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.

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.

A Single Ascending-Dose Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Respiratory Stimulant ENA-001.

Background ENA-001 (formerly known as GAL-021) is a novel, first-in-class respiratory stimulant. Pharmacokinetic and pharmacodynamic properties, plus safety and tolerability, were assessed in a randomized, single-center study of healthy volunteers. Methodology This four-period study was designed to test continuous two-hour intravenous infusion regimens of ENA-001 at doses of 0.96, 1.44, and 1.92 mg/kg/hour versus placebo. Each participant received four infusions with a seven-day minimum washout between them: one infusion each of the three doses of ENA-001 and one placebo. Pharmacokinetic and pharmacodynamic parameters were assessed and adverse events were recorded. Results A total of 17 participants completed the study. ENA-001 was generally safe and well tolerated over the dose range studied (0.96 to 1.92 mg/kg/hour). ENA-001 was able to drive hyperventilation in a dose-dependent manner in healthy participants. Increases in ventilation due to ENA-001 were not associated with like-magnitude blood pressure response. ENA-001-stimulated decreases in ETCO2 were associated with small, statistically significant, increases in SpO2 levels. Hyperventilation occurred in two participants at the highest dose level, leading to study discontinuation. The terminal half-life of ENA-001 was 6.33 hours. Conclusions The respiratory stimulant ENA-001 demonstrated well-behaved pharmacokinetics following the two-hour infusion. Mean peak plasma concentrations and the mean total systemic exposure values were approximately dose-proportional in the dose range studied.

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.

A Novel Agnostic Respiratory Stimulant as a Treatment for Apnea of Prematurity: A Proof-of-Concept Study.

AIM/OBJECTIVE: ENA-001 is a novel selective antagonist of large-conductance BK (big potassium) channels located in the carotid bodies, where they act as chemoreceptors that sense low arterial oxygen levels and establish a feedback loop to brainstem nuclei responsible for initiating spontaneous breathing and maintaining adequate oxygen to tissues. ENA-001 attenuates respiratory depression induced by a variety of chemical agents, essentially "agnostic" to the precipitating drug (e.g., opioid(s), benzodiazepine, alcohol, or propofol). But it had not been tested against respiratory depression resulting from a physiological cause, such as apnea of prematurity (AOP). This proof-of-principle study used a well-described animal model (premature lamb) to test the effectiveness of ENA-001 in the setting of an under-developed respiratory control system, similar to that in human AOP. MATERIALS AND METHODS: A set of twin lambs was delivered prematurely via caesarian section at 135 ± 2 d gestational age (GA). An arterial catheter was connected to a transducer for pressure monitoring and a venous catheter was connected to a pump for continuous infusion of 5% dextrose in water (D5W). Lambs were to receive four mechanical breaths for lung recruitment and then started on continuous positive airway pressure (CPAP). After a stabilization period of 15 minutes, the protocol called for the first lamb to be started on continuous infusion of ENA-001, with ascending dose hourly (0.4, 1.1, 2.0, 12.0 mg/kg/hr), while the second lamb was to serve as a sham (D5W) control. At least 10 representative breaths free of artifact from motion or atypical breaths were recorded using a pulmonary function system designed for neonatal research. To maintain a stable plane of anesthesia, repeat doses of fentanyl (1 µg IM) were given as needed based on blood pressure response to stimulation. RESULTS: Two male lambs were delivered. Unexpectedly, neither lamb exhibited a drive for spontaneous breathing. Each required manual ventilation, with a complete absence of spontaneous effort. Despite the poor prognosis owing to the absence of ventilatory effort, continuous infusion of the first dose of ENA-001 was started 20 minutes after birth. The test animal continued to require manual ventilation, which was continued for an additional 10 minutes. An intravenous (IV) bolus of ENA-001 was given. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously and did not require manual intervention for the remainder of the study. The sham animal was delivered approximately an hour following the test animal. As with the test animal, the sham animal lacked spontaneous breathing efforts. A decision was made to manually ventilate for 30 minutes to match the course for the test animal. At the 30-minute time point, an IV bolus infusion of ENA-001 was delivered. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously. After several minutes, the spontaneous breathing efforts abated, and manual ventilation was resumed. The animal was then sacrificed for tissue harvest. CONCLUSION: These results suggest that ENA-001 might be an effective therapy, alone or as a co-medication, for the treatment of AOP. They further suggest that ENA-001 might have broader applications in situations of neurological ventilatory insufficiency.

