Pill Pushing©

The Best of Pill Pushing - The benzos - Doctor please! Some more of these! - (7/15/2017)

By Dr. Ron Gasbarro
Drug(s) in question – The benzodiazepines
Society at the time 
The early 1960s were a time of change in America and society was influenced by the youth of the post-war baby boom - a generation with a fondness for change and far-out gadgets. A beautiful couple with their adorable young children moved into the White House. Life was getting better with new products being introduced Quaker Oats Company introduced 'Life' cereal. Fruit Loops, Coffee-Mate®, and Tab® (the diet soda so that you can keep “tabs” on your weight) became grocery store favorites. Planters introduced dry roasted peanuts. The pull tab for beverage cans is introduced. The one billionth McDonald's hamburger was served by Ray Kroc on the Art Linkletter Show. 
“Mashed Potato Time” by Dee Dee Sharp reached #1 on the charts. Booker T and the MG's released their instrumental single “Green Onions”, The Four Seasons “Sherry” hits #1 on the charts. “The Monster Mash” by Bobby “Boris” Picket and the Crypt Kickers skyrocketed to #1. The Beatles’ star began to rise during this time and their music would become a 180° turn for pop music.
USSRs’ Yuri Gargarin orbits Earth once and becomes the first man in space with USAs’ Alan Shepard becoming the first American in space a few weeks later. President Kennedy addressed Congress and challenged the nation to travel to the Moon before the end of the decade. That challenge was met in 1969. Inventions included the audio cassette, the first computer video game (Spacewar) and silicone breast implants.  The female birth-control contraceptive, “the pill”, was released in the United States after Food and Drug Administration (FDA) approval.
Marilyn Monroe overdosed and JFK was shot in the head paving the way for LBJ and his Civil Rights Act. 
Conflicts were rampant both here and abroad. Thousands of US military advisors were sent in South Vietnam as Communism threatened to move in from the north, signaling the start of the Viet Nam War. The Bay of Pigs Invasion occurred in an unsuccessful attempt by a CIA-trained force of Cuban exiles to invade southern Cuba with support from US government armed forces, to overthrow the Cuban government of Fidel Castro. The Portuguese Colonial War was just beginning between Portugal's military and the emerging nationalist movements in Portugal's African colonies. At home, there was a large increase in crime and urban unrest of all types. During this time, reported incidences of violence in the US nearly doubled. 
What the world needed by then was a big old dose of tranquility. Not the deadly barbiturates that took out Marilyn, but a whole shiny new class of sedatives called the benzodiazepines or the “benzos.”  
The good, the bad, and the ugly
Sedatives and tranquilizers have a long history of medicinal and recreational use—starting with alcohol, the original sedative drug. Bromides, chloral hydrate, and paraldehyde were developed in the 1800s, followed by barbiturates (e.g., Seconal®) and meprobamate (Miltown®) in the first half of the 20thcentury. All of these substances were limited by their high potential for abuse and dependence and their potentially fatal consequences of overdose. The benzos were to be a giant step forward in pharmacotherapy.
In 1954, Leo Sternbach, a pharmacist and chemist working at the Hoffmann-La Roche pharmaceutical company in Nutley, NJ, was tasked with developing a safer alternative to barbiturates and meprobamate. Over the next few years, Sternbach created about 40 new compounds, but none of them had any effects in animal tests. In 1956, he chemically modified one of these 40 compounds to make it more stable, labeled the resulting white powder Ro 5-0690, and placed it on the shelf where it was forgotten. By pure chance, the container of Ro 5-0690 was found during a laboratory cleanup a year later and sent to be tested for drug activity. The tests showed it had similar effects to meprobamate, exactly what Sternbach had been trying to discover for 3 years. The compound was renamed chlordiazepoxide, and introduced in the US in 1960 as a new anxiolytic (anti-anxiety) drug under the trade name Librium®. This was the world’s first clinically useful benzodiazepine. Librium was indicated for the short-term (2–4 weeks) treatment of anxiety that is severe and disabling or subjecting the person to unacceptable distress. It is also indicated as a treatment for the management of acute alcohol withdrawal syndrome [BNF, 2008].
