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.

Practical Tips on Epidermolysis Bullosa for Caregivers: Part 2.

The heritable condition epidermolysis bullosa (EB) is a rare but potentially devastating and life-threatening condition that is characterized primarily by cutaneous fragility, manifested when the dermis and epidermis fail to adhere properly. EB has no cure, and because of its rarity, few healthcare professionals have experience in treating it. Most families with an EB child are forced to rely on family caregiving which can be disruptive to family routines but, more importantly, place enormous time and emotional and financial burdens on the family. EB can be extremely painful, and families are often caught in the bind of trying to manage overwhelming financial burdens in an effort to help their children cope with excruciating pain. For many years, the nonprofit organization NoBabyBlisters.org has worked on five continents with families caring for EB children. Many of these families reside in under-developed nations with hot climates and limited healthcare resources. Over time, the healthcare professionals with NoBabyBlisters.org have worked with EB families both internationally and in the United States to develop a series of simple tips or "hacks" that may provide relief or great benefit to these children. The objective of this article is to share these field-tested tips with a wider audience. This is not a scientific study or a systematic review and is offered as a companion article to an earlier article on the same subject.

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.

The Emergence of the Old Drug Captagon as a New Illicit Drug: A Narrative Review.

First developed in the 1960s in Europe and approved briefly for use in the United States, fenethylline (sold as Captagon, one of its early trade names) is now a prominent drug of abuse in the Eastern Mediterranean Region. The drug was withdrawn from the United States market because of side effects that included hallucinations, visual distortions, and psychosis; it has also been linked to rare cases of myocardial infarction, seizures, and delusions. The chemical synthesis of fenethylline is straightforward and inexpensive. Manufactured in clandestine labs in Southern Europe and the Middle East, these amphetamines had been used by affluent Middle Eastern young people for recreation or study aids. Captagon has periodically emerged as a drug used in combat and conflict, and it was implicated in the 2015 riots in Paris. It has been described as "chemical courage" for combatants giving them focus, energy, and endurance in battle situations. Captagon is addictive but no cases of direct captagon-associated mortality have been reported. The use of drugs in war is nothing new, but captagon is also used heavily in the civilian population in war-torn areas to help them cope with food insecurity and maintain courage in dangerous situations. Captagon production and distribution drives the Syrian economy, but the drug's use is limited to certain regions and is rarely seen in North America. The drug is available online, but product may be contaminated with the inclusion of procaine, caffeine, or other substances.

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.

Epidermolysis Bullosa: Practical Clinical Tips From the Field.

Epidermolysis bullosa (EB) is a rare genetic condition characterized by fragile skin caused by impaired adhesion between the dermis and epidermis. EB is present at or near birth. There is no cure and treatments are supportive. Children with EB are at elevated risk of squamous cell cancer. Under ideal circumstances, EB patients benefit from interdisciplinary care teams who can offer state-of-the-art treatments. In reality and particularly in less-developed nations, care can be limited. In all cases, families dealing with a member with EB face great challenges in caregiving, much of which is managed at home, and incur great financial expenses for dressings, equipment, transportation, and out-of-pocket expenses. While research groups are working to find a cure for EB, clinicians working with EB patients around the world have found practical and relatively inexpensive tips to make life easier for people with EB. NoBabyBlisters.org, a nonprofit organization actively supplying monthly medical supplies for EB children on five continents and working on EB research, has innovated, developed, collected, and now offers here seven such practical and actionable items learned from its experience in the real world assisting children in less-developed nations, typically with hot climates. These are based on real-world clinical experience dealing with a complex disorder under challenging circumstances. The goal of this short paper is to provide advice to EB caregivers and their loved ones that may make things easier and enhance quality of life, including blister and pain reduction.

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.

Utility of Cupping Therapy in Substance Use Disorder: A Novel Approach or a Bizarre Treatment?

Substance use disorder is a psychiatric problem not bound by age, sex, ethnicity, sexual preference, geography, socio-economic status, educational level, or political and religious ideologies. While robust pharmacotherapy and psychotherapy treatments are available for de-addiction and managing withdrawal symptoms, patients from rural areas and lower socio-economic classes often prefer alternative medicine. Cupping therapy is one such ancient practice used mainly for organic physical conditions. A patient addicted to alprazolam, codeine, and tobacco presented to our psychiatry outpatient department for de-addiction and management of his withdrawal symptoms. He came to seek professional help after a trial of cupping therapy by an alternative medicine practitioner, which did not improve his condition. His withdrawal symptoms subsided after standard treatment. As found in this case, cupping therapy is not beneficial in treating substance use disorder or managing withdrawal symptoms. Awareness of the utility and consequences of cupping therapy and other alternative therapies is required to promote rational scientific treatments. Substantial reforms in health promotion and health education are required to educate the general population regarding the most effective treatments available, and the risks of iatrogenesis associated with traditional cures that are not evidentially backed.

