One of the most difficult challenges for any prescriber is distinguishing between the legitimate prescription of controlled substances and the prescription that may be used for illegitimate purposes. To discern the difference, prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain and the signs and symptoms of patients misusing controlled substances. Pain relief remains one of the most common reasons patients seek medical attention. Although many categories of pain medications are available, opioid analgesics are approved by the Food and Drug Administration (FDA) for moderate-to-severe pain. As such, they are a common choice for patients with acute, cancer-related, neurologic, and end-of-life pain. Prescribing opioid analgesics for chronic pain is controversial and fraught with inconclusive standards. In the 1990s, the chronic failure of health professionals to treat severe pain appropriately led to an expansion in opioid analgesic prescribing. Unfortunately, this resulted in increased overuse, diversion of drugs, opioid use disorder, and overdose. The Catch-22 is that health professionals either undertreat patients, leading to unnecessary suffering, or overtreat them, which can cause adverse effects such as increased risk of opioid analgesic use disorder and potential overdose. Opioid analgesic prescribing reached its highest point in 2011. Since then, both prescribing and overdose have been declining. However, as a society, in both the lay and scientific literature, there are significant concerns that we are still in the middle of an opioid crisis. One of the biggest challenges in caring for patients with pain is their varying tolerance levels, which necessitate different opioid doses to achieve adequate pain relief. Patients may exhibit a wide range of behavioral, cultural, emotional, and psychological responses to pain compared to those with a substance use disorder; often, distinguishing between the two can be challenging. All healthcare professionals engaged in pain control need an understanding of the treatment recommendations and safety concerns in prescribing opioid analgesics. Appropriate opioid prescribing requires a thorough patient assessment, short- and long-term treatment planning, close follow-up, and continued monitoring. All healthcare providers need to be aware of appropriate patient assessment, treatment planning, and the potential for substance use disorder, drug diversion, and hazardous behavioral responses to controlled substances, such as opioid analgesics, which differ from pseudoaddiction and physical dependence. Many clinicians have limited knowledge of opioid use disorder. They often fail to recognize it as a disease and mistakenly believe that opioid dependence is the same as opioid use disorder. A lack of clear understanding can lead to confusion between patients with chronic non-use disorder and those misusing their prescribed opioids. A lack of training and educational deficits often interfere with the appropriate prescription of opioid analgesic agents. To prevent the misuse of controlled substances, healthcare providers who prescribe controlled substances should learn prescribing practices that minimize or prevent adverse consequences. Definitions: Addiction: According to the American Society of Addiction Medicine (ASAM), addiction is a primary, chronic disease of brain reward, motivation, memory, and related circuitry. Dysfunction in these circuits leads to characteristic biological, psychological, social, and spiritual manifestations. This dysfunction is reflected in an individual pathologically pursuing reward or relief through substance use and other behaviors. Addiction is now termed substance use disorder and is characterized by an inability to consistently abstain, cravings for the drug, impairment in behavioral control, diminished ability to recognize significant problems with one's behaviors and interpersonal relationships, and a dysfunctional emotional response. Like other chronic diseases, substance use disorder often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, substance use disorder is progressive and can result in disability or premature death. : Appropriate opioid analgesic prescribing: This involves providing pain control while minimizing toxicity, substance use disorder, or the risk of substance use disorder and implementing safeguards to reduce drug diversion. Inappropriate opioid analgesic prescribing: Non-prescribing, inadequate prescribing, excessive prescribing, or continued prescribing despite evidence of the lack of effective opioid analgesic treatment. Controlled substances: These substances are drugs or medications that possess the potential for being misused and are considered to be substances that have a substantially high risk of resulting in substance use disorder. Opioid analgesics: These drugs dull the senses and relieve pain, such as morphine. In addition, these medications may induce sleep. The Drug Enforcement Administration (DEA, USA) uses the term narcotic to refer to drugs that are opioid analgesics. Characteristics of Addiction or Substance Use Disorder: Craving for drugs or rewards. Diminished recognition of significant problems in behavior. Dysfunctional emotional