Xanax is the brand name under which a drug called alprazolam. It is a medication that can only be taken with a prescription, and it is usually used in the management of panic disorders, nervousness, and anxiety disorders connected to depression. It can also be taken along with additional drugs addressing the same health issue rather than as a solitary prescription. Xanax is grouped in a class of medications that are termed as anti-anxiety agents. This classification is also called anxiolytics or benzodiazepines.
Apart from its intended use as a prescription drug to treat anxiety-related disorders, Xanax is often abused and used recreationally. Recreational users of Xanax report that it produces a calming or sedated feeling. These feelings of relaxation or calm are often used to produce a deep sleep in the users, and many reports passing out shortly after. Those who abuse high doses also report side effects such as memory loss. Xanax is one of the most commonly abused drugs in the U.S., and has been the focus of several drug abuse focused interventions so far (Addiction Center, 2020). As it is easy to develop a tolerance to it, individuals are often driven to take more and more of the drug to produce the same effects. It is highly addictive and readily available, which is a dangerous combination. Seventy per cent of teens in the U.S. who develop an addiction to Xanax obtain it from their medicine cabinet at home (Addiction Center, 2020).
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History and Epidemiology of Xanax
History
Xanax is known to be an anti-anxiety and antidepressant medication that was made by Upjohn Laboratories of Kalamazoo in Michigan. It was developed in the late 1960s to create a sleep aid. The general plan during its development was to create a great sleep aid that had qualities of muscle relaxation. However, as the research team in Upjohn continued to develop it, they realized that the drug would have a significant effect on mood disorders, panic, and anxiety.
At the time, this development was fortuitous due to the massive gap in the market for antidepressants that were non-toxic and milder. The antidepressants that were offered for patients struggling with mental illness at the time were generally harsh, and their toxicity created unpleasant side effects. While these early antidepressants – generally tricyclic depressants – pioneered psychotherapy as we know it today, they were also associated with several adverse effects. These included but were not limited to, memory disorders, constipation, blurred vision, dizziness, urine retention, hypotension, and sedation (Lopez-Munoz, 2009). Thus Upjohn Laboratories were aware that there were a need and a consumer base for a newer, milder form of psychotherapeutic medication.
At the time, benzodiazepines such as Xanax had been on the market for a while, and their demand was declining in favour of newer drugs. Being aware of this, Xanax was positioned not as an antidepressant but as a drug-specific to panic disorders. At the time, panic disorders had recently been recognized as a separate and independent diagnosis, and this allowed Xanax to become more widely used. The drug was presented as an anti-anxiety and antidepressant drug to the FDA, and around fifty studies were done in its analysis. These studies proved without a doubt that alprazolam – or Xanax – was a better alternative to all the drugs available at the time, both in efficacy and toxicity. Thus, Upjohn received a U.S. patent for the drug in 1969, and it was released onto the market in 1981.
By the time that the early 1990s were rolling around, Xanax had become the most popular drug in psychiatry for treating panic disorders. The studies that had been performed that proved its efficacy and low toxicity led to its increased prescription by a psychiatrist. Xanax slowly rose to the top and became the most prescribed benzodiazepine in the United States (Black Bear Rehab, 2018).
Epidemiology
The clinical use of Xanax has been a contested issue for the past few years due to the tension between its efficacy and its addictive nature. The majority of addiction specialists consider Xanax to be a highly addictive drug and consider this particular property one that limits how useful or efficient it can be in a clinical setting (Ait-Daoud, Hamby, Sharma & Blevins, 2018). However, on the ground, practising physicians continue to find its use practical, and prescribe it. In several cases, it is prescribed for longer than the recommended period, which increases the likelihood of adverse outcomes such as addiction (Ait-Daoud, Hamby, Sharma & Blevins, 2018). The drug is among one of the most frequently prescribed benzodiazepines, and there is a lack of research on its specific abuse liability, which is an uncommon feature for such a widely used drug (Ait-Daoud, Hamby, Sharma & Blevins, 2018).
Xanax is not only the utmost recommended benzodiazepine but also the most approved psychotropic drug in the country. In the past decade, it has accounted for more than 40 million of the prescriptions issued in the U.S. annually (Ait-Daoud, Hamby, Sharma & Blevins, 2018). The presence of high addictive liability, as well as severe withdrawal symptoms, has not slowed its popularity down, and it continues to be the go-to medication for several physicians. One study demonstrated this popularity by studying the prescriptions given in a region over a year and found that more than 50 per cent of the patients that visited the hospital received a Xanax prescription from their primary care physician even though some had risk factors for adverse events associated with taking the drug such as histories of addiction (Kroll et al., 2016). This frequency in prescription is associated with the lack of research on best practice with regards to alprazolam.