Pirates of Clinical Trials.

With the burgeoning numbers of clinical trials, the competition among sponsors for research subjects has grown intensely. Many clinical trials fail to meet their recruitment goals. Contract research organizations (CROs) that help conduct all or portions of a clinical study have transitioned from highly specialized niches, such as biostatistical analysis or regulatory compliance, to more overall functions to keep a trial moving forward. CROs establish agreements with sponsors, including how much a site will be paid per study subject. CROs are locked into that pricing, but over the course of a study's recruitment period, sponsors with deeper pockets may step in and offer more compensation per subject. The result is a competitive market place that favors big sponsors and puts smaller CROs and start-ups at a disadvantage.

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.

Brave New Healthcare: A Narrative Review of Digital Healthcare in American Medicine.

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.

Answering Big Questions in Pain Medicine.

The future of pain medicine is marked by many questions. What can other nations around the world learn from the opioid crisis that is still affecting the United States? The American opioid experience was mischaracterized and wrongly described, and its causes were misdiagnosed from the outset, leading to its mismanagement and the abandonment of many chronic pain patients to their suffering. There are a few new drugs in the analgesic armamentarium. What new targets do we have in pain medicine? There are many breakthroughs, discoveries, and potential new targets that could add to our analgesic prescribing choices. These include sigma receptors, d-amino acid oxidase, endoplasmic reticulum stress receptors, histone deacetylase, and others. Neuromodulation had been used with varying degrees of success for years, but with a simplistic approach based on the gate theory of pain. Despite our familiarity with neuromodulation and spinal cord stimulators, neuromodulation research indicates that the activation of glial cells may activate the immune system and enhance analgesia. Neuromodulation studies have concentrated on how electricity affects neuronal activity rather than how electrical activity could reduce pain. There are still more frontiers in our battle against pain and some promising avenues for treatments. This narrative review will try to summarize what can be done from the perspective of recent technological and pharmacological developments.

Advances in the Management of Acute Postsurgical Pain: A Review.

Despite the millions of surgeries performed every year around the world, postoperative pain remains prevalent and is often addressed with inadequate or suboptimal treatments. Chronic postsurgical pain is surprisingly prevalent, and its rate varies with the type of surgery, as well as with certain patient characteristics. Thus, better clinical training is needed as well as patient education. As pain can be caused by more than one mechanism, multimodal or balanced postsurgical analgesia is appropriate. Pharmacological agents such as opioid and nonopioid pain relievers, as well as adjuvants and nonpharmacologic approaches, can be combined to provide better and opioid-sparing pain relief. Many specialty societies have guidelines for postoperative pain management that emphasize multimodal postoperative analgesia. These guidelines are particularly helpful when dealing with special populations such as pregnant patients or infants and children. Pediatric pain control, in particular, can be challenging as patients may be unable to communicate their pain levels. A variety of validated assessment tools are available for diagnosis. Related to therapy, most guidelines agree on the fact that codeine should be used with extreme caution in pediatric patients as some may be "rapid metabolizers" and its use may be life-threatening. Prehabilitation is a preoperative approach that prepares patients in advance of elective surgery with conditioning exercises and other interventions to optimize their health. Prehabilitation may have aerobic, strength-training, nutritional, and counseling components. Logistical considerations and degree of patient adherence represent barriers to effective prehabilitation programs. Notwithstanding all this, acute postoperative pain represents a clinical challenge that has not yet been well addressed.

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.

The Emerging Role of Sigma Receptors in Pain Medicine.

Sigma receptors are protein chaperones with the unexpected characteristic of being activated by ligand binding. As such, they represent intriguing new targets for potential drug development. As a protein chaperone, these "receptors" escort proteins from the endoplasmic reticulum to their destinations and act to correct misfolded proteins. The two subtypes of sigma receptors, named σ1 and σ2, are markedly distinct from each other. Agonists and antagonists at these receptors show promise as new drug targets, addressing a range of diseases including neurodegenerative disorders, cancer, and cardiac disorders, and may also be analgesic agents and rehabilitation drugs for opioid use disorder. As an analgesic, sigma receptors seem to be more effective in treating neuropathic than nociceptive pain. New bifunctional compounds are being developed with opioids, because agents targeting sigma receptors may have an opioid-sparing effect. The pipeline of agents based on the sigma receptors is long and may treat things from Fragile X syndrome to Parkinson's disease to Huntington's disease to cancer. A novel agent ADV502 acts as a high-affinity σ1 antagonist and partial agonist at the µ-opioid receptor and may be an important agent both for the treatment of neuropathic cancer pain and for rehabilitation of opioid use disorder. Since there has been little recent innovation in pain medicine regarding new compounds and drug targets, drugs that affect the sigma receptor system seem promising and encouraging.

From Antidepressant Tianeptine to Street Drug ZaZa: A Narrative Review.

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.

Old Drugs and New Challenges: A Narrative Review of Nitazenes.

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.