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.

The limited management options for apnoea of prematurity.

WHAT IS KNOWN AND OBJECTIVE: About 10% of all infants are born prematurely. Almost all of those of gestational age less than about 30 weeks, and about half of those of gestational age up to about 35 weeks, are subject to unpredictable interruptions of breathing-known as "apnoea of prematurity" (AOP). We present a synopsis of the problem and point out the limited management options. COMMENT: A basal rate for spontaneous breathing is normally maintained by integrated action of generator cells in the brainstem and feedback from central and peripheral chemosensors. In AOP, there are intermittent periods (seconds) lacking spontaneous firing, which results in hypoxia and hypercapnia. The long-term consequences of these interruptions in oxygen supply to tissues are not known. Although many treatment modalities are used, including drug therapy, nonpharmacologic care and mechanical intervention, there is no universally effective first-line management for AOP. Caffeine citrate is generally the most frequently used pharmacotherapeutic agent, but its side effect profile narrows with higher doses and the upper limit is still being investigated to discern the greatest benefit-to-risk ratio; thus, most infants do not achieve complete resolution of apnoeas. WHAT IS NEW AND CONCLUSION: Given the widespread and serious nature of the problem of AOP, there is a surprising lack of treatment options. A more consistent and effective treatment, alone or as adjunct, would be welcome.

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.

Wooden Chest syndrome: The atypical pharmacology of fentanyl overdose.

WHAT IS KNOWN AND OBJECTIVE: A large percentage of opioid overdose fatalities involve fentanyl or one of its legal or illegal analogs (F/FAs). Is there something about the pharmacology of these drugs that make them unusually dangerous in an overdose? COMMENT: Some of the reasons for the dangers of overdose of F/FAs is their high potency and low cost (that leads to wide distribution). But it is rarely asked if the basic pharmacology of F/FAs differ in some fundamental way from conventional opioids such as morphine and heroin. In addition to centrally mediated respiratory depression via opioid receptors, F/FAs cause rigidity in the key respiratory muscles of the chest, upper airway and diaphragm ("wooden chest syndrome," WCS) by a non-opioid mechanism. WHAT IS NEW AND CONCLUSION: WCS is an atypical pharmacology of F/FAs. Because of its rapid onset and non-opioid mechanism, WCS makes F/FA overdose particularly dangerous.

Benefit-Risk Analysis of Buprenorphine for Pain Management.

Health care providers in the United States are facing challenges in selecting appropriate medication for patients with acute and chronic pain in the midst of the current opioid crisis and COVID-19 pandemic. When compared with conventional opioids, the partial µ-opioid receptor agonist buprenorphine has unique pharmacologic properties that may be more desirable for pain management. The formulations of buprenorphine approved by the US Food and Drug Administration for pain management include intravenous injection, transdermal patch, and buccal film. A comparison of efficacy and safety data from studies of buprenorphine and conventional opioids suggests that buprenorphine may be a better-tolerated treatment option for many patients that provides similar or superior analgesia. Our benefit-risk assessment in this narrative review suggests that health care providers should consider that buprenorphine may be an appropriate alternative for pain management over other opioids.

Overdoses due to fentanyl and its analogues (F/FAs) push naloxone to the limit.

WHAT IS KNOWN AND OBJECTIVE: Food and Drug Administration (FDA) risk evaluation and mitigation strategies (REMs) encourage emergency responders, paramedics, law enforcement agents, and even laypeople to be trained in the administration of naloxone with the intent of rescuing individuals from a known or suspected opioid overdose. COMMENT: Although naloxone is generally safe and effective at reversing respiratory depression caused by a conventional opioid such as morphine or heroin by competing with the opioid and displacing it from the µ-opioid receptor, questions increasingly are arising as to whether naloxone can adequately reverse opioid overdoses that may involve the potent opioids fentanyl and its analogues (F/FAs). In other words, as more and more opioid overdoses involve F/FAs, can naloxone keep up? WHAT IS NEW AND CONCLUSION: As a competitive antagonist at µ-opioid receptors, naloxone is often a life-saving agent in cases of overdose caused by conventional opioids, but it may not be versatile or powerful enough to combat the rising tide of overdoses due to fentanyl and its illicit analogues, or in cases of overdose involving combinations of opioids and non-opioids.