By 1963, the Librium molecule was rearranged and the subsequent drug was found to have properties that Librium did not have, such as treating muscle spasms, seizures, insomnia and restless legs syndrome, as well as anxiety [Calcaterra, 2014]. This drug was named diazepam and sold under the trade name Valium®. 
How do the benzos work?
The exact mechanism of action of benzodiazepines is not known, but they appear to work by affecting neurotransmitters in the brain, chemicals that nerves release in order to communicate with other nearby nerves [Ogbru, 2016]. One of these neurotransmitters is gamma-aminobutyric acid (GABA), a neurotransmitter that suppresses the activity of nerves. Scientists believe that excessive activity of nerves may be the cause of anxiety and other psychological disorders, and benzodiazepines reduce the activity of nerves in the brain and spinal cord by enhancing the effects of GABA.
Since its introduction, the drug class has ballooned and includes even more indications.  Benzodiazepines differ in how quickly they start working, how long they continue to work, and for what they are most commonly prescribed.
Diazepam (Valium®) and clorazepate (Tranxene®) have fast onsets of action and usually start working within 30 to 60 minutes. 
Oxazepam (Serax®) has a slow onset, and lorazepam (Ativan®), alprazolam (Xanax®), clobazam (Onfi®) and clonazepam (Klonopin®) have intermediate onsets of action.
Clorazepate (Tranxene®), midazolam (Versed®), and triazolam (Halcion®) are short-acting agents with durations of action of 3 to 8 hours.
Alprazolam (Xanax®), lorazepam (Ativan®), estazolam (Prosom®), and temazepam (Restoril®) are intermediate-acting agents with durations of action of 11 to 20 hours.
Chlordiazepoxide (Librium®), clonazepam (Klonopin®), diazepam (Valium®), flurazepam (Dalmane®), and quazepam (Doral®) are long-acting agents with duration of action of 1 to 3 days.
Although most benzodiazepines are used interchangeably, some are most commonly used for certain conditions.
Xanax, Librium, Tranxene, Valium, Ativan, and Versed are used for anxiety disorders.
Klonopin, Tranxene, Ativan, Onfi, and Valium are used for seizure disorders.
Prosom, Dalmane, Doral, Restoril and Halcion are used for insomnia or trouble sleeping.
Versed, Ativan, and Valium are used in anesthesia.
Valium is also used for muscle relaxation.
Librium is used for alcohol withdrawal.
Better than older drugs but not perfect
Benzodiazepines quickly became recreational drugs. This abuse is partially related to the toxic effects that they produce and also to their widespread availability. They can be chronically abused or, as seen more commonly in hospital emergency departments, intentionally or accidentally taken in overdose. Death and serious illness rarely result from benzodiazepine abuse alone; however, they are frequently taken with either alcohol or other medications. The combination of benzodiazepines and alcohol can be dangerous -- and even lethal.
Benzos have also been used as a "date rape" drug because they can markedly impair and even abolish functions that normally allow a person to resist or even want to resist sexual aggression or assault. In recent years, the detection and conviction of people involved in this has increased dramatically. The drug is usually added to alcohol-containing drinks or even soft drinks in powder or liquid forms and can be hard to taste.
The ugly side – A case for Karen
Karen Ann Quinlan (March 29, 1954 – June 11, 1985) was an American woman who became an important figure in the history of the right to die controversy in the United States [McDougal, 2007]. When she was 21, Quinlan became unconscious after she consumed Valium along with alcohol while on a crash diet (no food for the previous 2 days) to fit into a dress. She lapsed into a coma, followed by a persistent vegetative state that lasted until 1985 – 10 years. After doctors refused the request of her parents, Joseph and Julia Quinlan, to disconnect Quinlan's respirator, which they believed constituted extraordinary means of prolonging her life, her parents filed suit to unplug Quinlan’s respirator.
