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Lorazepam—Efficacy, side effects, and rebound phenomena
Abstract
Lorazepam, 4 mg, was evaluated in an 18-night sleep-laboratory study involving five insomniac subjects. Hypnotic effectiveness and effects on sleep stages and related parameters were assessed. Placebo was given on baseline nights 1 to 4, lorazepam on nights 5 to 11, and placebo was given again on withdrawal nights 12 to 18. Subjective and objective data clearly demonstrated that lorazepam was effective for both inducing and maintaining sleep. Sleep latency was reduced from a baseline value of 34.6 min to 17.9 min (P less than 0.01) and total wake time was reduced from 75.9 to 38.5 min (P less than 0.01). On the third and fifth nights of drug withdrawal total wake time rose above baseline levels (termed rebound insomnia) and sleep latency increased by 77% and 60% over baseline (P less than 0.01). Subjective estimates of daytime anxiety also increased above baseline (rebound anxiety) during the withdrawal period. All subjects experienced severe hangover and varying degrees of impaired functioning during the first 3 days on drug. Three subjects also experienced anterograde amnesia during the day after the first drug night. These side effects diminished in intensity over the course of the study. Our results suggest that while 4 mg lorazepam may be effective in inducing and maintaining sleep, this dose induces clinically significant side effects that are followed by consistent rebound phenomena after withdrawal.
... SSRIs and oral antipsychotics (Chouinard and Chouinard, 2015;Chouinard et al., 2017) and in 1-5 days for some benzodiazepines such as in patients with anxiety experiencing rebound after abrupt discontinuation of triazolam (Fontaine et al., 1984) and Figure 5 and in the cases of patients with insomnia after abrupt withdrawal of alprazolam (Kales et al., 1987) or lorazepam (Scharf et al., 1982). ...
... Rebound anxiety or panic attacks resulted from abrupt withdrawal of BZ such as alprazolam, lorazepam, diazepam, clorazepate, and bromazepam (Scharf et al., 1982;Fontaine et al., 1984;Pecknold et al., 1988;Rickels et al., 1988;Roy-Byrne et al., 1989;Chouinard, 2004). Anxiety patients more frequently experience rebound with short-and intermediate-acting BZ than longacting (Chouinard, 2004). ...
The purpose of this article is to describe dependence and withdrawal phenomena related to CNS drugs discontinuation and to clarify issues related to the evaluation of clinical drug withdrawal and rebound as they relate to safety in new drug development. The article presents current understanding and definitions of drug dependence and withdrawal which are also relevant and important features of addiction, though not the same. Addiction, called substance use disorder in DSM-5, affects an individual's brain and behaviour, represents uncontrollable drug abuse and inability to stop taking a drug regardless of the harm it causes. Characteristic withdrawal syndromes following abrupt discontinuation of CNS-active drugs from numerous drug classes are described. These include drugs both scheduled and non-scheduled in the Controlled Substances Act, which categorizes drugs in five schedules based on their relative abuse potentials and dependence liabilities and for regulatory purposes. Schedules 1 and 2 contain drugs identified as those with the highest abuse potential and strictest regulations. Less recognized aspects of drug withdrawal, such as rebound and protracted withdrawal syndromes for several drug classes are also addressed. Part I presents relevant definitions and describes clinical withdrawal and dependence phenomena. Part II reviews known withdrawal syndromes for the different drug classes, Part III describes rebound and Part IV describes protracted withdrawal syndromes. To our knowledge, this is the first compilation of withdrawal syndromes for CNS drugs. Part V provides details of evaluation of dependence and withdrawal in the clinical trials for CNS drugs, which includes general design recommendations, and several tools, such as withdrawal questionnaires and multiple scales that are helpful in the systematic evaluation of withdrawal. The limitations of different aspects of this method of dependence and withdrawal evaluation are also discussed.
... The lorazepam is one of famous medicines that used to treat anxiety [12]. There are several reports of adverse effects of lorazepam use such as dizziness, tiredness and weakness [13]. Therefore, monitoring of this medicine is so important in during treatment [14]. ...
