- Prescription Medications for the Treatment of Insomnia and Risk of Suicide Attempt: a Comparative Safety Study. [Journal Article]J Gen Intern Med 2019; 34(8):1554-1563JG
- CONCLUSIONS: Compared to zolpidem, hazard of suicide attempt was 61% higher with trazodone (< 200 mg). No significant differences in suicide attempt risk were identified between benzodiazepines or sedating antihistamines and zolpidem, respectively. These findings provide the first comparative effectiveness evidence against the use of trazodone for insomnia.
- Melatonin, temazepam and placebo in hospitalised older patients with sleeping problems (MATCH): a study protocol of randomised controlled trial. [Journal Article]BMJ Open 2019; 9(5):e025514BO
- Hospitalised older patients frequently suffer from inadequate sleep, which can lead to patient distress and delayed recovery from acute illness or surgical procedure. Currently, no evidence-based treatments exist for sleeping problems in hospitalised older patients. Benzodiazepines, such as temazepam, are regularly prescribed by physicians, although they have serious side effects; for older patie…
Hospitalised older patients frequently suffer from inadequate sleep, which can lead to patient distress and delayed recovery from acute illness or surgical procedure. Currently, no evidence-based treatments exist for sleeping problems in hospitalised older patients. Benzodiazepines, such as temazepam, are regularly prescribed by physicians, although they have serious side effects; for older patients in particular. Melatonin is proposed as a safe alternative for sleeping problems in hospitalised older patients, but the efficacy of melatonin is unclear in this population. Therefore, the aim of this study is to investigate the effects of melatonin and temazepam compared with placebo on sleep quality among hospitalised older patients with sleeping problems.
- Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile. [Journal Article]J Sex Med 2019; 16(6):763-766JS
- CONCLUSIONS: Serum plasma concentrations of vaginally administered diazepam are low; however the half-life is prolonged.Vaginal administration of diazepam results in lower peak serum plasma concentration, longer time to peak concentration, and lower bioavailability than standard oral use. Providers should be aware that with diazepam's long half-life, accumulating levels would occur with chronic daily doses, and steady-state levels would not be reached for up to 1 week. This profile would favor intermittent use to allow participation in physical therapy and intimacy. Larish AM, Dickson RR, Kudgus RA, et al. Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile. J Sex Med 2019;16;763-766.
- High throughput bar adsorptive microextraction: A novel cost-effective tool for monitoring benzodiazepines in large number of biological samples. [Journal Article]Talanta 2019; 199:195-202T
- In this work, we propose an innovative high throughput (HT) apparatus using the bar adsorptive microextraction (BAμE) technique, which enables the simultaneous enrichment of up to 100 samples. This novel configuration was combined with microliquid desorption and high-performance liquid chromatography-diode array detection to monitor trace levels of eight benzodiazepines (diazepam, prazepam, broma…
In this work, we propose an innovative high throughput (HT) apparatus using the bar adsorptive microextraction (BAμE) technique, which enables the simultaneous enrichment of up to 100 samples. This novel configuration was combined with microliquid desorption and high-performance liquid chromatography-diode array detection to monitor trace levels of eight benzodiazepines (diazepam, prazepam, bromazepam, oxazepam, lorazepam, alprazolam, temazepam and loflazepate) in biological samples. The proposed methodology was fully developed, optimized and validated, resulting in suitable intraday and interday precision (RSD ≤ 15%), with recovery yields ranging from 33.0% to 104.5%. The lower limits of quantification were between 20.0 and 100.0 µg L-1, using 1.0 mL of urine and 0.5 mL of plasma or serum samples. The application of the proposed methodology to real matrices resulted in average sample preparation time of around 2 min per sample, demonstrating that it is user-friendly, cost-effective and a rapid decision-making tool, whenever large number of samples are involved.
