of the face below the eye around the cheekbone. The cause of trigeminal neuralgia is sometimes a damaged nerve or a nerve that has lost part of its outer protective sheath (myelin). However, trigeminal neuralgia may have other neurological causes as well. Pain can be triggered by touch, pressure, or chewing and it tends to occur in very painful brief attacks followed by pauses with little or no pain. There are two types of drug treatment for trigeminal neuralgia: drugs to stop an ongoing attack (which are often administered in an emergency room or hospital intravenously) and drugs that are taken orally over the long term to reduce or prevent attacks.The two most effective drugs for trigeminal neuralgia are carbamazepine and oxcarbazepine, which are actually drugs to prevent seizures. They are effective in reducing the pain intensity and number of attacks of trigeminal neuralgia but they have side effects. In fact, these side effects can be so severe that people stop taking the drugs.Many new drugs have come to market recently that may work for trigeminal neuralgia, although none was specifically developed for this use. The newest generation of anti-seizure medications including eslicarbazepine, lacosamide, levetiracetam, and retigabine, may be just as effective as the older carbamazepine and oxcarbazepine drugs with fewer side effects. Clinical studies are needed to test them in trigeminal neuralgia patients but their mechanisms of action suggest that they might work well.There are some new drugs developed for migraine headache that inhibit a substance in the body called CGRP. Migraine headaches and trigeminal neuralgia have some of the same symptoms but they are different conditions but both involve too much CGRP.Other new drugs include lasmiditan, pimozide (used for Tourette syndrome), tizanidine (muscle relaxant), lamotrigine and vixotrigine (anti-seizure drugs) may also be beneficial. It may be that people with trigeminal neuralgia will have to take combination therapy, the use of two or more drugs with different mechanisms of action. Older drugs like ketamine and cannabinoids are also being considered as possible add-on agents for therapy for trigeminal neuralgia.

Bispecific Sigma1R-Antagonist/MOR-Agonist Compounds for Pain.

Recent research has significantly advanced an understanding of sigma receptors, which consist of two distinct subtypes designated as S1R and S2R (s1R and s2R gene products, respectively). Both subtypes have recently been cloned and their crystal structures have been published. As a result, highly selective S1R and S2R agonist and antagonist ligands are now available. Unlike the confusion generated from prior use of non-selective 'sigma' compounds, these tool compounds have begun to add clarity about the function of sigma receptors in health and disease.  The discovery of compounds with high-affinity (nM range) S1R/S2R or S2R/S1R subtype selectivity (>100-fold), and selectivity over off-target sites (>1,000-fold) has brought the study of sigma receptor pharmacology into the modern era. Computer modeling has contributed to a better understanding of the binding processes, structural requirements for chemical synthesis, and potential therapeutic uses. Several lines of evidence converge on pain as a therapeutic target for S1R-antagonists (as single mechanism or as part of a multi-mechanistic approach). We highlight here some compounds reported over the past few years that have promise for use as analgesics, specifically some mono-mechanistic S1R-antagonists, and some that are 'bispecific', i.e., have more than one mechanism of action, for example, complementary action of the mu-opioid receptor (MOR). We concentrate on some compounds that are further along in development, in particular, some of the bispecific S1R-antagonist/MOR-agonist compounds.

Innovative Applications of Telemedicine and Other Digital Health Solutions in Pain Management: A Literature Review.

Since the COVID-19 pandemic, healthcare systems are facing extraordinary challenges. Our approaches to medicine have changed and created a whole new generation of people who have chronic pain. Various medical services were postponed. The pandemic significantly impacted the bio-psychosocial model of pain and the management of chronic pain. These new challenges affected millions of patients worldwide, with more burden on patients with chronic pain. Telemedicine and digital health rather than traditional office visits have become essential tools for communications, resulting in an unmatched surge in telehealth adoption. This new approach facilitated the remote treatment and follow-up of patients who have difficulty to access the healthcare services, particularly patients with chronic pain and those who were receiving regular controlled medications. An extensive computer search was conducted, during the period (from January 2014 to March 2024), and included literature from PubMed, Scopus, MEDLINE, and Google scholar. According to preset inclusion and exclusion criteria, a total of 38 articles have been included in this review article. This literature review focuses on the innovation of telemedicine and digital health in pain management, especially in the context of the challenges posed by the COVID-19 pandemic. The manuscript provides a comprehensive overview of telemedicine and digital communications, their evolution, and their significance in healthcare. It also emphasizes the benefits, challenges, limitations, and the ethical concerns of telemedicine in pain management after the COVID-19 pandemic. Furthermore, the document explores the different modes of the telecommunications and discusses the future directions of the digital health technology.

Bracketing Estimation of Intentional Polysubstance Use in the United States.