The measurement of pharmaceutical compounds in biological fluids is considered an effective way to evaluate their effectiveness. On the other hand, lorazepam is a drug with good efficiency in treatment and some side effects, which measurement is very important. In this study, the ZnO nanoparticle was synthesized as an electrocatalyst by chemical precipitation method. In continuous a simple modification on paste electrode (PE) by ZnO nanoparticle (ZnO-NPs) and 1-hexyl-3-methylimidazolium chloride (HMImCl) was made and new sensor was used for sensing of lorazepam. The HMImCl/ZnO-NPs/PE showed catalytic behavior on oxidation signal of lorazepam and improved its signal about 2.17 times compared to unmodified PE. On the other hand, oxidation signal of lorazepam was reduced about 110 mV at surface of HMImCl/ZnO-NPs/PE compare to unmodified PE that confirm accelerating the electron exchange process after modification of sensor by HMImCl and ZnO-NPs as powerful catalysts. The HMImCl/ZnO-NPs/PE was used for monitoring of lorazepam in water and injection samples and results showed recovery data 98.5 to 103.5 % that are acceptable for a new sensor.
... Les dosages utilisés varient selon les études, depuis des bolus croissants de 65, 135 puis 270 mg lorsque le PB est utilisé après échec des BZD (31,50), jusqu'à des doses de charge doses administrées à intervalles rapprochés autorisaient jusqu'à 120 mg/dose et permettaient une réduction significative du recours à l'intubation et la ventilation contrôlée (31). La demi-vie plus longue du diazépam comparée à celle du lorazépam est également un avantage : ses taux sériques diminuent plus lentement et fluctuent moins entre les doses, minimisant ainsi les résurgences symptomatiques inter-doses, les phénomènes de rebond et les convulsions tardives (36)(37)(38). Par ailleurs, aucune des multiples études cliniques sur le diazépam dans le SEA ne fait apparaître de risque majoré lié à une métabolisation plus lente chez les patients souffrant de pathologies hépatiques, malgré leur forte prévalence dans les populations étudiées (21), pour autant que la posologie soit individualisée et adaptée en fonction des symptômes. ...
Acute alcohol withdrawal is a frequent medical condition among hospitalized patients. Severe forms are associated with significant morbidity and mortality, which can be sharply reduced with proper drug therapy. A good understanding of the pathophysiology as well as the pharmacokinetic and pharmacodynamic properties of the various drug used is paramount. The medications must target the imbalance between inhibitory and excitatory neurotransmitter systems responsible for the clinical picture. Proper drug therapy allows not only rapid symptomatic relief but also limit disease progression and complications while diminishing resource use, notably invasive ventilation and stay duration in the intensive care unit. GABA agonist drugs are the first line treatment, notably benzodiazepines and barbiturates. Other class, such as alpha-2 adrenoreceptor agonists may be used to control the dysautonomic features of the disease but are at best adjunctive.
... Because of its shorter elimination half-life, the levels of lorazepam fluctuate to a greater extent and decline more rapidly between doses than do the levels of diazepam and desmethyldiazepam. Therefore, inter-dose breakthrough symptoms and rebound phenomena occur more frequently and more abruptly and increase in severity more rapidly when lorazepam is used [27,37,[44][45][46][47][48][49][50][51]. Indeed, during treatment for alcohol withdrawal, patients treated with lorazepam experience more pronounced reemergence of withdrawal symptoms, anxiety, and depression, and their mean daily pulse rate is significantly elevated compared with patients treated with diazepam [23,52]. ...