- StatPearls: Prescription of Controlled Substances: Benefits and Risks [BOOK]StatPearls Publishing: Treasure Island (FL)BOOK
- One of the single most difficult challenges for any prescriber is to distinguish between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate purposes. To discern the difference prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain as well as the signs and symptoms of patients using controlled substanc…
One of the single most difficult challenges for any prescriber is to distinguish between the legitimate prescription of controlled substances versus the prescription potentially used for illegitimate purposes. To discern the difference prescribers need to understand the signs, symptoms, and treatment of acute and chronic pain as well as the signs and symptoms of patients using controlled substances for non-legitimate purposes. A common reason people seek the care of medical professionals is pain relief. While many categories of pain medications are available, opioid analgesics are FDA-approved for moderate to severe pain. As such, they are a common choice for patients with acute, cancer-related, neurologic, and end-of-life pain. The prescribing of opioid analgesics for chronic pain is controversial and fraught with inconclusive standards. In the 1990s, due to the chronic failure of health professionals to undertreat severe pain, opioid analgesic prescribing was expanded. Unfortunately, this led to increased overuse, diversion of drugs, opioid use disorder, and overdose. The "Catch-22" seems to be either health professionals undertreat, and there is needless suffering, or they overtreat, with a potential to cause adverse effects like increased opioid analgesic use disorder and potential overdose. The prescription of opioid analgesics peaked in 2011, since then both prescribing and overdose has been declining; yet as a society, in both the lay and scientific literature, there are grave concerns that we are still in the middle of an opioid crisis. Perhaps the biggest challenge of caring for patients with pain is that individuals have different levels of tolerance and require variable opioid doses to obtain adequate pain relief. Patients may have a range of behavioral, cultural, emotional, and psychologic responses to pain versus a substance use disorder; often it is challenging to tell the difference. All health professionals engaged in pain management 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 providers need to be aware of not only appropriate patient assessment and treatment planning but also the possibility of use disorder, diversion, and potentially dangerous behavioral responses to controlled substances, e.g., opioid analgesics differ from pseudo-addiction and physical dependence. It is unfortunately clear that many clinicians know little about opioid use disorder; they do not understand it is a disease, and many believe opioid dependence is the same as opioid use disorder. Lack of a clear understanding results in clinicians confusing a chronic non-use disorder pain patient from the one who is misusing their prescribed opioid. Lack of training and educational deficits often interferes with the appropriate prescription of opioid analgesic agents. To prevent misuse of controlled substances, providers that 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 biologic, psychologic, social, and spiritual manifestations. This is reflected in an individual pathologically pursuing reward or relief by substance use and other behaviors." Addiction is now termed "use disorder," and is characterized by an inability to consistently abstain, craving, 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, use disorder often involves cycles of relapse and remission. Without treatment or engagement in recovery activities, use disorder is progressive and can result in disability or premature death." Appropriate opioid prescribing - providing pain control while minimizing use disorder or risk of same, and toxicity; and implementing safeguards to reduce drug diversion. Inappropriate opioid analgesic prescribing - non-, inadequate, excessive, or continued prescribing despite evidence of the lack of effective opioid treatment. Controlled substances - 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. Narcotics - comes from the Greek word for stupor and originally referred to drugs that dulled the senses and relieved pain, e.g., morphine. Also, narcotics were any drug that induced sleep. A more precise term for this class of drugs, with less uncertainty regarding its meaning, is opioid analgesics. Please note that the Drug Enforcement Administration (DEA, USA) uses the term narcotic to refer to drugs that are opioid analgesics. Five Characteristics of Addiction/Use Disorder (ASAM): 1. Craving for drug or reward. 2. Diminished recognition of significant problems in one's behavior. 3. Dysfunctional emotional response. 4. Impairment in behavioral control. 5. Inability to consistently abstain Drug Schedules of Controlled Substances All providers should be familiar with the guidelines and laws for each schedule which have as their basis the purpose of the drug and the risk of use disorder. In the United States, controlled substances are under strict regulation by both federal and state laws which guide their manufacture and distribution. Controlled substances have a high risk of resulting in an addiction and substance use disorder. As the schedules decrease, I-V, the drugs listed within each category have a lower potential to cause a substance use or addiction disorder. Controlled Substance Act In the United States, the Comprehensive Drug Abuse Prevention and Control Act was passed in 1970, and it included the Controlled Substance Act. The Controlled Substance Act covers drug: Classification and regulation, according to their content and purpose. Manufacturing. Distribution. Exportation and sale. The Controlled Substance Act established five drug schedules and classified them to control their manufacture and distribution. Part of regulation requires providers that prescribe scheduled drugs and pharmacists that fill them to obtain a license from the Drug Enforcement Administration. Health