Evidence from diverse sources suggests that persons who have a substance use disorder (SUD) often have problems with one or more additional substances, a situation broadly, if imprecisely, termed polysubstance use or more preferably multiple substance use disorder (mSUD). Because of the heavy toll of maladaptive neuronal dysregulation, morbidity, and mortality of SUDs, and increasingly of mSUD, on the individual, their families, the healthcare system, insurers, regulators, and society at large, it seems of value to have an estimate of the prevalence of mSUD. This turns out to be surprisingly difficult, due to nebulous or disparate definitions and to weaknesses in data acquisition methodology. We here attempt a pragmatic way of bracketing an estimate of mSUD prevalence in the US. We conclude that a reasonable estimated range of mSUD in the US is about 8 to 14 million persons. This approach provides a quick estimate for stakeholders involved in efforts to understand or deal with the immediate crisis of mSUD, as more refined estimations are pursued.

Recent Developments in Sigma-2 Receptor Compounds for Pain.

After years of enigmatic pharmacology, non-selective ligands, and uncertain clinical application, sigma receptors have emerged as interesting therapeutic drug discovery-development targets. Two subtypes of sigma receptors have now been cloned, sigma-1 receptor (S1R) and sigma-2 receptor (S2R), and there has been much complementary and converging information from advances in molecular biology, computer modeling, virtual screening, and in vitro and in vivo testing. One of several evolving areas of therapeutic potential is for the treatment of pain. In particular, there is accumulating recent evidence from preclinical models that the demonstrated positive effects of S2R compounds in these models suggest possible positive implications for clinical effectiveness against pains that have a neuropathic component. Such pain conditions have imperfect therapeutic options currently. The addition of new drugs to the now available armamentarium would represent a very significant advance for the large number of patients who suffer from these types of intractable pain. Further research is needed to identify and characterize compounds that have not only good in vitro activity but also the characteristics needed to enter clinical trials. Here, we summarize some of the recent reports of the analgesic activity of S2R compounds.

Incorporation of "Artificial Intelligence" for Objective Pain Assessment: A Comprehensive Review.

Pain is a significant health issue, and pain assessment is essential for proper diagnosis, follow-up, and effective management of pain. The conventional methods of pain assessment often suffer from subjectivity and variability. The main issue is to understand better how people experience pain. In recent years, artificial intelligence (AI) has been playing a growing role in improving clinical diagnosis and decision-making. The application of AI offers promising opportunities to improve the accuracy and efficiency of pain assessment. This review article provides an overview of the current state of AI in pain assessment and explores its potential for improving accuracy, efficiency, and personalized care. By examining the existing literature, research gaps, and future directions, this article aims to guide further advancements in the field of pain management. An online database search was conducted via multiple websites to identify the relevant articles. The inclusion criteria were English articles published between January 2014 and January 2024). Articles that were available as full text clinical trials, observational studies, review articles, systemic reviews, and meta-analyses were included in this review. The exclusion criteria were articles that were not in the English language, not available as free full text, those involving pediatric patients, case reports, and editorials. A total of (47) articles were included in this review. In conclusion, the application of AI in pain management could present promising solutions for pain assessment. AI can potentially increase the accuracy, precision, and efficiency of objective pain assessment.

A New Rat Study Suggests There May Be a Biologic Explanation for Higher Fentanyl Mortality in Men Than in Women.

Could it be possible that we should give some weight to the contribution of biological differences as contributors to the greater fentanyl mortality in males than in females? Most current explanations for a sex difference are based largely on psychosocial and other non-physiologic contributions. Our recent findings suggest a biological contribution. This could have broad implications for the interpretation and prevention of fentanyl overdose deaths.

Reversal of Propofol-induced Depression of the Hypoxic Ventilatory Response by BK-channel Blocker ENA-001: A Randomized Controlled Trial.

BACKGROUND: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response. METHODS: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics. RESULTS: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%. CONCLUSIONS: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.

A Randomized Controlled Trial of a Novel Formulation of Ketorolac Tromethamine for Continuous Infusion (NTM-001) in Healthy Volunteers.