Benzodiazepines ameliorate or prevent the symptoms and complications of moderate to severe alcohol withdrawal, which can include autonomic hyperactivity, agitation, combativeness, hallucinations, seizures, delirium, and death. The benzodiazepines most commonly used for this purpose are lorazepam, chlordiazepoxide, oxazepam, and diazepam. It is widely asserted that no member of this group is superior to the others for treatment of alcohol withdrawal. However, of these, diazepam has the shortest time to peak effect, which facilitates both rapid control of symptoms and accurate titration to avoid over-sedation. Furthermore, diazepam and its active metabolite, desmethyldiazepam, have the longest elimination half-lives, so their levels decrease in a gradual, self-tapering manner, resulting in a smoother withdrawal, i.e., a lower incidence and severity of both breakthrough symptoms and rebound phenomena, including a possibly decreased seizure risk. Importantly, the fear of increased risk of over-sedation with diazepam compared with other benzodiazepines is based on a misunderstanding of its pharmacokinetics and is unfounded. Similarly, the notion that diazepam should be avoided in patients with liver disease and elderly patients to avoid prolonged over-sedation is based on no more than conjecture. In fact, there is clinical evidence that diazepam is safe for the treatment of alcohol withdrawal in these patients when administered using a simple symptom-based approach. There is one instance in which diazepam should not be used: when intramuscular administration is the only option, the lipophilicity of diazepam can result in slow absorption—either lorazepam or, when rapid control of symptoms is required, midazolam should be used. The comparative pharmacokinetics of the benzodiazepines used in the treatment of alcohol withdrawal together with a comprehensive review of the literature on their use strongly suggest that diazepam should be the preferred benzodiazepine for the treatment of patients experiencing moderate to severe alcohol withdrawal under most circumstances.
Breast cancer and depression are two prevalent health conditions that require effective treatment. Traditional medicinal systems have identified several plants with activity against these conditions, but their mechanism of action remain unclear. This study aims to predict and verify the potential molecular targets and pathways of a polyherbal phytoformulation in the treatment of breast cancer and associated depression. We review 61 plant species with anti-breast cancer and anti-depressant properties, and narrowed down our selection to three plants for further investigation. Using criteria for oral bioavailability (OB ≥ 30%), drug likeness (DL ≥ 0.18) and "Rule of five" (RO5), we extracted 71 active ingredients and 168 associated targets. We evaluated the clinical efficacy of phytoformulations containing Moringa oleifera (M.O), Coccinia indica (C.I), and Amaranthus spinosus (A.S) as active constituents, and determined their effective chemical components. Network phar-macology analysis identified key targets and pathways of the polyherbal phytoformulation in the treatment of breast cancer and associated depression. Additionally, molecular docking verified the core components and the targets of the formulation, predicting the interaction sites. Our results indicate that polyherbal phytoformulations (MCA) targets potential molecular targets and pathways for breast cancer and associated depression treatment. We identified several key targets and pathways of the formulation and verified the core components and targets using molecular docking. In conclusion, our study provides a theoretical and scientific basis for the clinical application of MCA and may be useful in developing more effective treatments for breast cancer and depression.
An electrochemical approach was developed for monitoring lorazepam as an anxiety disorders drug in an aqueous solution. In this regard, NiO/SWCNTs was synthesized by a simple and one-pot strategy (chemical precipitation in this case) method. Afterward, the carbon paste electrode (CPE) was modified with NiO/SWCNTs for fabrication of a highly sensitive electrochemical sensor, and a new sensor was used for sensing lorazepam. The NiO/SWCNTs/CPE amplified the oxidation signal of lorazepam about 1.86 times at optimum conditions. A linear dynamic range of 0.1–280 µM with a detection limit of 50 nM was observed for sensing lorazepam using NiO/SWCNTs/CPE as an analytical tool. The NiO/SWCNTs/CPE successfully monitored lorazepam with a recovery range of 97.5–104.58% in real samples.
