Claraeliz13


 * An Examination of the Benzodiazepines Drug Class; Widespread Use, Abuse & Impact to Memory**

This review paper encompasses the class of benzodiazepines "BZDs" from a broad and general perspective although there are instances where commonly prescribed BZDs are discussed, specifically. The review discusses use, abuse, impacts to memory as well as some common misconceptions. The use of BZD is widespread throughout the world in both developed and underdeveloped countries and the class of BZDs have many factors which contribute to their abuse and misuse. Drugs within the class have uniqueness because of the side chains housed on the core fused benzene and diazpeine ring indicative of this class of molecules. Dosing is diferent for each class of compound, demonstrating that not are all equal which may be an important point for users or patients who dabble among various products in this class. Memory impairment is typically noted as a side effect of BZD use, and is referred to abundantly in the literature however an examination of a rather large memory impairment study still does not entirely explain the subject. Also there have been no studies which evaluate possible irreversible changes to the brain which can be a factor in the process of making memories (which can be the greater concern for those taking BZD therapeutically but wishing to live and maintain a healthy lifestyle). It seems there may be certain misconceptions about BZD use. Long terms use of BZD does not equate to brain damage despite the conflicting literature. BZD's combination with narcotics actually lowers the chances of death compared to if one were taking narcotics alone which is contrary to widespread view.
 * Abstract**

Introduction of Benzodiazepines A class of compounds known as benzodiazepine(s), referred to hereafter as BZD(s), (Figure 1) are characterized by their core structure (Figure 2) made by the fusion of a benzene ring (Figure 3) and a diazepine ring (Figure 4) [1]. The drugs belonging to the drug class BZDs are psychoactive, psychopharmaceutical or psychotropic meaning the drug directly affects the brain altering perception, mood, consciousness, cognition and behavior [2]. This drug class alters ones state of mind, an experience which can be pleasant or advantageous to the user which increases it’s likelihood of misuse and abuse [2]. The drug class is becoming increasingly popular for recreational purposes [3]. Although they have become quite common in todays popular culture, BZDs have been around for over 50 years beginning with the discovery librium (Figure 5) in the 1950’s shortly following by the discovery of valium (Figure 6) in the early 1960s [1]. Since the discovery of valium, many more drugs have been discovered belonging to the BZD class. True to form, each drug has the core ring fusion of benzene and diazepine, however specific locations indicated by the R groups in Figure 1 on the fused benzodiazepine ring house various side chains, and the constituents of these side chains give rise to the unique properties specific to each individual compound [1]. There are about thirty different drugs belonging to this class [3]. This review paper includes structures, chemical names, generic and brand names of thirteen different BZDs belonging to this drug class to provide the reader with an appreciation of the diversity associated with this drug class (Figures 5 through 17). As BZDs were introduced, they gradually replaced their sedative predecessors, the barbituric acid (Figure 18) class, referred to as barbituates, which were considered more toxic with a higher risk of overdosing and dependence [3]. The mechanism of action of BZDs is an enhancing effect of the neurotransmitter: gamma-aminobutyric acid, GABA, (Figure 19) [3]. Generally short acting drugs in the class are prescribed to treat insomnia and long acting drugs in the class are prescribed to treat anxiety [3]. The mechanism explaining why pharmacological activity differs remains unclear but the conformation of BZDs and their electronic charge distriubution at the molecular level could provide new insights [4]. The BZD class of compounds all have sedative or some form of hypnotic effects on the human body and are typically prescribed for insomnia and anxiety, hence referred to as anxiolytics (defined as inhibiting anxiety) [1].



