Chlordiazepoxide

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Chlordiazepoxide

Common Trade Names: Librium

Other Names: Chlordiazepoxide HCl, 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide

Chlordiazepoxide is a long-acting benzodiazepine that is FDA-approved for the management of anxiety disorder and preoperative apprehension and anxiety among adults. It is a Schedule IV medication that is associated with a strong potential for abuse and addiction. To know more about chlordiazepoxide, read on.

A Brief History of Chlordiazepoxide

Chlordiazepoxide was synthesized in 1957 by Dr. Leo Sternbach, a Polish-American chemist who was then working at a New Jersey-based laboratory of Hoffman-La Roche. During his postdoctoral education in Poland, Dr. Sternbach worked on an unexplored class of compounds called benzheptoxdiazines. However, it was only in 1957 when Dr. Sternbach decided to treat one of its derivatives with methylamine. The resulting compound was labeled Ro 5-0690, a white, crystalline water-soluble powder later to be known as chlordiazepoxide.

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Dr. Sternbach submitted the compound for evaluation to the pharmacological research laboratory of Hoffman-La Roche. In that same year, Dr. Lowell Randall, then the head of pharmacology at Roche, reported that the compound had “hypnotic, sedative, and antistrychnine effects in mice similar to meprobamate.” After several toxicity and pharmacology studies, clinical trials on chlordiazepoxide soon began.

Several years later, Dr. Irvin Cohen and two other scientists participated in the clinical trials that were being conducted among neuropsychiatric patients in an office-based chlordiazepoxide therapy. They discovered the drug’s potent anxiolytic activity with only mild side effects. The success of the Phase III clinical trials led to the approval of chlordiazepoxide by the US Food and Drug Administration in February 1960. One month later, chlordiazepoxide was introduced to the market under the trade name Librium.

How Does Chlordiazepoxide Work in the Human Body?

Chlordiazepoxide has anxiolytic, sedative, and weak analgesic properties. It works by binding to benzodiazepine receptors at the gamma-aminobutyric A (GABA-A) ligand-gated chloride channels within the nervous system. By activating these receptors, chlordiazepoxide increases the frequency of the opening of chloride channels, leading to the hyperpolarization of the cell membrane and an increase in the excitation threshold. In addition, chlordiazepoxide has been shown to inhibit the neuronal activity in the fear circuits located in the amygdala. This spectrum of actions is responsible for chlordiazepoxide’s anxiolytic, hypnotic, and sedative effects.

Chlordiazepoxide is approved by the US FDA in the management of moderate to severe anxiety disorder, withdrawal symptoms of alcohol use disorder, and preoperative anxiety among adults. It is also FDA-approved in the management of anxiety among patients older than six years old.

Off-label uses of chlordiazepoxide include treatment of catatonia, bipolar disorder, and psychotic disorder.

Chlordiazepoxide use is contraindicated in patients with known allergic or hypersensitivity to it or any of its components and patients with angle-closure glaucoma. Caution must be observed when using it concomitantly with other central nervous system (CNS) depressants or opioid drugs because strong drug interactions exist that can lead to life-threatening sequelae such as severe respiratory depression and increased sedation, which can progress to coma and death. To mitigate these complications, dose adjustments must be made when using these drugs together. In addition, chlordiazepoxide is also not recommended for use by pregnant patients especially at the first trimester, as it has been known to cause congenital anomalies.

Physicians must prescribe chlordiazepoxide judiciously to patients suffering from any respiratory disease. Moreover, chlordiazepoxide increases suicidal ideation particularly in patients with major depressive disorder. It also diminishes mental and physical abilities, so it must not be taken prior to doing a high-risk task such as driving a vehicle.

How Is Chlordiazepoxide Taken or Administered?

Chlordiazepoxide is available in 5mg, 10mg, and 25mg capsules. The following are the recommended doses of chlordiazepoxide:

Anxiety

Mild to moderate: 5 to 10mg every 6 to 8 hours
Severe: 20 to 25mg every 6 to 8 hours

Preoperative Anxiety and Apprehension

5 to 10mg every 6 to 8 hours

What Are the Immediate and Long-Term Effects of Chlordiazepoxide Use?