The national emergency department keeps track of visit data from health institutions all over the United States. According to this database, Xanax is the most common benzodiazepine involved in visits to the Emergency Department about drug abuse or misuse. Furthermore, benzodiazepines are involved in 30 per cent of suicide attempts or intentional overdoses (Ait-Daoud, Hamby, Sharma & Blevins, 2018). Data on poisoning admissions further show that cases, where Xanax is involved with other toxic compounds, have an increased period of recovery and stay, as well as likelihood to be admitted into the ICU in comparison to other co-ingested drugs.
Pharmacology
Alprazolam is a triazolo analogue of 1,4-benzodiazepine. Benzodiazepines are a class of compounds known to be active in the central nervous system, creating a variety of effects. The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine (Greenblat & Wright, 1993). The drug is manufactured as a white precipitate which is not solvable in water but is solvable in ethanol and methanol. Each tablet of Xanax generally contains 2 mg, 1 mg, 0.5 mg, or 0.25 mg of alprazolam (Greenblat & Wright, 1993).
The mechanism of action of Xanax is in the binding of benzodiazepine receptors found within the central nervous system. In particular, the drug targets two receptors, BNZ1 and BNZ2. BNZ1 is a receptor involved in the regulation of sleep, and BNZ2 is a receptor involved in the relaxation of muscles, anticonvulsant activity, motor coordination, and memory. Both of these receptors are bound to the gamma-aminobutyric acid receptors (GABA receptors) ( Masiulis, Desai, Uchański, Martin, Laverty, Karia & Steyaert, 2019) . Xanax works by binding to BNZ1 and BNZ2. While it is bound to these two receptors, the action of GABA receptors is increased ( Masiulis, Desai, Uchański, Martin, Laverty, Karia & Steyaert, 2019). Thus, the GABA receptors gain an increased affinity for GABA, which is the goal of this interaction.
An increased affinity for GABA means that GABA will bind to its receptor more frequently. That enhances the effects of GABA for the user. GABA works as an inhibitory neurotransmitter, which means it decreases function (Wu & Sun, 2015). In particular, it decreases neuron excitability, which limits the strength of the signal that nerves transmit to each other. GABA specifically decreases neurotransmission, that creates muscle tremors and anxiety (Wu & Sun, 2015). As a result of its connection to sleep regulation, this can also result in increased drowsiness. The result is that patients experiencing anxiety or muscle tremors will have reduced symptoms.
Manufacturing Process
Alprazolam is manufactured with the starting point of using 2,6-dichloro-4-phenylquinoline. This reaction of this compound with hydrazine produces 6-chloro-2-hydrazino-4-phenylquinoline (Vardanyan & Hruby, 2016). The derivative is heated in xylene with triethyl orthoacetate in xylene, which leads to heterocyclization (Vardanyan & Hruby, 2016). The result is a triazole derivative. The manufacturer then carries out oxidative cleavage with ruthenium dioxide and sodium periodate in an acetone-water system. The product is 2-[4-(3′-methyl-1,2,4-triazolo)]-5-chlorobenzophenone (Vardanyan & Hruby, 2016).
One of the final steps is the use of formaldehyde to carry out oxymethylation. The hydroxyl group that results from this process is substituted by phosphorous tribromide to produce 2-[4-(3′-methyl-5′-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone (Vardanyan & Hruby, 2016). Ammonia is then used to substitute the bromine atom with an amino group. That creates a spontaneous heterocyclization that produces alprazolam (Vardanyan & Hruby, 2016).
The white crystalline powder is then used to create tablets of varying dosage, with inactive ingredients added. These ingredients generally consist of corn starch, lactose, cellulose, silicon dioxide, docusate sodium, and magnesium stearate (RXList, 2020). The tablets are also colour-coded according to dosage. The 0.5 mg tablet is coloured yellow by the addition of FD&C Yellow no. 6. The 1mg tablet, on the other hand, is coloured blue by the addition of FD&C Blue no. 2 (RXList, 2020).