The Widespread Use and Abuse of Benzodiazepines There seems to be a gray area when evaluating use and abuse of BZD. Before examining use and abuse, clarity to the terminology is needed. Abuse is defined as taking large doses either regularly or sporadic but not for medical use and accompanied by drug seeking behavior [5]. Misuse is taking large doses but not always obtained by a prescription [5]. Misuse usually beings in the medical context but then usage expands from the medical context by taking larger doses [5]. Drug seeking behavior begins when the user feels the supply may be restricted [5]. Physical dependence is when physical symptoms arise when stopping the drug, drug seeking behavior will commence when the user feels the supply may become restricted [5]. This class of drugs has a very high abuse potential in terms of forged prescriptions [6].Mixing of BZD with alcohol intensifies the sedative nature and one could argue that the mere act of combination of these would qualify as abuse of the drugs. BZD use in combination with alcohol (Figure 20 ) presents with some conflicting finds. A study of the Canadian population shows that alcohol and BZD is not linked and users of BZD are not heavy drinkers [6]. The study indicates no correlation of BZD to alcohol use and actually showed that BZD users drank less than non-users, perhaps this could be specific to Canada only since the study was carried out with a Canadian population [6]. It should still be noted that within the Canadian population these findings were independent of differences in physical health, socioeconomic and demographic factors [6]. In direct contrast to these findings Miller states that alcoholics combine alcohol with other substances and that BZDs is a frequent choice citing that studies show that up to 50% of alcoholics use BZDs [7]. Another danger is the synergistic effects of combining BZD with alcohol in which they act together on the central nervous system to produce depression and suicidal thoughts [7]. Physicians, especially general practitioner are most often the prescribers of BZDs, but they cannot be certain if the use is truly for medical or non-medical reasons. [7]. Further, this class of drugs seems to have a very high abuse potential in terms of forged prescriptions [6]. Psychotropic drugs are prescribed to 20% of nonpsychiatric patient populations [7]. BZDs are of the most widely used medications in the world [8]. The American Pyschiatric Association recommends that these drugs be prescribed at the lowest therapeutic dose and for the briefest period to time, typically no longer than two to four weeks of continued use [8]. To understand the prevalence of use there are two main methods, counting the number of written perscriptions through a prescription audit and through the use of surveys conducted periodically by the National Institute on Drug Abuse [9].



Abusers of BZD may acquire the drug by prescription, they actively campaign for scripts from their physicians who may wind up prescribing this under false or exaggerated information from their patients [8]. It also seems that prescription rules are largely being ingnored as relates to period of use which is adding to possibilities for abuse and dependence [8]. Generally, BZDs are considered to be safe and effective in the short term but long term use remains controversial due to the potential for dependence and addiction [3]. Reynolds [10] chronicals the trends in three BZDs (Figures 5, 6, 15) in Austrailia over the years of 2007 through 2011 and equates hospital visits as recreational abuse of BZDs, qualifying abusers as male and female alike which he notes is different from abusers of other drugs where men are twice as likely to wind up in the hospital versus pharmaceutical drugs (for the purpose of tis review pharmaceutical drug implies a prescribed pharmaceutical drugs) where women are twice as likely to wind up in the hospital [10]. BZDs prescription rates are high which contributes to their abuse, findings from the National Household survey on Drug Abuse in 1985 which diazepam (Figure 5) 49% were from legal perscriptions, 3% were stolen, 7.7% were illegally purchased and only 0.1% were from forged perscriptions [9]. The forged prescription statistic seems rather low compared to Veldhuizen’s statement that there is a large amount of pescrption forgeries but the discrepancy may lie in the fact that in 38.8% gave no source for the drug [6,9]. Of the three drugs, Figure 6 induced hospital visits increased steadily over 2007 to 2011 while the others declined some years (Figure 21) [10].