Xuefu Zhuyu Decoction (XFZYD) is a traditional Chinese medicine prescription used for the clinical treatment of traumatic brain injury (TBI). The purpose of this work was to develop a sensitive and rapid UHPLC‐MS/MS method to simultaneously study the pharmacokinetics of nimodipine and eight components of XFZYD, namely, amygdalin, hydroxysafflor yellow A, rutin, liquiritin, narirutin, naringin, neohesperidin and saikosaponin A, in rats with and without TBI. MRM was highly selective in the detection of 9 analytes and the internal standard without obvious interference. The calibration curves displayed good linearity (r > 0.99) over a wide concentration range. The mean absolute recoveries of the nine analytes were 85‐106%, and all matrix effects were in the range of 80‐120%. The intra‐ and inter‐day precision and accuracy were acceptable (RSD, below 15%; RE%, ±20%). The validated method was successfully applied to compare the pharmacokinetics in four experimental groups, including control rats orally administered XFZYD and TBI model rats orally administered XFZYD, XFZYD and nimodipine, or nimodipine. The results showed that herb‐drug interactions occurred between XFZYD and nimodipine in the treatment of TBI, nimodipine affected the pharmacokinetics of XFZYD, and XFZYD affected the absorption, distribution and excretion of nimodipine in vivo.
Studies on psychotropic medications decrease, discontinuation, or switch have uncovered withdrawal syndromes. The present overview aimed at analyzing the literature to illustrate withdrawal after decrease, discontinuation, or switch of psychotropic medications based on the drug class (i.e., benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonists, antidepressants, ketamine, antipsychotics, lithium, mood stabilizers) according to the diagnostic criteria of Chouinard and Chouinard [Psychother Psychosom. 2015;84(2):63-71], which encompass new withdrawal symptoms, rebound symptoms, and persistent post-withdrawal disorders. All these drugs may induce withdrawal syndromes and rebound upon discontinuation, even with slow tapering. However, only selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, and antipsychotics were consistently also associated with persistent post-withdrawal disorders and potential high severity of symptoms, including alterations of clinical course, whereas the distress associated with benzodiazepines discontinuation appears to be short-lived. As a result, the common belief that benzodiazepines should be substituted by medications that cause less dependence such as antidepressants and antipsychotics runs counter the available literature. Ketamine, and probably its derivatives, may be classified as at high risk for dependence and addiction. Because of the lag phase that has taken place between the introduction of a drug into the market and the description of withdrawal symptoms, caution is needed with the use of newer antidepressants and antipsychotics. Within medication classes, alprazolam, lorazepam, triazolam, paroxetine, venlafaxine, fluphenazine, perphenazine, clozapine, and quetiapine are more likely to induce withdrawal. The likelihood of withdrawal manifestations that may be severe and persistent should thus be taken into account in clinical practice and also in children and adolescents.
Five benzodiazepine drugs (diazepam, flunitrazepam, flurazepam hydrochloride, nitrazepam, and triazolam) were evaluated separately in 15 sleep laboratory studies. Rebound insomnia, a worsening of sleep compared with baseline, occurred following withdrawal of triazolam, nitrazepam, and flunitrazepam after they had been given in only single, nightly doses for short periods. The rebound insomnia was attributed to the short and intermediate half-lives of these drugs. Diazepam and flurazepam, which have longer half-lives, did not cause rebound insomnia on withdrawal. Rebound insomnia may play a role in the development of hypnotic drug dependence with shorter-acting benzodiazepine drugs. (JAMA 241:1692-1695, 1979).
Methods for constructing simultaneous confidence intervals for all possible linear contrasts among several means of normally distributed variables have been given by Scheffé and Tukey. In this paper the possibility is considered of picking in advance a number (say m) of linear contrasts among k means, and then estimating these m linear contrasts by confidence intervals based on a Student t statistic, in such a way that the overall confidence level for the m intervals is greater than or equal to a preassigned value. It is found that for some values of k, and for m not too large, intervals obtained in this way are shorter than those using the F distribution or the Studentized range. When this is so, the experimenter may be willing to select the linear combinations in advance which he wishes to estimate in order to have m shorter intervals instead of an infinite number of longer intervals.