Chlordiazepoxide is considered the least harmful among all benzodiazepine derivatives. However, like all other medications, chlordiazepoxide may be associated with several adverse effects, including:

  • Dizziness
  • Weakness
  • Confusion
  • Fatigue
  • Forgetfulness
  • Sedation
  • Depression
  • Body incoordination
  • Slurred speech

Some of the rare side effects include:

  • Weight gain
  • Mania
  • Hallucination
  • Dry mouth
  • Increased salivation
  • Skin eruptions
  • Menstrual irregularities
  • Hypotension

Although rarely, chlordiazepoxide may also cause severe, life-threatening adverse effects, especially when taken in excessive amounts. These include:

  • Renal and hepatic impairment
  • Blood dyscrasias
  • Respiratory depression

Abrupt cessation of chlordiazepoxide use can also lead to severe withdrawal symptoms, such as:

  • Vomiting
  • Increased sweating
  • Muscle cramps
  • Tremors
  • Seizures

Signs of Chlordiazepoxide Use Disorder

Chlordiazepoxide is listed as a Schedule IV controlled substance by the Drug Enforcement Administration. As such, it is a prescription-only medication. Clinical studies have demonstrated that chlordiazepoxide is associated with a significant abuse potential and can cause addiction, particularly in patients with a history of substance abuse or those who are on chronic chlordiazepoxide therapy.
The Diagnostic and Statistical Manual of Mental Disorderds – 5th Edition (DSM-5) lists 11 Criteria for Substance Use Disorders (SUD). These pathologic behavioral patterns associated with chlordiazepoxide use disorder are further divided into four main categories:

  1. Impaired control
  2. Social impairment
  3. Risky use
  4. Pharmacological indicators (tolerance and withdrawal)

The criteria necessary for the clinical diagnosis of chlordiazepoxide use disorder are listed below:

Impaired Control

  1. Taking chlordiazepoxide in excessively large amounts or for a longer time than prescribed
  2. Not being able to reduce or stop chlordiazepoxide use despite many attempts
  3. Spending a lot of time trying to get, use or recover from chlordiazepoxide
  4. Feeling strong cravings for chlordiazepoxide

Social Impairment

  1. Chlordiazepoxide use disables one from fulfilling personal, social, and family obligations
  2. Chlordiazepoxide use gives rise to interpersonal problems
  3. Chlordiazepoxide use causes one to miss out on important social and recreational activities

Risky Use

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  1. Continued use of chlordiazepoxide in high-risk or dangerous situations such as while operating heavy machinery or motor vehicle
  2. Continued use of chlordiazepoxide despite it worsening or exacerbating existing medical conditions or causing new ones

Physical Tolerance

  1. Requiring higher doses of chlordiazepoxide in order to achieve or maintain its desired effects in the body (tolerance)
  2. Developing withdrawal symptoms after abrupt termination of chlordiazepoxide use (withdrawal)

Rehab and Treatment for Chlordiazepoxide Use Disorder

The cornerstone of treatment of chlordiazepoxide use disorder remains to be drug rehabilitation. One of the most critical factors in a successful drug rehab is prompt recognition of signs and symptoms that could indicate possible drug abuse or misuse. The DSM-5 Criteria for Substance Use Disorder is a useful tool to help determine whether or not one has developed drug addiction. Prompt diagnosis of drug addiction allows for early institution of interventions, which has historically been proven to positively impact success rates of drug rehab.

Most drug rehab programs begin with a process called detoxification. Detoxification, or detox, refers to the elimination of any drug or substance (in this case, chlordiazepoxide) that has accumulated in the body over time because of chronic misuse or abuse. The goal of detoxification is to reverse the patient’s dependence and tolerance to the drug and let the body recover from the damage caused by the buildup of toxic substances.

The general approach to detox is slow discontinuation of the drug over a certain period of time. Sudden withdrawal from chlordiazepoxide is not recommended under any circumstance because this can result in severe withdrawal symptoms, such as those mentioned above. Drug replacement therapy can also be initiated, in which chlordiazepoxide is replaced with an alternative drug that has the same anxiolytic effects but with a much lower potential for abuse.

There are also several psychosocial and behavioral interventions that can be utilized to support the detox process. The goal of these non-medical interventions is to reduce relapse episodes and promote abstinence by helping patients identify their relapse triggers and teaching them ways to overcome them successfully. Some of the most commonly used non-medical strategies in drug rehab include psychotherapy and counselling.

Because no single treatment is right for everyone, a comprehensive evaluation of the patient is necessary before beginning any drug rehab program to ensure that the strategies to be employed are tailor-fit to their needs and capacities. This includes a complete history taking, physical examination, and laboratory workups.

The treatment programs mentioned above can be administered either in an inpatient or an outpatient setting, depending on several factors such as the severity of drug dependence, the patient’s financial status, and the level of their commitment to treatment. Generally, outpatient therapy may be more suitable for patients with mild drug dependence and whose adherence to therapy can be guaranteed. On the other hand, inpatient therapy may be recommended for people experiencing severe withdrawal symptoms or those with a history of non-compliance to therapy.

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