Use in Underdeveloped Countries

Since the introduction in the 1960s and rapid rise of use, BZDs have rose to one of the most commonly consumed psychiatric medication classes in both developed and underdeveloped countries [6]. Side effects are generally noted as minor compared to other drugs although the dependence aspect associated with chronic use can be cause for concern [7]. Studies show that users take these drugs for a long period of time, defined as one year or more [7]. Prescription and sales data is tracked and therefore abundant in developed countries compared to underdeveloped countries. Underdeveloped countries face a much tougher health issue due to many unadvantageous factors including lack of data, economic factors and misinformed perscribers. Kapczinski focuses a review of BZD abuse specifically in the country of Brazil as a representation of many of the health problems faced by underdeveloped countries. Adding to the confusion, even in developed countries The nonmedical use in medical populations is underestimated and underdiagnosed. The nonmedical use is also misdiagnosed in nonmedical populations as medical use [7]. Normal-dose physical dependence was first considered in the early part of the 1970s but it was not until the early 1980s that scientific evidence established the reality and frequency [9]. A reaction has set in against these drugs, with attempts to limit them to short-term use [9].Dependence will occur in anybody who takes an addictive drug and displays symptoms characteristic of tolerance and withdrawal [10]. Tolerance is the need to increase the dose to achieve the desired effects, withdrawal is symptoms that appear when use is stopped. Appearance of the following symptoms are the main signs of physical dependence: insomnia, gastric problems, temors, agitation, fearfulness and muscle spasms with lesser frequent symptoms being characterized as: irritability, sweating, depersonalization, hypersensitivity to stimuli, depression, suicidal behavior, psychosis, seizures and delirium tremens [3]. In patients with complicated dependence, lowering of the dose can provide a better quality of life [11]. The main predictors of dependence severity were found to be: 1. being a self help patient, 2. higher BZD dose, longer BZD use and younger patient 3. Non-native origin, lower level of education, receiving treatment for alcohol or drug dependence, interaction of dose with duration of use [12] but a limited number of recognizeable risk factors can predict the severity of BZD dependence [12].

Studies have revealed the complex nature of withdrawal [9]. Physical dependence is unclear due to the wide variability in withdrawal type syndromes, ranging from 5% to 75% over various studies [6]. In the UK 15% of users reported failed attempts at stopping the drug [9].Symptoms of withdrawal are very similar to what’s listed above for dependence and are listed as nausea, vomiting, irritability, tremor, incoordination, insomnia, restlessness, blurred vision, sweating, anorexia, weakness as well as anxiety. [9] This further adds to the confusion surrounding this class of drugs, as the signs for dependence are similar to the signs of withdrawal, and some of the effects from using and stopping the drug present as symptoms in which a patient may have began taking the drug in the first place! For instance, a patient with anxiety may take a BZD, but getting off the medication can cause anxiety too. It seems almost like a vicious circle.