Treatment Process
Dosage
The administration of Xanax is done orally, and it is available as orally disintegrating tablets in varying strengths, from 0.25 mg to 2 mg. These tablets are for regular release administration. In cases where extended-release is preferred, the tablets are available in strengths varying from 0.5 mg to 3 mg. For cases where tablets are undesirable, Xanax is also available as an oral solution. This solution is produced in strengths of 0.5 mg/5mL, and 1 mg/10mL.
Xanax may be administered without having the patient eat food first. However, for patients who experience upset stomachs after Xanax administration, it is recommended that they take their dose after food. Administration regulations for Xanax and other versions of Alprazolam state that it must never be removed from its original packaging and placed in a pillbox. The drug should be kept in its original packaging.
The dosage and treatment using Xanax differ according to the specific illness that has been diagnosed. For the treatment of anxiety disorders, the oral dosage for adults is recommended to be the 0.25 or the 0.5 mg regular release tablets taken three times a day (George & Tripp, 2020) . Any increases in dosage should be done at intervals of 3 to 4 days. There should not be increments larger than 1mg a day. The maximum dose for adults is 4 mg a day. For geriatric patients, the recommended dose is 0.25 mg 2 to 3 times daily (George & Tripp, 2020) .
For treating panic disorders, extended-release tablets are used. The adult dosage for this is recommended to be 0.5 to 1 mg, once a day (George & Tripp, 2020) . The maintenance dose is 3 to 6 mg daily. The maximum day-to-day dose is 10 mg a day. For geriatric patients, the recommended dose is 0.5 mg daily. For the solution of alprazolam, the 0.5 mg solution is taken thrice daily, and the maximum dose is still 10 mg a day. For geriatric patients, 0.25 mg is recommended thrice daily (George & Tripp, 2020) .
Dose Reduction
It should be noted that its addictive nature makes the reduction of dosage complicated. For Xanax, the abrupt discontinuation of administration creates a danger for withdrawal. Thus, the gradual reduction is best. The recommended reduction is a minimum of 0.5 mg every three days (George & Tripp, 2020) . For some patients, this reduction must be even slower. Longer-acting benzodiazepines can also be used to substitute Xanax during this period.
Expected Effects and Side Effects
The expected effects of taking Xanax have reduced anxiety, reduced muscle tension, and alleviated insomnia. Adverse effects of taking the drug include fatigue, drowsiness, low balance, slurred speech, memory problems, diarrhoea, lowered concentration span, irritability, blurred vision, constipation, nausea, headaches, lowered libido, and insomnia (George & Tripp, 2020)
Rehabilitation Treatments
Rehabilitation from Xanax addiction is generally done within treatment centres, as this is where it is best managed. The process consists of medical detox followed by a rehabilitation process. The medical detox assists with the process of withdrawal by reducing the adverse effects of this period. For out-patient rehabilitation situations where the addiction is mild or the individual is unable to be admitted due to other responsibilities, the medical detox is done with a consulting health practitioner. Following the detox process for both in- and out-patient experiences are the aftercare section. That consists of counselling and support group attendance, including the use of a 12-step program.
References
Addiction Center. (2020). Xanax Addiction and Abuse. Retrieved from https://www.addictioncenter.com/benzodiazepines/xanax/
Ait-Daoud, N., Hamby, A. S., Sharma, S., & Blevins, D. (2018). A review of alprazolam use, misuse, and withdrawal. Journal of addiction medicine , 12 (1), 4.
Black Bear Rehab. (2019). The History of Xanax. Retrieved from https://blackbearrehab.com/blog/xanax-history/
George, T. T., & Tripp, J. (2020). Alprazolam. In StatPearls [Internet] . StatPearls Publishing.
Kroll, D. S., Nieva, H. R., Barsky, A. J., & Linder, J. A. (2016). Benzodiazepines are prescribed more frequently to patients already at risk for benzodiazepine-related adverse events in primary care. Journal of general internal medicine , 31 (9), 1027-1034.
Masiulis, S., Desai, R., Uchański, T., Martin, I. S., Laverty, D., Karia, D., ... & Steyaert, J. (2019). GABA A receptor signalling mechanisms revealed by structural pharmacology. Nature , 565 (7740), 454-459.
Wu, C., & Sun, D. (2015). GABA receptors in brain development, function, and injury. Metabolic brain disease , 30 (2), 367-379.
Vardanyan, R., & Hruby, V. (2016). Synthesis of best-seller drugs . Academic press.
RX List. Xanax. Retrieved from https://www.rxlist.com/xanax-drug.htm#description