professionals licenses include specific license numbers allowing controlled substance prescriptions to be tracked and linked to a particular provider or distributor. Of the five schedules, each has parameters based on their medical value, the risk of addiction, and ability to cause harm. The schedules range from schedule I (most potential for addiction and use disorder) to schedule V (least potential for addiction/use disorder). Schedule I: Schedule I drugs possess the highest potential for use disorder and misuse. They have no medical use and are illicit or “street” drugs. Examples of Schedule I drugs include heroin, lysergic acid diethylamide, mescaline, methylenedioxymethamphetamine (MDMA), 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 use disorders than I. They are high risk for both physical and psychological dependence. They have a high capacity for both use disorder and misuse. They are typically prescribed to treat severe pain, anxiety, insomnia, and ADHD. Examples of Schedule II substances include fentanyl, hydromorphone, meperidine, methadone, morphine, oxycodone, fentanyl, dextroamphetamine, methylphenidate, methamphetamine, pentobarbital, and secobarbital. They previously had to be prescribed only via paper prescription, but now are permitted to be electronically transmitted. (Electronic Prescribing of Controlled Substances or EPCS). No refills are allowed. Schedule II drugs have the tightest regulations when compared to other prescription drugs. Schedule III : Schedule III drugs are those with a lower misuse potential than I and II. Drugs in this category may cause physical dependence but more commonly lead to psychological dependence. Medications in this category are often used for pain control, or 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 milligrams of codeine per dosage unit, and buprenorphine. Schedule III drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS. Within a six-month time frame, refill requirements are such that the drug can only have five refills. Schedule IV: Schedule IV drugs have an even lower misuse potential than I, II, or III. They 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 utilized for pain control as long as the provider deems the drug to be medically necessary and that the patient would benefit. Schedule IV drugs are prescribable verbally over the phone, with a paper prescription, or via EPCS. Refills are permitted up to five times in a six-month timeframe from the issuance date. Schedule V: Schedule V drugs are the least likely controlled substances to be misused. They result in very limited physical dependence or psychological dependence. Examples include cough medicines with codeine, antidiarrheal medications that contain atropine/diphenoxylate, pregabalin, and ezogabine. Schedule V drugs despite their low abuse potential, still need to be managed appropriately and administered with care. When they contain codeine, it must have less than 200 mg of codeine per 100 mL. Partial prescription fills cannot occur more than six months after the date of issue. 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 Use disorder of a drug differs from abuse and misuse of a drug. The drugs taken may be illicit street or stolen drugs or obtained via a legal prescription. Misusing a drug usually involves taking the drug in a harmful or detrimental way that results in personal, professional, or social problems. A patient that is abusing an opioid analgesic may no longer be appropriately interacting with their family, friends, or be able to perform their duties at work. Misuse of a controlled substance refers to the use of a prescribed drug in a way that was not intended. It may be deliberate or accidental. A negative result may or may not occur. Examples of misuse include taking too much of a drug, using an incorrect dose route, or using prescription drugs written for another person. Controlled substances include both prescription drugs and illicit drugs with no recognized medical value. Both have the potential to be abused or misused. While schedule I drug use is illegal, prescription drugs found in schedules II-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 has declared prescription drug abuse is a problem of epidemic proportions. The CDC believes that absent checks and balances on the prescription and distribution of controlled substances, including those prescribed for medical use, the potential for abuse and misuse will continue to increase. Pill Shopping Unfortunately, a common practice among those that deliberately misuse controlled substances is to seek out multiple sources of drugs. They do this by seeing different health care providers, and they present with a different list of complaints that are often fictitious and different for each provider. The patient may be able to obtain multiple prescriptions and then fill them at different pharmacies. Many states have enacted systems that allow providers to see all of the prescriptions written for each patient. Use of these systems is gradually curbing "pill shopping." Diversion Some prescription drugs will sell on the street for as much as $50 a tablet. Diversion is when a patient sells their drugs as a method of earning money. Drugs may also be sold to buy food, pay expenses, or purchase more potent street drugs. Worse, in some cases, healthcare providers may divert drugs from patients for the providers own personal use or sell them to someone else. Some individuals use controlled substances in ways for which they were not originally intended. 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 as well as illicit drugs imported or manufactured. In both instances, these drug sales and usage result in increased criminal activity as well as dangerous overdoses and death. Methods of Obtaining Prescription Drugs A review of multiple studies demonstrates a variety of means individuals obtain prescription drugs. The following summarizes the studies' findings. 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% from theft from medical practice or pharmacy. Less 1% from internet. Studies also reveal the source of the majority of these drugs was a single legal prescriber.