History of Respiratory Stimulants.

The interest in substances that stimulate respiration has waxed and waned throughout the years, intensifying following the introduction of a new class of drugs that causes respiratory depression, and diminishing when antidotes or better drug alternatives are found. Examples include the opioids--deaths increasing during overprescribing, diminishing with wider availability of the opioid receptor antagonist naloxone, increasing again during COVID-19; the barbiturates--until largely supplanted by the benzodiazepines; propofol; and other central nervous system depressants. Unfortunately, two new troubling phenomena force a reconsideration of the status-quo: (1) overdoses due to highly potent opioids such as fentanyl, and even more-potent licit and illicit fentanyl analogs, and (2) overdose due to polysubstance use (the combination of an opioid plus one or more non-opioid drug, such as a benzodiazepine, sedating antidepressant, skeletal muscle relaxant, or various other agents). Since these now represent the majority of cases, new solutions are again needed. An interest in respiratory stimulants has been revived. This interest can be informed by a short review of the history of this interesting class of medications. We present a short history of the trajectory of advances toward more selective and safer respiratory stimulants.

Are opioid receptor antagonists adequate for "Opioid" overdose in a changing reality?

WHAT IS KNOWN AND OBJECTIVE: Deaths due to opioid-induced respiratory depression (OIRD) continue to rise despite intense regulatory and professional actions. COVID-19 has only worsened this situation.1 An opioid receptor antagonist (ORA) such as naloxone is the most common intervention for OIRD. However, with increasing overdose from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy of ORA seems warranted and timely. COMMENT: OIRD results from the binding of an excess number of agonist molecules to opioid receptors. Mechanistically, it makes sense to reverse this by displacing agonist molecules by administering an ORA. But realistically, the trend to higher-potency agonists and polysubstance abuse diminishes the effectiveness of this approach. We are left facing a crisis without a solution. WHAT IS NEW AND CONCLUSION: For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Alternatives are needed-soon.

Neuronal Effects of Listening to Entrainment Music Versus Preferred Music in Patients With Chronic Cancer Pain as Measured via EEG and LORETA Imaging.

Previous studies examining EEG and LORETA in patients with chronic pain discovered an overactivation of high theta (6-9 Hz) and low beta (12-16 Hz) power in central regions. MEG studies with healthy subjects correlating evoked nociception ratings and source localization described delta and gamma changes according to two music interventions. Using similar music conditions with chronic pain patients, we examined EEG in response to two different music interventions for pain. To study this process in-depth we conducted a mixed-methods case study approach, based on three clinical cases. Effectiveness of personalized music therapy improvisations (entrainment music - EM) versus preferred music on chronic pain was examined with 16 participants. Three patients were randomly selected for follow-up EEG sessions three months post-intervention, where they listened to recordings of the music from the interventions provided during the research. To test the difference of EM versus preferred music, recordings were presented in a block design: silence, their own composed EM (depicting both "pain" and "healing"), preferred (commercially available) music, and a non-participant's EM as a control. Participants rated their pain before and after the EEG on a 1-10 scale. We conducted a detailed single case analysis to compare all conditions, as well as a group comparison of entrainment-healing condition versus preferred music condition. Power spectrum and according LORETA distributions focused on expected changes in delta, theta, beta, and gamma frequencies, particularly in sensory-motor and central regions. Intentional moment-by-moment attention on the sounds/music rather than on pain and decreased awareness of pain was experienced from one participant. Corresponding EEG analysis showed accompanying power changes in sensory-motor regions and LORETA projection pointed to insula-related changes during entrainment-pain music. LORETA also indicated involvement of visual-spatial, motor, and language/music improvisation processing in response to his personalized EM which may reflect active recollection of creating the EM. Group-wide analysis showed common brain responses to personalized entrainment-healing music in theta and low beta range in right pre- and post-central gyrus. We observed somatosensory changes consistent with processing pain during entrainment-healing music that were not seen during preferred music. These results may depict top-down neural processes associated with active coping for pain.

The problem of postoperative respiratory depression.