response. Impairment in behavioral control. Inability to consistently abstain . Drug Schedules of Controlled Substances All healthcare providers should be familiar with the guidelines and laws for each schedule, which are based on the purpose of the drug and the risk of substance use disorder. In the United States, controlled substances are subject to strict regulation by both federal and state laws that govern their manufacture and distribution. Controlled substances have a high risk of resulting in addiction and substance use disorder. As the schedules decrease from I to V, the drugs listed within each category have a lower potential to cause a substance use or addiction disorder. Controlled Substances Act In the United States, the Comprehensive Drug Abuse Prevention and Control Act was passed in 1970 and included the Controlled Substances Act. The Controlled Substances Act covers various aspects of drugs as follows: Classification and regulation of drugs, according to their content and purpose. Manufacturing of drugs. Distribution of drugs. Exportation and sale of drugs. The Controlled Substances Act established 5 drug schedules to regulate the manufacture and distribution of controlled substances. As part of the regulation, healthcare providers who prescribe controlled substances and pharmacists who fill these prescriptions must obtain a license from the DEA. These licenses include specific license numbers allowing controlled substance prescriptions to be tracked and linked to a specific healthcare provider or distributor. These schedules categorize substances based on their medical value, risk of addiction, and potential to cause harm. The schedules range from Schedule I, which has the highest potential for addiction and substance use disorder, to Schedule V, which has the lowest potential for addiction and substance use disorder. Schedule I: Schedule I drugs possess the highest potential for substance use disorder and misuse. These drugs have no medical use and are illicit or street drugs. Examples of Schedule I drugs include heroin, lysergic acid diethylamide, mescaline, methylenedioxymethamphetamine, and methaqualone. Marijuana, which is legal in some states, is still classified as a Schedule I drug at the federal level as of this writing. Schedule II: Schedule II drugs have a reduced potential for substance use disorder compared to Schedule I. These drugs are at high risk for both physical and psychological dependence. These drugs have a high capacity for both substance use disorder and misuse. Schedule II drugs are typically prescribed to treat severe pain, anxiety, insomnia, and attention-deficit hyperactivity disorder. Examples of Schedule II substances include fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, dextroamphetamine, methylphenidate, methamphetamine, pentobarbital, and secobarbital. These drugs were previously prescribed only through a paper prescription, but they are now permitted to be transmitted electronically through Electronic Prescriptions for Controlled Substances (EPCS). No refills are allowed. . Schedule II drugs have the tightest regulations compared to other prescription drugs. Schedule III: Schedule III drugs have a lower misuse potential compared to Schedule I and II drugs. These drugs may cause physical dependence but more commonly lead to psychological dependence. Medications in this category are often used for pain control, anesthesia, or appetite suppression. Examples of Schedule III substances include benzphetamine, ketamine, phendimetrazine, and anabolic steroids. Opioid analgesics in this schedule include products containing not more than 90 mg of codeine per dosage unit and buprenorphine. Schedule III drugs may be prescribed verbally over the phone, with a paper prescription, or through EPCS. Within a 6-month timeframe, refill requirements are such that the drug can only have 5 refills. . Schedule IV: Schedule IV drugs have a lower potential for misuse compared to Schedule I, II, or III drugs. These drugs have a limited risk of physical or psychological dependence. Examples of Schedule IV substances include alprazolam, carisoprodol, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, tramadol, and triazolam. Drugs in this class may be used for pain control as long as the healthcare provider deems the drug medically necessary and the patient is likely to benefit. Schedule IV drugs can be prescribed verbally over the phone, with a paper prescription, or through EPCS. Refills are permitted up to 5 times in a 6-month timeframe from the issuance date. Schedule V: Schedule V drugs are the least likely of the controlled substances to be misused. These drugs result in minimal physical or psychological dependence. Examples include cough medicines containing codeine, antidiarrheal medications containing atropine or diphenoxylate, pregabalin, and ezogabine. Despite their low abuse potential, they still need to be managed appropriately and administered with care. When these medicines contain codeine, they must have less than 200 mg of codeine per 100 mL. Partial prescription fills cannot occur more than 6 months after the issue date. When a partial fill occurs, it is treated in the same manner and with the same