- Formation of biologically active benzodiazepine metabolites in Arabidopsis thaliana cell cultures and vegetable plants under hydroponic conditions. [Journal Article]Sci Total Environ 2019; 662:622-630ST
- The use of recycled water for agricultural irrigation comes with the concern of exposure to crops by contaminants of emerging concerns (CECs). The concentration of CECs in plant tissues will depend on uptake, translocation and metabolism in plants. However, relatively little is known about plant metabolism of CECs, particularly under chronic exposure conditions. In this study, metabolism of the p…
The use of recycled water for agricultural irrigation comes with the concern of exposure to crops by contaminants of emerging concerns (CECs). The concentration of CECs in plant tissues will depend on uptake, translocation and metabolism in plants. However, relatively little is known about plant metabolism of CECs, particularly under chronic exposure conditions. In this study, metabolism of the pharmaceutical diazepam was investigated in Arabidopsis thaliana cells and cucumber (Cucumis sativus) and radish (Raphanus sativus) seedlings grown in hydroponic solution following acute (7 d)/high concentration (1 mg L-1), and chronic (28 d)/low concentration (1 μg L-1) exposures. Liquid chromatography paired with mass spectrometry, 14C tracing, and enzyme extractions, were used to characterize the metabolic phases. The three major metabolites of diazepam - nordiazepam, temazepam and oxazepam - were detected as Phase I metabolites, with the longevity corresponding to that of human metabolism. Nordiazepam was the most prevalent metabolite at the end of the 5 d incubation in A. thaliana cells and 7 d, 28 d seedling cultivations. At the end of 7 d cultivation, non-extractable residues (Phase III) in radish and cucumber seedlings accounted for 14% and 33% of the added 14C-diazepam, respectively. By the end of 28 d incubation, the non-extractable radioactivity fraction further increased to 47% and 61%, indicating Phase III metabolism as an important destination for diazepam. Significant changes to glycosyltransferase activity were detected in both cucumber and radish seedlings exposed to diazepam. Findings of this study highlight the need to consider the formation of bioactive transformation intermediates and different phases of metabolism to achieve a comprehensive understanding of risks of CECs in agroecosystems.