WHAT IS KNOWN AND OBJECTIVE: Postsurgical recovery is influenced by multiple pre-, intra- and perioperative pharmacotherapeutic interventions, including the administration of medications that can induce respiratory depression postoperatively. We present a succinct overview of the topic, including the nature and magnitude of the problem, contributing factors, current limited options, and potential novel therapeutic approach. COMMENT: Pre-, intra- and perioperative medications are commonly administered for anxiety, anaesthesia, muscle relaxation and pain relief among other reasons. Several of the medications alone or in joint-action can be additive or synergistic producing respiratory depression. Given the large number of surgical procedures that are performed each year, even a small percentage of postoperative respiratory complications translates into a large number of affected patients. WHAT IS NEW AND CONCLUSION: Due to the large number of surgeries performed each year, and the variety of medications used before, during, and after surgery, the occurrence of postoperative respiratory depression is surprisingly common. It is a significant medical problem and burden on hospital resources. There is a need for new strategies to prevent and treat the acute and collateral problems associated with postoperative respiratory depression.

The conundrum of polysubstance overdose.

WHAT IS KNOWN AND OBJECTIVE: Treating an opioid overdose using an opioid receptor antagonist (such as naloxone) makes mechanistic sense and can be effective. Unfortunately, the majority of current drug overdose deaths involve polysubstance use (i.e., an opioid plus a non-opioid). COMMENT: Respiratory depression induced by opioids results from excessive opioid molecules binding to opioid receptors. This effect can be reversed by an opioid receptor antagonist. However, the respiratory depression induced by non-opioid drugs is not due to action at opioid receptors; thus, an opioid receptor antagonist is ineffective in many of these cases. For respiratory depression induced by non-opioids, receptor antagonists are either not available (e.g., for propofol overdose) or there may be attendant risks with their use (e.g., seizures with flumazenil). This gives rise to a need for more effective ways to treat polysubstance overdose. WHAT IS NEW AND CONCLUSION: A new approach to treating opioid-induced respiratory depression due to drug overdose focuses on agents that stimulate respiratory drive rather than competing for opioid receptors. Such an approach is "agnostic" to the cause of the respiratory depression, so might be a potential way to treat polysubstance overdose.

Bone fractures during the time of coronavirus.

WHAT IS KNOWN AND OBJECTIVE: In response to rapid spread of coronavirus (SARS-CoV-2) and lack of vaccine or effective treatment for COVID-19 disease, governments imposed measures that resulted in a shift from work and school to isolation at home. Studies from three countries (China, Belgium and the United States) report the consequences on traumatic bone fractures. COMMENT: The coronavirus pandemic has resulted in a widespread change to a relative sedentary lifestyle and decreased exposure to light (vitamin D). A consequence of the stay-at-home policies is a negative change in bone-health and environmental surroundings that has led to age-related changes in the number of traumatic bone fractures. WHAT IS NEW AND CONCLUSION: A consequence of stay-at-home policies has been a decline in bone fractures for young and middle-aged adults; but an increase for the elderly. The trends are predicted to reverse, and present new problems, when isolation restrictions are removed.

Benzodiazepines: Thinking outside the black box.

WHAT IS KNOWN AND OBJECTIVE: The United States Food and Drug Administration (FDA) recently issued a Drug Safety Communication requiring Boxed Warning updating and other changes in order to improve the safe use of the benzodiazepine drug class. These changes were prompted because 'The current prescribing information for benzodiazepines does not provide adequate warnings about [the] serious risks and harms associated with these medicines so they may be prescribed and used inappropriately'. COMMENT: The FDA Communication points out that benzodiazepines can be an important option for treating disorders for which these drugs are indicated. However, the acknowledged problems of these drugs, which historically were considered an acceptable trade-off against their benefits, need to be reassessed in light of their widespread (over?) prescribing (for example, in 2019 an estimated 92 million benzodiazepine prescriptions were dispensed from US retail and mail-order pharmacies). WHAT IS NEW AND CONCLUSION: The FDA Communication can be viewed as an important step in reminding healthcare providers of the 'serious risks and harms associated with these medicines', and validation of such reports by patients. Importantly, the FDA Communication includes an often-neglected aspect of benzodiazepine prescribing, namely how to discontinue use, and the perplexing protracted withdrawal syndrome experienced by some patients. The Communication advises to providers: 'No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage, and ensure ongoing monitoring and support as needed to avoid serious withdrawal symptoms or worsening of the patient's medical condition'.