INTRODUCTION: There is an urgent unmet medical need for a safe, effective, nonopioid analgesic agent for postoperative pain control. METHODS: This first-in-man study was designed to explore a data-informed, model-based candidate dosage regimen and safety of a novel formulation of ketorolac tromethamine (NTM-001) delivered as a 12.5-mg intravenous (IV) bolus followed immediately by 3.5 mg/h continuous infusion over 24 h compared versus IV bolus dosing of 30 mg generic ketorolac every 6 h. The study evaluated pharmacokinetic parameters and safety profiles based on a targeted product profile. A graphical overlay method and model-based comparisons were used to assess the concentration-time curve. RESULTS: Healthy adults (n = 28, 50% men) received NTM-001 and bolus dosing in an open-label crossover design. Observed plasma concentrations were tightly aligned with predicted values with no outliers. Graphical overlay comparisons showed low between-subject variability and agreed with forecasted concentration-time targets. The pharmacokinetic (PK) base models fit with preliminary PK data from both the NTM-001 and bolus groups with model fit median profiles within 95% prediction limits and no updating of the models. Consistent with serum concentration-time profiles, pain relief scores fell within predicted limits, with initial pain relief scores of NTM-001 slightly above the target profile, likely because the initial serum ketorolac concentrations were somewhat higher than predicted. The 24-h pain relief predicted for NTM-001 based on the area under the median ketorolac pain relief versus time curve was about 6% below that of the pain relief target. Both treatments were well tolerated and no subject withdrew because of adverse events. CONCLUSIONS: The PK parameters for NTM-001 and comparator bolus were similar to the modeling targets with no updating of the base model. There were no outliers and little intersubject variability. NTM-001 delivered as a bolus of 12.5 mg IV followed immediately by continuous infusion of 3.5 mg/h using a standard hospital infusion pump may offer an alternative to opioids for acute postoperative pain control.

Opioids are effective analgesics but the risk for opioid use disorder (OUD) and opioid-associated side effects limit their use even for postoperative pain. Ketorolac is an established nonopioid pain reliever that may be as efficacious as morphine in this setting. This study evaluated a new ketorolac product (NTM-001) compared to generic ketorolac. Both were delivered using a standard hospital intravenous (IV) drug pump. The new ketorolac product was administered first with a loading dose of 12.5 mg followed immediately by a continuous IV infusion of 3.5 mg/h. This was compared to IV generic ketorolac administered as a bolus dose of 30 mg every 6 h. The study enrolled 28 healthy adult volunteers. As a crossover study, subjects underwent both treatments: once with the continuous infusion (NTM-001) and once with the IV injection every 6 h (bolus group) with a "washout" period in between. Blood was collected from the volunteers at several time-determined points during the 48-h study to chart ketorolac concentrations in the blood, which can be correlated to predicted levels of pain control. In this study, blood concentrations of ketorolac were reliably predictable and side effects were generally mild with no unexpected adverse events. The continuous infusion group achieved analgesic benefit at a lower total dose than did the every-6-h group over 24 h.

Identifying risk factors for chronic postsurgical pain and preventive measures: a comprehensive update.

INTRODUCTION: Chronic postsurgical pain (CPSP) is a prevalent condition that can diminish health-related quality of life, cause functional deficits, and lead to patient distress. Rates of CPSP are higher for certain types of surgeries than others (thoracic, breast, or lower extremity amputations) but can occur after even uncomplicated minimally invasive procedures. CPSP has multiple mechanisms, but always starts as acute postsurgical pain, which involves inflammatory processes and may encompass direct or indirect neural injury. Risk factors for CPSP are largely known but many, such as female sex, younger age, or type of surgery, are not modifiable. The best strategy against CPSP is to quickly and effectively treat acute postoperative pain using a multimodal analgesic regimen that is safe, effective, and spares opioids. AREAS COVERED: This is a narrative review of the literature. EXPERT OPINION: Every surgical patient is at some risk for CPSP. Control of acute postoperative pain appears to be the most effective approach, but principles of good opioid stewardship should apply. The role of regional anesthetics as analgesics is gaining interest and may be appropriate for certain patients. Finally, patients should be better informed about their relative risk for CPSP.

The majority of surgery patients experience pain right after surgery that diminishes day by day as the tissue heals. Surgeons can usually advise patients how long their postsurgical pain will last, but in some cases, pain persists much longer and can even become chronic. Chronic postsurgical pain or CPSP is a condition that occurs most often in people who have open-chest surgery, breast surgery, or have a lower limb amputated. However, CPSP can occur after any type of surgery, even minimally invasive procedures with no complications.CPSP is a form of chronic pain and can be treated as chronic pain. CPSP can be mild or severe. In some patients, CPSP can include a form of numbness or 'pins and needles' around the affected area.There are certain things that can increase a person's risk for developing CPSP. Some of these things cannot be changed, like the higher risk for females, younger people, and for certain types of surgery. Pre-existing pain before surgery can increase the risk of CPSP and so can having a very negative attitude called 'catastrophizing.' People who 'catastrophize' tend to focus and think constantly about worst-case scenarios. Genetics may also play a role in CPSP, but less is known about what genes are involved and how to reduce the risk.Some CPSP is unavoidable, such as a surgery that might cut or compress a nerve. In other cases, the inflammation following surgery can set the stage for CPSP.The best strategy to prevent or minimize CPSP is for the clinical team to effectively treat the acute postsurgical pain.] The recommended approach is to use a multimodal pain therapy which is based on two or more agents and may also combine nonpharmacologic approaches as well. Multimodal pain care solves two pain problems. First, CPSP tends to be different types of pain that occur together in something called a 'mixed pain syndrome.' Multimodal pain treatment uses more than one agent with different mechanisms of action. Second, multimodal pain regimens reduce or may even eliminate the use of opioid pain relievers. By using the lowest effective amount of opioids, patients are spared opioid-associated side effects and fewer opioids are used. Opioids are associated with opioid use disorder and new policies about good opioid stewardship urge hospitals and prescribers to use opioids only to the extent appropriate.