rules as a refill of the drug. Drug Use Disorder, Abuse, and Misuse Drug use disorder differs from drug abuse and misuse. Drugs taken may be illicit street drugs, stolen drugs, or those obtained through a legal prescription. Misusing a drug typically involves taking the drug in a harmful or detrimental way, resulting in personal, professional, or social problems. A patient abusing an opioid analgesic may no longer be able to interact appropriately with their family or friends and perform their duties at work. Misuse of a controlled substance refers to using a prescribed drug in a way that was not intended, whether intentionally or accidentally. A negative result may or may not occur. Examples of misuse include taking too much of a drug, using an incorrect dose, an incorrect route, or using prescription drugs written for another person. Controlled substances include both prescription drugs and illicit drugs with no recognized medical value. Both categories have the potential to be abused or misused. Although the use of Schedule I drugs is illegal, prescription drugs found in Schedules II through V are also commonly abused and misused, and their misuse is a challenging problem that has increased over the last several years. The Centers for Disease Control and Prevention (CDC) has declared prescription drug abuse a problem of epidemic proportions. The CDC believes that the absence of checks and balances on the prescription and distribution of controlled substances, including those prescribed for medical use, has the potential for abuse, and misuse is likely to continue increasing. Prescriber Shopping A common practice among individuals who intentionally misuse controlled substances is to seek multiple sources for drugs. These individuals visit different healthcare providers, presenting a list of complaints that are often fictitious and vary from one healthcare provider to another. As a result, they may be able to obtain multiple prescriptions, which they then fill at different pharmacies. To combat this practice, known as prescriber shopping, many states have implemented systems that enable healthcare providers to view all the prescriptions written for each patient. The use of these systems is helping to gradually reduce such misuse. Diversion Some prescription drugs can be sold on the street for as much as $50 per tablet. Diversion is when a patient sells their drugs as a method of earning money. Patients may also sell their drugs to buy food, pay expenses, or purchase more potent street drugs. In some worst cases, healthcare providers may divert drugs from patients for their personal use or sell them to others. Some individuals use controlled substances for purposes other than their intended medical use. Rather than pain control, they may be used to stay awake, induce sleep, or get high. Before the popularity of prescription drug diversion, the only method to obtain illicit drugs was to import from other countries or manufacture them in private labs. Today, law enforcement agencies have the tremendous challenge of dealing with prescription drugs sold by diversion and illicit drugs imported or manufactured. In both instances, these drug sales and usage result in increased criminal activity, dangerous overdoses, and death.  Methods of Obtaining Prescription Drugs A review of multiple studies highlights a variety of ways individuals obtain prescription drugs. The findings are summarized below: 55% free from a friend or relative. 20% from a prescriber. 10% purchased from a friend or relative. 5% stolen from a friend or relative. 5% purchased from a drug dealer. 2% from multiple doctors. 1% through theft from a medical practice or pharmacy. Less than 1% obtained them from the internet. Studies also reveal that the source of the majority of these drugs was a single legal prescriber. Opioid Knowledge Deficit Among Healthcare Providers There are significant knowledge gaps regarding appropriate and inappropriate opioid analgesic prescribing, including a lack of understanding of current research, legislation, and proper prescribing practices. Healthcare providers often have knowledge deficits that include: Understanding of addiction. At-risk opioid addiction populations. Prescription versus non-prescription opioid addiction. The belief that addiction and dependence on opioids are synonymous. The belief that opioid addiction is a psychological problem instead of a chronic painful disease. Due to a long history of misunderstanding, poor society, insufficient education for healthcare providers, and inconsistent laws, prescribing opioids has resulted in significant societal challenges. These challenges can only be addressed through comprehensive education and training. Misuse of Controlled Substances The misuse of controlled substances resulting in morbidity and mortality is rampant. According to the 2016 National Survey on Drug Use and Health conducted by the United States Department of Health and Human Services, over 10 million people misuse prescription pain medications, and over 2 million misuse sedatives, stimulants, and tranquilizers each year. The survey also identified pain relief as the most common reason for misuse. The CDC estimates that more than 40,000 individuals die each year from an opioid overdose.  