In a double-blind crossover study involving 15 insomniac subjects, the hypnotic efficacy of lorazepam, 2 and 4 mg, was compared with flurazepam, 15 and 30 mg, and placebo. Five subjective measures were used: onset, length, and depth of sleep, number of times awakened, and satisfaction with the hypnotic. Lorazepam in 2- and 4-mg doses was comparable in hypnotic efficacy to flurazepam, 30 mg, according to most parameters of measurement. Side effects were minor, although relatively numerous at the 4-mg doses.
Eight healthy male subjects received single 2-mg oral doses of lorazepam containing 24 muCi/mg of 2-14C-lorazepam. Multiple venous blood samples were drawn during the first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first-order half-life of 15 min. The peak plasma concentration was 16.9 ng/ml, measured in the pooled sample drawn 2 hr after the dose, This corresponded to the time at which clinical effects appeared to be maximal. The apparent elimination half-life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.
The metabolic disposition of lorazepam (Wy-4036) in man, dog, cat, rat and miniature swine is compared. Except in the cat, absorption of lorazepam is rapid in these species. Absorption in humans is nearly complete. Lorazepam glucuronide is the major metabolite in all species except the rat in which a dihydrodiol derivative is the main product of lorazepam biotransformation. Lorazepam glucuronide, which has no demonstrable CNS activity, is also present in the plasma of all species investigated. The concentrations of lorazepam in rat brain correlate well with those in plasma but are about three times higher. The urinary route of excretion predominates in man, dog and miniature swine while in the rat the bulk of the drug-related material is eliminated with the feces as a consequence of biliary excretion.
1 Six volunteers of mean age 59 years received placebo for week, then fosazepam (60 mg) nightly for 3 weeks, then placebo for 3 weeks. Subjective ratings and all-night electrophysiological recordings were made. 2 Fosazepam administration improved subjective sleep quality nut impaired feelings of morning vitality. Its withdrawal was associated with anxiety, impaired concentration and continuing impairment of morning vitality. Measured sleep duration increased on fosazepam, sleep was less broken, slow wave sleep stages 3 and 4 diminished in duration and so did REM sleep. 3 Despite the short-life of fosazepam some drug effects persisted for several days after withdrawal, suggesting action of a long half-life metabolite.
Five benzodiazepine drugs (diazepam, flunitrazepam, flurazepam hydrochloride, nitrazepam, and triazolam) were evaluated separately in 15 sleep laboratory studies. Rebound insomnia, a worsening of sleep compared with baseline, occurred following withdrawal of triazolam, nitrazepam, and flunitrazepam after they had been given in only single, nightly doses for short periods. The rebound insomnia was attributed to the short and intermediate half-lives of these drugs. Diazepam and flurazepam, which have longer half-lives, did not cause rebound insomnia on withdrawal. Rebound insomnia may play a role in the development of hypnotic drug dependence with shorter-acting benzodiazepine drugs.
(JAMA 241:1692-1695, 1979)
Rebound insomnia followed the withdrawal of three benzodiazepine hypnotic drugs, each of which had been administered in a single nightly dose for only short-term periods. The intense worsening of sleep is attributed to the short duration of the action of these drugs. A hypothesis involving benzodiazepine receptors in the brain is proposed in which there is a delay or lag in replacement of endogenous benzodiazepine-like molecules after the abrupt withdrawal of exogenous drugs.
: The safety of lorazepam was compared with that of a standard drug, glutethimide, in 50 chronically ill geriatric patients. Repeated physical examinations, laboratory determinations and other tests indicated that any organic disease in these patients had become stabilized before the study and was not affected by the test drugs. Early morning drowsiness, dizziness and lethargy were noted with each drug during the first and second weeks. More patients in the glutethimide series discontinued therapy because of side effects than in the lorazepam series. Dosage reduction to 1 mg nightly was necessary in many of those treated with lorazepam. Lorazepam is useful for aiding elderly patients to sleep. The initial dosage should be 1 mg nightly. If necessary, this dosage usually can be increased with safety to 2 mg nightly.