Quinlan had suffered irreversible brain damage after experiencing an extended period of respiratory failure (lasting no more than 15–20 minutes). No precise cause of her respiratory failure has been given. Her brain was damaged to the extent that she entered a persistent vegetative state, a state of completely altered consciousness. Her eyes were "disconjugate" (they no longer moved in the same direction together). Her EEG showed only abnormal slow-wave brain activity. Over the next few months she remained in the hospital and her condition gradually deteriorated. She lost weight—eventually weighing less than 60 pounds at her death. She was prone to unpredictable, violent thrashing of her limbs. She had a feeding tube to nourish her. 
Quinlan's case continues to raise important questions in moral theology, bioethics, euthanasia, legal guardianship and civil rights. Her case has affected the practice of medicine and law around the world. A significant outcome of her case was the development of formal ethics committees in hospitals, nursing homes and hospices.
Impact of the drugs on culture
With its first major mark on popular culture in the Rolling Stone’s song “Mother’s Little Helper” in 1966, Valium quickly became the go-to drug to help Americans reduce their anxiety [RehabToday, 2016]. Valium was easily the first pill for emotional health that was prescribed and used on a mass scale. By 1974, Americans were downing 60 million prescriptions for the anti-anxiety medication a year. The invention and marketing of Valium has changed America’s relationship with their own uncomfortable feelings and opened the door to a pharmacological industry of medicating emotions that continues today. Has the drug has been overprescribed? Has it had the effect of teaching people to avoid working through their negative emotions by popping a pill instead? Do we even know what range of human emotions is normal? In the 1960s when Valium and its predecessor, Librium, were being developed, it was not typical to ask a doctor for a pill to help with stress and anxiety. Back then, for individuals struggling with diagnosed mental illness, barbiturates were the prescription doctors used to help calm anxiety. These pills worked to help reduce emotional stress, but they made people drowsy and put them into a trance-like state. Although this type of pill was used in acute cases of stress or mental illness, it was not a pill the mass public was willing to purchase.
Then along comes Librium, the first psychoactive medication with a catchy name and marketing aimed directly at the public [RehabToday, 2016]. One advertisement showed a young women heading off to college with the caption, “A Whole New World … of Anxiety.” This statement implied that healthy individuals embarking on stressful new adventures might need some help from a prescription. The ad listed the following potential causes of anxiety for the young co-ed including: Making new friends, living in a new environment, pressure of grades, tests of morality. 
Until Librium appeared on the scene, all of these issues would have been seen as challenges and character-building opportunities – not symptoms requiring medication. Once Librium had greased the wheels, Valium was primed to hit the scene, resulting in the sale of millions of pills each year.
Valium was used and abused by many people since its introduction. A number of celebrities have admitted to abusing Valium, often in combination with other drugs, to get high. Both Elizabeth Taylor and Tammy Faye Baker used the drug. Taylor combined Valium with whiskey while Baker used nasal spray. And the King of rock-n-roll himself, Elvis Presley, relied on a concoction of prescription drugs including Valium before addiction led to his eventual death.
The benzos have been increasingly abused in the general population. The figure below is a bar chart showing the total number of U.S. overdose deaths involving benzodiazepines from 2001 to 2014. The chart is overlayed by a line graph showing the number of deaths by females and males. From 2001 to 2014 there was a 5-fold increase in the total number of deaths. 

Mother’s Little Helper
The Rolling Stones
What a drag it is getting old
"Kids are different today,"
I hear ev'ry mother say
Mother needs something today to calm her down
And though she's not really ill
There's a little yellow pill
She goes running for the shelter of a mother's little helper
And it helps her on her way, gets her through her busy day
"Things are different today,"
I hear ev'ry mother say
Cooking fresh food for a husband's just a drag
So she buys an instant cake and she burns her frozen steak
And goes running for the shelter of a mother's little helper
And two help her on her way, get her through her busy day
Doctor please, some more of these
Outside the door, she took four more
What a drag it is getting old
Songwriters: Keith Richards, Mick Jagger
© Abkco Music, Inc.; 1965 
Where the drugs are today
Most benzodiazepines are now available generically, making them very affordable. Diazepam is on the World Health Organization's List of Essential Medicines, which is comprised of the most important medications needed in a basic health system. 