Controlled Substances Three major classes of controlled substances are frequently misused—opioids, depressants, and stimulants. Opioids: Opioids are commonly prescribed for pain control by binding to mu-opioid receptors in the central nervous system (CNS), which reduces the transmission of pain signals to the brain. In addition, opioids affect receptors in the gastrointestinal tract and respiratory system. These medications are used to treat pain, diarrhea, and cough. Common opioids: Codeine: Codeine is one of the most commonly used opioid medications. This medication is at the center of the opioid addiction problem in the United States and thus is highly regulated. Codeine is primarily prescribed for pain and cough. FDA-approved indication: Pain: Codeine is used to treat mild to moderate pain. The use of codeine is recognized in chronic pain due to ongoing cancer and palliative care. However, the use of codeine to treat other types of chronic pain remains controversial. Chronic pain, defined by the International Association for the Study of Pain, is pain persisting beyond the standard tissue healing time, which is 3 months. The most common causes of non-cancer chronic pain include back pain, fibromyalgia, osteoarthritis, and headache. Non–FDA-approved indications: Cough: Codeine is useful in treating various etiologies that produce a chronic cough. Additionally, 46% of patients with chronic cough do not have a distinct etiology despite undergoing a proper diagnostic evaluation. In such cases, codeine has been shown to reduce both the frequency and severity of coughs. However, the evidence supporting its effectiveness in treating chronic cough is limited. The dose can vary from 15 to 120 mg/d. In specific populations such as lung cancer, codeine is indicated for managing prolonged cough, typically as 30 mg every 4 to 6 hours as needed. Restless leg syndrome: Codeine is effective in treating restless leg syndrome when given at night, especially for individuals whose symptoms are not relieved by other medications. Persistent diarrhea (palliative): Codeine and loperamide are equally effective for managing persistent diarrhea. The choice between codeine and loperamide depends on the physician's evaluation of codeine's addictive potential versus loperamide's higher cost, along with the patient's susceptibility to adverse effects. Fentanyl: Transdermal patches and intravenous formulations are commonly abused and used in combination with other drugs. Fentanyl is a synthetic opioid that is 80 to 100 times stronger compared to morphine and is often added to heroin to increase its potency. This drug can cause severe respiratory depression and death, particularly when mixed with other drugs or alcohol. Fentanyl has a high potential for addiction. Hydrocodone: Hydrocodone is a Schedule II semi-synthetic opioid medication used to treat pain. Immediate-release hydrocodone is available only in combination with other agents, such as acetaminophen and ibuprofen, and is approved by the FDA for managing pain severe enough to require an opioid analgesic and for which alternative (nonopioid) treatments are inadequate. Single-entity hydrocodone is only available in extended-release formulations and is approved by the FDA to treat persistent, severe pain requiring around-the-clock, long-term opioid therapy when alternative options are insufficient. Hydrocodone is also an antitussive and is indicated for the treatment of cough in adults. Morphine sulfate: Morphine sulfate is approved by the FDA for moderate-to-severe pain, whether acute or chronic. Most commonly used in pain control, morphine provides significant relief to patients afflicted with pain. Clinical situations that significantly benefit from medicating with morphine include managing palliative or end-of-life care, active cancer treatment, and vaso-occlusive pain during sickle cell crises. Morphine is widely used off-label for almost any condition that causes pain. In the emergency department, morphine is given for musculoskeletal pain, abdominal pain, chest pain, arthritis, and even headaches when patients fail to respond to first- and second-line agents. Although morphine is rarely used for procedural sedation, clinicians sometimes combine a low dose of morphine with a low dose of benzodiazepine, such as lorazepam, for minor procedures. Oxycodone: Oxycodone is an opioid agonist prescription medication. The immediate-release formulation is approved by the FDA for managing acute or chronic moderate-to-severe pain when alternative treatments are inadequate and opioid therapy is deemed appropriate. The extended-release formulation is approved by the FDA for managing pain severe enough to require continuous (24 h/d), long-term opioid treatment, and for which there are no alternative options to treat the pain. The oxycodone to morphine dose equivalent ratio is approximately 1:1.5 for immediate-release and 1:2 for extended-release formulations. Tramadol: Tramadol is an FDA-approved medication for pain relief. This medication has specific indications for moderate-to-severe pain. Tramadol is classified as a Schedule IV drug by the FDA. Due to its potential for abuse and