Memory Impairment Memory Impairment resulting from BZD use in medical practice is well known, so much so that a slang term for Figure 6 is forgetful pills which comes from their known anterograde amnesia effect [13]. It should be noted that memory is impaired only when the drug is in the body and the memory has been shown to recover in a linear way following overdose from BZD [14]. Anterograde amnesia is when memories are not formed properly after taking BZDS, which is why poor memory is associated with use [15]. It is noted that BZD impairs memory formation by impairing the consolidation process and impacting state-dependency aspect of memory retrieval [15]. Another idea is that memory impairment can also be a by-product of sedation [15]. The basic process for making memories, or consolidation, is encoding, storing and retrieving and these stages are deeply intertwined [15]. There is some suggestion that BZD impairs the consolidation aspect of memory making. State-dependent learning is when memory stored in a situation is best recalled in the same situation, memories stored in an altered state may best be retrieved in that same altered state of mind [15]. This offers an explanation why memories formed under the influence of the drug would have a greater chance at being retrieved while under the influence [15]. If the memory made with drug in the body and attempted at retrieval after the drug has metabolized out of the body then perhaps one would not be able to produce that memory, however with the addition of drug the memory may be able to be better retrieved. This is much like a queue for user to jog the memory just like a song, a smell, an environment might jog memories. This was not studied exactly but was discussed. Diazepam (Figure 5) exerts it’s most profound central effect on memory functions” [15], a startling and scary statement to read for those prescribed users who aspire to lead a productive and healthy lifestyle in which memory is of paramount importance to the tasks and events of daily life. BZDs differ pharmacologically which means their impact to the memory is different for the different drugs [15]. Different drugs within the BZD family have a range of half life, spanning from 3 hours to 100 hours half life [15]. Some medications can be out of the system in six hours where as some others will take 200 hours to get out of the system, which equates to 8 days in the body. If the user is taking a dose everyday as prescribed this may mean the drug will keep building, this could imply that the potential for perpetual lack of proper memory making is possible. Xanax is of the body in less than 24 hours whereas Valium can be in the system for days [15]. Most people take BZDs for weeks or even years, the majority of studies (80%) evaluated effects after just a single dose of BZD [15]. Some other studies looked at 2-3 doses, and some others over a period of 5 days [15]. Although generally memory declined after use of BZD the studies show variability depending on the dose, route of administration, the actual memory test (test standardization was identified as a weakness), and last the time at which information was presented versus retrieval and characteristics of the patient populations [15]. It has been established the BZDs do not impair retrieval of information acquired before drug administration which provides further evidence that it’s the consolidation process that becomes impaired. Very few studies have investigated memory effects of BZDs over anything close to a normal treatment period [15].There are references to BZDs causing memory impairment [15] but after the review of sever papers it remains unclear if the possibility exists that continual use or abuse of BZDs can change the brain and result in irreverseable permanent memory impairment, either in short or long term memory. Further it is not clear if memory impairment is due to acute use and then resolves itself and if this would be the scenario for chronic long term use of BZDs. Also, no studies found evaluated how memory is effected due to intermittent use of the drug class, meaning going on the medicine and going off for periods of time. It is a possibility that people may rely on such drugs to help them through certain stressful or depressing time periods in their lifetime associated with traumatic life events.



Combining BZDs with Narcotics Opiate addicts use high-doses of BZDs and 30% to 50% of opiate addicts are BZD users [6]. Contrary to widely cited views, diazepam and oxazepam actually block lethal effects of narcotics (morphine and methodone, Figure 23 and 24, respectively) and increase their lethal dose [16]. This is counter-intuitive to common perception of combining BZDs with narcotics would increase their lethality [16]. The LD50 are pretty high cited as 2,000 mg/kg for Xanax and 710 mg/kg for Valium [Quinnones 17]. However, Erowid shows quite a large range in the LD50 (Figure 6 is stated as ranging 331 – 2171 mg/kg) [13].



Brain Damage from Long Term Use Conflicting results have been presented regarding changes in the brain and long term BZD use. [18] A study was undertaken to compare 20 long term users against (experimental group) versus 36 age as well as sex-matched controls (control group) [18]. Both groups were given CT scans of the brain to assess atrophy by measuring the various parts of the brain. No differences in atrophy was found between the experimental group and the control group [18]. The processes in the brain are complex and account for a cycle of sleep-wake patterns which equates to our biological clock creating rise and fall in the body’s natural sleep chemicals, when this process becomes disrupted, this is defined as insomnia for which drugs in the BZD class are a common cure [19]. The magnitude of reduction in thalamic metabolism correlates with the degree of sleepiness [ 20]. A strong relationship exists between a level of consciousness and the amount of activity in the thalamus, basal forebrain and occipital lobe [20].

Conclusion It is clear BZD use is widespread throughout the world. The lines between use, misuse and abuse become easily blurred. Sometimes the very symptoms these drugs are intended to provide relief from bring about the very same symptoms when improperly used and when use is discontinued. The literature reveals conflicting finds as relates to combining benzodiazepines with alcohol and other drugs. It is clear that BZDs impair the memory while under the influence but it seems that memory recovers when the drug leaves the body. BZDs work by acting through a neurotransmitter, GABA, to directly effect the brain. One study shows that the brain does not become damaged with use of BZDs. BZDs have a high lethal dose but often the discontinuation of BZD can bring about suicidal gestures. Reducing thalamic metabolism correltes with the degree of sleepiness.