- Racemization of oxazepam and chiral 1,4-benzodiazepines. DFT study of the reaction mechanism in aqueous solution. [Journal Article]Org Biomol Chem 2019; 17(6):1471-1479OB
- The tranquilizer and hypnotic drug oxazepam undergoes the racemization process in aqueous medium, which is relevant for its pharmacological profile. The experimental barrier value (ΔG‡298 ≈ 91 kJ mol-1) was determined earlier, but the exact mechanism of enantiomerization is not known. Four different mechanisms have been proposed in the literature: C3-H/H exchange reaction, keto-enol tautomerizati…
The tranquilizer and hypnotic drug oxazepam undergoes the racemization process in aqueous medium, which is relevant for its pharmacological profile. The experimental barrier value (ΔG‡298 ≈ 91 kJ mol-1) was determined earlier, but the exact mechanism of enantiomerization is not known. Four different mechanisms have been proposed in the literature: C3-H/H exchange reaction, keto-enol tautomerization, solvolytic identity reaction, and ring-chain tautomerization. However, none of the reported reactions has been confirmed as the main pathway for racemization. In this work, all these mechanisms were subjected to comprehensive analysis performed by high-level quantum-chemical models. Two density functionals (B3LYP and M062X) were employed for geometry optimization of all stationary points at the corresponding potential surfaces, and the double-hybrid model (B2PLYP) was used for improved energy calculations. Out of all the tested mechanisms, only the ring-chain tautomerism fits the two experimental targets: the measured energy barrier and the pH-rate profile of racemization. The latter reveals that no acid/base catalysis is required for racemization to occur. The ring-chain tautomerism is initiated by intramolecular proton transfer from the C3-hydroxyl group to the imine nitrogen, which triggers the benzodiazepine ring opening and the formation of the achiral aldehyde intermediate. The latter undergoes ring closure which results in the inverted configuration at the C3-chiral atom of oxazepam. Our computational results suggest that the same mechanism is operative in the fast racemization of different 1,4-benzodiazepines, which posses the hydroxyl group at the stereogenic C3-centre (e.g. lorazepam or temazepam). In other benzodiazepine members (e.g. cinazepam or camazepam) the keto-enol tautomerization and/or the C3-H/H exchange mechanism may become relevant for their much slower racemization. This computational study is not only revealing in terms of mechanistic details, but also has predictive power for optical stability estimates in the family of benzodiazepines and similar heterocycles.
- Expanded table: Some oral hypnotics for chronic insomnia. [Review]Med Lett Drugs Ther 2018; 60(1546):e209-e213ML
New Search Next
- Investigating tissue bioconcentration and the behavioural effects of two pharmaceutical pollutants on sea trout (Salmo trutta) in the laboratory and field. [Journal Article]Aquat Toxicol 2019; 207:170-178AT
- Pharmaceuticals entering aquatic ecosystems via wastewater effluents are of increasing concern for wild animals. Because some pharmaceuticals are designed to modulate human behaviour, measuring the impacts of exposure to pharmaceuticals on fish behaviour has become a valuable endpoint. While laboratory studies have shown that pharmaceuticals can affect fish behaviour, there is a lack of understan…
Pharmaceuticals entering aquatic ecosystems via wastewater effluents are of increasing concern for wild animals. Because some pharmaceuticals are designed to modulate human behaviour, measuring the impacts of exposure to pharmaceuticals on fish behaviour has become a valuable endpoint. While laboratory studies have shown that pharmaceuticals can affect fish behaviour, there is a lack of understanding if behaviour is similarly affected in natural environments. Here, we exposed sea trout (Salmo trutta) smolts to two concentrations of two pharmaceutical pollutants often detected in surface waters: temazepam (a benzodiazepine, anxiolytic) or irbesartan (an angiotensin II receptor blocker, anti-hypertensive). We tested the hypothesis that changes to behavioural traits (anxiety and activity) measured in laboratory trials following exposure are predictive of behaviour in the natural environment (downstream migration). Measures of anxiety and activity in the laboratory assay did not vary with temazepam treatment, but temazepam-exposed fish began migrating faster in the field. Activity in the laboratory assay did predict overall migration speed in the field. In contrast to temazepam, we found that irbesartan exposure did not affect behaviour in the laboratory, field, or the relationship between the two endpoints. However, irbesartan was also not readily taken up into fish tissue (i.e. below detection levels in the muscle tissue), while temazepam bioconcentrated (bioconcentration factor 7.68) rapidly (t1/2 < 24 h). Our findings add to a growing literature showing that benzodiazepine pollutants can modulate fish behaviour and that laboratory assays may be less sensitive at detecting the effects of pollutants compared to measuring effects in natural settings. Therefore, we underscore the importance of measuring behavioural effects in the natural environment.