addiction, tramadol should be reserved for pain that is unresponsive to other treatments, including nonopioid analgesics. Tramadol is available in 2 formulations: extended-release and immediate-release. The immediate-release form is not intended for use as an as-needed medication; instead, it is for pain of less than 1 week duration. For pain lasting more than 1 week, the extended-release form is preferred, as it is indicated for pain control under 24-hour management or an extended period. Tramadol has demonstrated off-label effectiveness in the management of premature ejaculation and restless leg syndrome that is refractory to other treatments. For the off-label use of tramadol for premature ejaculation, both sporadic and daily use is effective for treating the condition. Patients generally prefer as-needed therapy for premature ejaculation due to the lack of adverse effects compared to the daily use of tramadol. Addiction, Dependence, and Tolerance Although each of these terms is similar, healthcare providers should be aware of the differences. Addiction: The constant need for a drug despite harmful consequences. Pseudoaddiction: Constant fear of being in pain and hypervigilance; typically, there is a resolution with pain resolution. Dependence: Physical adaptation to a medication where it is necessary for normal function, and withdrawal occurs with the lack of drugs. Tolerance: The lack of expected response to a medication, increasing dose to achieve the same pain relief, resulting from CNS adaptation to the medication over time. Mainstreaming Addiction Treatment Act The Mainstreaming Addiction Treatment (MAT) Act updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all healthcare providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder, just as they prescribe other essential medications. The MAT Act aims to help destigmatize a standard of care for opioid use disorder and integrate substance use disorder treatment across all healthcare settings.  As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for opioid use disorder in their practice if permitted by applicable state law, and the Substance Abuse and Mental Health Services Administration encourages practitioners to do so. Prescribers who were registered as DATA-Waiver prescribers receive a new DEA registration certificate reflecting this change; no action is required on their part. There are no longer any limits on the number of patients with opioid use disorder that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and do not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information to proceed. Practitioners are still required to comply with any applicable state limits regarding the treatment of patients with opioid use disorder. For more information or assistance, contact your State Opioid Treatment Authority.

Euthanasia agents should induce a rapid and painless loss of consciousness, followed by cardiopulmonary arrest and subsequent brain death. Injectable drugs such as pentobarbital sodium are commonly used for laboratory rodents due to their quick and smooth action. However, the discontinuation of pharmaceutical-grade pentobarbital sodium and secobarbital sodium in Japan, along with a global shortage of pentobarbital in late 2020, has increased the demand for new injectable euthanasia drugs. In Japan, the combination of medetomidine, midazolam, and butorphanol (MMB), as well as a newer formulation in which midazolam is replaced with alfaxalone (MAB), have been widely used as balanced anesthesia for rodents. To evaluate their potential as alternative euthanasia agents in mice, we compared mortality rates and the time intervals to the loss of the righting reflex, respiratory arrest, and cardiac arrest following anesthetic administration. An intraperitoneal injection of MAB at five times the anesthetic dose induced death within 10 min with the loss of the righting reflex, respiratory arrest, and cardiac arrest occurring at 1.5 min, 4 min, and 9 min respectively, in all mice, which was comparable to those observed with 300 mg/kg of secobarbital. In contrast, none of the mice administered MMB at five times the anesthetic dose experienced cardiopulmonary arrest within 30 min. Intraperitoneal overdose of MAB induces rapid and irreversible death, supporting its potential use as an effective euthanasia agent in mice.

Because there is little published experience with secobarbital during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant. If secobarbital is used, monitor the infant for sedation, poor feeding and poor weight gain.

The gastric stability of eight barbiturates (BARs) (barbital, primidone, allobarbital, phenobarbital, cyclobarbital, pentobarbital, secobarbital, and thiobutabarbital (TBB)) was examined in artificial gastric juice using LC/UV detection. Among the eight BARs, only TBB was degraded at higher temperatures. Furthermore, the degradation product of TBB was isolated, structurally analyzed, and finally identified as 5-butan-2-yl-5-ethyl-1,3-diazinane-2,4,6-trione, also known as butabarbital. The study elucidated that butabarbital was formed by substituting the sulfur atom of the carbonyl group at the 2-position of TBB with an oxygen atom under acidic condition.