The Sex Data Gap Within Implantable Cardioverter Defibrillator (ICD) Studies: A Retrospective Study of Literature From 1980 Until 2022.

Implantable cardioverter defibrillators (ICDs) are a form of cardiac therapy used to prevent death in patients at risk for sudden heart failure. Using 100 articles from the introduction of ICDs until now, a retrospective literature review was conducted. These studies were analyzed for sex disparity over the past 40 years. The difference in the number of male participants to female participants was statistically significant for both the earlier and later study groups (p = 0.0014 and p = 0.0004 respectively), indicating a significant and consistently lower number of females in ICD research over time. This review shows no significant difference in the sex disparity since the implementation of ICDs. Unfortunately, due to a gap in the literature, the reason for this disparity between the sexes in ICD literature can only be speculated. This disparity may be partly due to a lack of incentive and encouragement for women to participate in research.

What Do We Need to Know About Rising Rates of Idiopathic Pulmonary Fibrosis? A Narrative Review and Update.

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.

Current and emerging COX inhibitors for treating postoperative pain following oral surgery.

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.

The Challenges of Pain Assessment in Geriatric Patients With Dementia: A Review.

Pain in dementia patients is common, poorly measured, and undertreated. It is important to discuss the challenges in the pain assessment and management to find a possible solution for adequate pain management. The aim of this article is to discuss the challenges in the assessment of pain in geriatric patients with dementia. An extensive online database search was conducted via multiple websites using the following keywords: "dementia," "pain assessments," "pain assessment with dementia," "causes of pain with dementia," "pain assessments using recent technology," "geriatric," and "old age" to identify the relevant articles. Our inclusion criteria were articles that focused on pain in geriatric patients diagnosed with dementia, in English, published between January 2018 and January 2023, and available as free full text and those which were clinical trials, observational studies, review articles, systemic reviews, meta-analysis, or case series. The exclusion criteria were articles that did not have pain in geriatric patients diagnosed with dementia as their primary focus, involving geriatric or non-geriatric patients with major psychological distress, not in the English language, not published between January 2018 and January 2023, and not available as free full-text and those which were case reports and editorial articles. After manually excluding the articles that did not meet our inclusion criteria, we ended up with 38 articles. In conclusion, any instruments have been made for the pain assessment in patients with dementia. The two most common tools used to assess pain in this vulnerable population are the Pain Assessment in Advanced Dementia (PAINAD) and Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC) scales. The utilization of new technology may offer promising solutions for the pain assessment in patients with dementia.

Pharmacotherapeutic management of trigeminal neuropathic pain: an update.

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.

Effects of Digoxin in Heart Failure (HF) With Reduced Ejection Fraction (EF).

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).

The epidemiology of apnoea of prematurity.

WHAT IS KNOWN AND OBJECTIVE: Many premature infants less than 37 weeks gestational age (GA), and almost all infants less than 28 weeks GA, will experience apnoea of prematurity (AOP)-a cessation of respiration for 20 or more seconds (or less than 20 s if accompanied by other signs). Because the treatment options for AOP are so limited, we explore its epidemiology, with the ultimate hope of learning how to decrease its incidence. COMMENT: Although AOP usually resolves with maturation of the respiratory system, many short- and long-term negative effects are correlated statistically with AOP (although direct causality has not been established). The primary risk factor for AOP is preterm birth, but delivery technique, genetics, socioeconomic status, racial disparities and other influences are suspected to be involved. Anaemia, asthma and gastric reflux have also been associated with preterm birth, but the relationship with AOP is unclear. The postulated associations and the strength of the evidence are briefly reviewed and discussed. WHAT IS NEW AND CONCLUSION: Attempts to elucidate the epidemiology of apnoea of prematurity have been challenging. Studies of AOP are hampered in part by challenges in monitoring the condition, the interplay of multiple comorbidities in preterm neonates and lack of expert consensus definitions. However, since the primary risk factor is preterm birth, efforts to decrease the prevalence of preterm birth would have a positive secondary effect on the prevalence of AOP. Until then, better pharmacotherapeutic options are needed.

Potential neurological manifestations of COVID-19: a narrative review.

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.

Pharmacologic agents directed at the treatment of pain associated with maladaptive neuronal plasticity.

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.