All benzodiazepines are listed as DEA schedule IV controlled substances, meaning abuse of the drug may lead to limited physical dependence or psychological dependence. To compare, oxycodone is a DEA schedule II controlled substance; it has a high risk of addiction. As controlled substances, all benzodiazepines have the potential for abuse, addiction and diversion.
The benzos are still greatly abused
Benzodiazepines, particularly those having a rapid onset, are abused to produce a euphoric effect [DEA, 2013]. Abuse of benzodiazepines is often associated with multiple-substance abuse. Diazepam and alprazolam are used in combination with methadone to potentiate methadone’s euphoric effect. Cocaine addicts use benzodiazepines to relieve the side effects (e.g., irritability and agitation) associated with cocaine binges. Benzodiazepines are also used to augment alcohol’s effects and modulate withdrawal states. The doses of benzodiazepines taken by abusers are usually in excess of the recommended therapeutic dose. Benzodiazepines have been used to facilitate sexual assault. The American Association of Poison Control Centers reports 81,427 case mentions, 31,255 single exposures, and 11 deaths associated with benzodiazepines in 2010. There were an estimated 345,691 emergency department visits attributed to benzodiazepines in 2010, a statistically significant increase from 271,698 visits in 2008. Of the ED visits, 124,902 were due to alprazolam, 62,811 were due to clonazepam, 36,675 were due to lorazepam, and 26,860 were due to diazepam. According to the 2011 National Survey for Drug Use and Health (NSDUH), 20.4 million individuals aged 12 and older have misused benzodiazepines in their lifetime.
Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. See figure below. Benzodiazepines were ranked 7th in dependence, physical harm, and social harm [Nutt, 2007].
Other uses for the benzos
Benzodiazepines are used in veterinary practice in the treatment of various disorders and conditions. As in humans, they are used in the first-line management of seizures, status epilepticus, and tetanus, and as maintenance therapy in epilepsy (in particular, in cats). They are widely used in small and large animals, including horses, pigs, cattle and exotic and wild animals, for their anxiolytic and sedative effects, as pre-medication before surgery, for induction of anesthesia and as adjuncts to euthanasia. California and Florida offer diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program, although the state of California has not executed a prisoner since 2006.
Bottom line – For over half a century, the psychoactive benzos have been highly effective drugs for a variety of neurological based conditions. Unfortunately, they also have the potential for abuse and even death, especially when mixed with other illicit drugs and/or alcohol. Generally safe when used as directed, almost all are generic and very affordable. 

Ron Gasbarro, PharmD is a registered pharmacist, medical writer, and principal at Rx-Press.com. Write him with any ideas or comments at ron@rx-press.com.

British National Formulary; Committee on Safety of Medicines. Chlordiazepoxide hydrochloride. BNF.org; 2008. 
Calcaterra NE, Barrow JC. Classics in chemical neuroscience: diazepam (valium). ACS Chemical Neuroscience. 2014;5:253–60.
Drug Enforcement Agency. Benzodiazepines; 2013. http://www.deadiversion.usdoj.gov/drug_chem_info/benzo.pdf 
MacLaren E. Valium history and statistics. DrugAbuse.com; 2016. 
McDougall J; Gorman M. Euthanasia: A Reference Handbook. Santa Barbara, CA: ABC-CLIO; 2007. 
Nutt D, King LA, Saulsbury W, Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse. Lancet. 2007;369:1047-53.
Ogbru A. Benzodiazepine drug information. Rxlist.com; 2016.

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