A rapid, straightforward, and sensitive approach to quantifying enantiomeric barbiturates in serum was developed by integrating ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) with large-volume sample stacking (LVSS) in capillary electrophoresis (CE). UA-DLLME was employed for sample preparation, and on-column preconcentration by using LVSS with polarity switching was implemented to enhance sensitivity. We thoroughly investigated and optimized various parameters influencing extraction and stacking to achieve optimal detection performance with the highest enrichment efficiencies. Under optimal extraction conditions (injection of a mixed solution containing 40 μL of CHCl3 and 200 μL of tetrahydrofuran into 1 mL of a sample solution at pH 10.0), LVSS was performed using 600 mM Tris-boric acid (pH 9.5) containing 35 mM hydroxypropyl-β-cyclodextrin and sodium taurodeoxycholate hydrate. A voltage of 20 kV was applied and a preinjection water plug was loaded at a height of 25 cm for 10 s. Subsequently, the sample solution was injected at a height of 25 cm for 480 s, after which a voltage of -20 kV was applied and the sample stacking was initiated. The stacking process was completed when 95 % of the separation current was attained. Under optimized conditions, the contraction folds of the four barbiturate analytes (R, S-Secobarbital, R, S-pentobarbital) were improved by approximately 6400-fold, achieving detection limits of 0.1 ng/mL. The limits of quantification for all analyte enantiomers were 0.5-50 ng/mL, demonstrating good linearity (r > 0.997). Migration times exhibited a relative standard deviation of less than 1.7 %, whereas peak areas for the four analytes exhibited a deviation of 8.7 %. Finally, the established method was effectively applied to the analysis of human serum samples.

Euthanasia agents should rapidly induce death and loss of consciousness without causing pain or distress. Various methods exist for the euthanasia of laboratory animals, and injectable anesthetics, particularly barbiturate derivatives, are widely used due to the rapid onset of unconsciousness induced by these agents. Moreover, pharmaceutical-grade drugs should be used to eliminate undesirable side effects as much as possible. However, in Japan, the sale of pharmaceutical-grade pentobarbital sodium (PB) ended in 2019, and that of secobarbital sodium (SB) ended in 2023, leading to a demand for new pharmaceutical-grade injectable euthanasia drugs. This study evaluates thiamylal sodium (TM), a barbiturate derivative that is available domestically, as a euthanasia agent for mice. The results showed that when administered at dosages of 200 mg/kg or more, TM exhibited effects equivalent to those of PB and SB. In addition, the impact of TM administration on hematological characteristics was examined. In female mice administered TM, decreased blood chloride and calcium levels and increased aspartate aminotransferase and alanine aminotransferase levels, which are markers of liver damage, were observed. These findings suggest that high concentrations of TM may affect renal and liver function. This study revealed that TM is effective as a euthanasia agent at dosages of 200 mg/kg or more. However, considering the potential risks of renal and liver damage due to TM administration, it may be preferable to use alternative euthanasia drugs when these risks could affect the objectives or outcomes of the research.

We hereby present a fast, high-throughput, and clinical LC-MS/MS assay for the simultaneous analysis of barbiturates in human urine. It is deployed as a quantitative assay for phenobarbital, butalbital, pentobarbital/amobarbital, and secobarbital, as well as for confirmations following positive immunoassay drug screens in patient urine. Briefly, urine specimens are processed via dilute and shoot, i.e., by mixing the sample with 20 times volume of internal standard reagent and injecting 50 μL of that mixture into the analytical instrument. Chromatographic separation is performed using a reversed-phase C18 column in a mobile-phase system doped with <1 mM ammonium fluoride. Mass spectrometric detection occurs via negative-mode electrospray ionization multiple reaction monitoring in the TSQ Quantiva triple-quadrupole instrument. All the analytes in the mixture are detected and quantified simultaneously with respect to internal calibration in the range 20-2500 ng/mL. However, the assay cannot distinguish pentobarbital from amobarbital, which are isobaric analytes. Nonetheless, the assay is sensitive, robust, and amenable to harmonization with other assays that employ barbiturate cutoffs in the range of 20-150 ng/mL.

In the method described here, an aliquot of a urine sample is analyzed to detect barbiturates through dilution and ultra-high-performance chromatography-tandem mass spectrometry (UPLC-MS/MS) using deuterated internal standards. This assay detects the presence of nine barbiturate drugs-amobarbital, barbital, butalbital, butabarbital, mephobarbital, secobarbital, pentobarbital, phenobarbital, and thiopental. This protocol describes two LC separation methods-first LC method (2.2 min/sample) is intended to be used as a first step of the analysis that does not separate amobarbital and pentobarbital, and a second, longer (2.7 min/sample) LC method is intended to be used only for samples which have a peak in the amobarbital/pentobarbital retention time on the shorter LC method. Since the frequency at which amobarbital and pentobarbital are observed in clinical populations is low, the shorter LC method helps gain efficiency in a high-volume laboratory environment. Additional features of this protocol that help in efficiency gain are automated extraction using Hamilton™ liquid handling system and algorithmic data review using Ascent™ software.

Barbiturates are highly susceptible to dissociation in mass spectrometry (MS) because of their long side chains combined with a nonaromatic ring consisting of several carbonyl and amine groups. As a result, they exhibit extensive α-cleavage and subsequent rearrangement, making the identification of these compounds difficult. Although a library of electron ionization MS (EIMS) is available, most barbiturates have very similar fragment patterns. Accordingly, it would be desirable to develop a technique for soft ionization, providing a molecular ion and large fragment ions as well. In this study, a molecular ion was clearly observed, in addition to large fragment ions, for a variety of barbiturates based on multiphoton ionization MS (MPIMS) using a tunable ultraviolet femtosecond laser as the ionization source (fs-LIMS). This favorable result was achieved when the optimal laser wavelength for minimizing the excess energy remaining in the ionic state was used. An examination of the photofragmentation pathways suggested that an H atom in the side chain was abstracted by an oxygen atom in the carbonyl group in the ring structure thus initiating fragmentation and subsequent rearrangement. Barbiturates that are substituted with alkyl groups (amobarbital and pentobarbital) had narrower spectral regions for optimal ionization than the other barbiturates with alkyl and alkenyl groups (butalbital and secobarbital) and more with alkyl and phenyl groups (phenobarbital). All of the barbiturates studied provided unique mass spectral patterns in fs-LIMS, which was useful for the reliable identification of these compounds in practical trace analysis.

Thiamylal is an ultrashort-acting barbiturate used for intravenous administration or general anesthesia induction. However, some cases of poisoning and suicide with thiamylal administration have been reported. Additionally, there are few reports on its analysis in the organs and adipose tissue, which requires purification by column chromatography and evaporation. A rapid and sensitive method was developed for quantifying thiamylal and its metabolite, secobarbital, in the adipose tissue, serum, and liver using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Samples were prepared using modified QuEChERS extraction. For adipose tissue samples, an acetonitrile-hexane partitioning step was added to the extraction. This method was applied to investigate a suspected self-poisoning autopsy case. The quantitation accuracy for thiamylal added to porcine pericardial fat (0.18 µg/g), human serum (0.015 µg/mL), and porcine liver (0.18 µg/g) was 103%, 113%, and 95.3%, respectively. The quantitation limits calculated for porcine pericardial fat, human serum, and porcine liver at a signal-to-noise ratio of 10 were 0.06 µg/g, 0.005 µg/mL, and 0.06 µg/g, respectively. In addition, the thiamylal and secobarbital levels in the forensic autopsy case were 140 and 1.5 µg/g, respectively, in myocardial fat; 3.5-4.9 and 0.12-0.20 µg/mL, respectively, in serum; and 6.2-42 and 0.58-1.1 µg/g, respectively, in liver tissue. Thiamylal is especially distributed in the adipose tissue. The thiamylal-to-fat ratio may help estimate the time from administration to death. The developed modified QuEChERS extraction method with acetonitrile-hexane partitioning is suitable for analyzing hydrophobic compounds, such as thiamylal, in the adipose tissue.

A 94-year-old woman was found unresponsive in her room at an independent living facility. Upon paramedic arrival, the patient had a Glasgow Coma Scale of 3, and she was transported to the emergency department (ED). In the ED, she was unresponsive but spontaneously breathing, bradycardia, and hypothermia. Serum concentrations of both secobarbital (3.3µg/mL; therapeutic 1.0-2.0µg/mL) and pentobarbital (9.5µg/mL; therapeutic < 5.0µg/mL) were detected and elevated. This type of poisoning is quite rare and should be considered in patients presenting with hypothermia and coma, even in patients showing brain death signs. The use of hemodialysis for refractory pentobarbital poisoning may be helpful.

The legislation Bill C-14 legalized medical assistance in dying (MAiD) in Canada. After thorough assessments of eligibility by two clinicians, Bill C-14 allows for both intravenous-assisted death by a clinician (euthanasia) and prescription of oral medication for self-administration (assisted suicide). Nevertheless, since inception in June 2016, intravenous euthanasia is the main form of delivery of assisted death in Canada. The reasons why oral MAiD is underutilized in Canada are multifactorial. Currently, there is no consensus on either the medications or the protocols for oral administration, nor a comprehensive understanding of the potential side effects and complications associated with different regimens. The quality of evidence for optimal MAiD medications is low, so any suggested recommendations can only be informed by the global but generally anecdotal experience. The challenges for implementing oral MAiD in Canada include a need to enhance clinician comfort in prescribing oral medications as an alternative to intravenous administration. The goals for ideal oral MAiD medications are 100% effectiveness and minimal side effects, while ensuring that the needed dose is both palatable and deliverable in a tolerable oral volume. The Netherlands has the most experience worldwide and barbiturates have emerged as the most common, efficacious, and tolerable agents by patients. Based on this global experience and the over-arching goals for oral MAiD, we recommend the use of a secobarbital suspension combined with antiemetic prophylaxis.

The present study aimed to investigate the potential inhibitory effects of 21 clinically available hypnotics on acetylcholine (ACh)-induced contractions in rat urinary bladder smooth muscle (UBSM) in order to predict whether these hypnotics could induce voiding impairment. ACh-induced contraction in rat UBSM was inhibited only by diphenhydramine (a histamine H1 receptor antagonist) at a concentration that was clinically relevant. ACh-induced contraction was also significantly inhibited by flurazepam (a benzodiazepine hypnotic) and suvorexant (an orexin receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. These three drugs (at 10-5 M) also inhibited high-KCl (80 mM) Locke-Ringer solution-induced contractions. In contrast to the effects of the abovementioned hypnotics, ACh-induced contractions were not significantly affected by triazolam, etizolam, brotizolam, lormetazepam, estazolam, flunitrazepam, nitrazepam (benzodiazepine hypnotics), thiopental, thiamylal, pentobarbital, amobarbital, secobarbital, phenobarbital (barbiturate hypnotics), zolpidem (an imidazopyridine hypnotic), zopiclone (a cyclopyrrolone hypnotic), ramelteon (a melatonin receptor agonist), bromovalerylurea, and chloral hydrate. These findings suggest that most clinically used hypnotics are not likely to result in anticholinergic-induced dysuria within their clinically achievable blood concentration ranges. Diphenhydramine may, however, induce voiding impairment, an action attributable to diminished UBSM contractility within its clinical dose range.

Drug poisoning deaths have more than doubled in the United States since 2000 with fentanyl and fentanyl analogues primarily responsible for the jump in opioid deaths. Robust data indicate a convincing correlation between the exposure of the fetus to other labor medications (morphine, pethidine hydrochloride, barbiturates, phenobarbitone, meperidine, and secobarbital) and the later addiction of young adults to the same category of drug. We present the hypothesis that this effect is also true of the opioid, fentanyl: there is a causal relationship between the increased popularity of fentanyl as a labor anesthetic in the United States since the 1980's and the current epidemic of fentanyl abuse.