Category: Mental Health Treatment

What is Partial Hospitalisation?

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Introduction

Partial hospitalisation, also known as PHP (partial hospitalisation programme), is a type of programme used to treat mental illness and substance abuse. In partial hospitalisation, the patient continues to reside at home, but commutes to a treatment centre up to seven days a week. Partial hospitalisation focuses on the overall treatment of the individual and is intended to avert or reduce in-patient hospitalisation.

The pioneer of partial hospital programmes, Dr. Albert E. Moll, believed that some patients would be unable to be away from their families or from work and that these programmes would reduce the cost of long-term care.

Partial hospitalisation programmes in the United States can be provided in either a hospital setting or by a free-standing community mental health centre (CMHC).

Treatment during a typical day may include group therapy, psych-educational groups, skill building, individual therapy, and psychopharmacological assessments and check-ins.

Programmes:

  • Are available for the treatment of alcoholism and substance abuse problems, Alzheimer’s disease, anorexia and bulimia, depression, bipolar disorder, anxiety disorders, schizophrenia, and other mental illnesses.
  • Geared specifically toward geriatric patients, adult patients, adolescents, or young children also exist.
  • For adolescents and children usually include an academic programme, to either take the place of or to work with the child’s local school.

Funding

Service providers in the United States are funded by private insurance as part of a designated continuum of care as well as Medicare and, for some states, Medicaid.

Currently, many providers are moving the partial hospitalisation model of day treatment toward more acute short-term services. Hospitals and community mental health organisations are using PHP’s to handle acutely ill persons who are able to better understand their illness, become adjusted to medication regimes, develop important coping skills, and set recovery goals that enable them to function effectively as recovered individuals in the society.

Most programs are required to pass comprehensive reviews from national, state, and insurance bodies. Specific guidelines for assessment, treatment, facility maintenance, performance improvement, and client outcome studies are integral to partial hospitalisation programmes. The Association of Ambulatory Behavioural Health is the premier national group providing Standards and Guidelines, recently completed in 2015.

What is an Intensive Outpatient Programme?

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Introduction

An intensive outpatient programme (IOP) is a kind of treatment service and support programme used primarily to treat eating disorders, bipolar disorder (including mania; and for Bipolar I and Bipolar II), unipolar depression, self harm and chemical dependency that does not rely on detoxification.

Refer to Partial Hospitalisation.

Background

IOP operates on a small scale and does not require the intensive residential or partial day services typically offered by the larger, more comprehensive treatment facilities.

The typical IOP programme offers group therapy and generally facilitates 6-30 hours a week of programming for addiction treatment. IOP allows the individual to be able to participate in their daily affairs, such as work, and then participate in treatment at an appropriate facility in the morning or at the end of the day. With an IOP, classes, sessions, meetings, and workshops are scheduled throughout the day, and individuals are expected to adhere to the strict structure of the program. Online IOP has shown to be effective, as well.

The typical IOP programme encourages active participation in 12-step programmes in addition to IOP participation. IOP can be more effective than individual therapy for chemical dependency.

IOP is also used by some HMOs as transitional treatment for patients just released from treatment in a psychiatric ward.

What is Habit Reversal Training?

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Introduction

Habit reversal training (HRT) is a “multicomponent behavioural treatment package originally developed to address a wide variety of repetitive behaviour disorders”.

Behavioural disorders treated with HRT include tics, trichotillomania, nail biting, thumb sucking, skin picking, temporomandibular disorder (TMJ), lip-cheek biting and stuttering. It consists of five components: awareness training, competing response training, contingency management, relaxation training, and generalisation training.

Research on the efficacy of HRT for behavioural disorders have produced consistent, large effect sizes (approximately 0.80 across the disorders). It has met the standard of a well-established treatment for stuttering, thumb sucking, nail biting, and TMJ disorders. According to a meta-analysis from 2012, decoupling, a self-help variant of HRT, also shows efficacy.

For Tic Disorders

In the case of tics, these components are intended to increase tic awareness, develop a competing response to the tic, and build treatment motivation and compliance. HRT is based on the presence of a premonitory urge, or sensation occurring before a tic. HRT involves replacing a tic with a competing response – a more comfortable or acceptable movement or sound – when a patient feels a premonitory urge building.

Controlled trials have demonstrated that HRT is an acceptable, tolerable, effective and durable treatment for tics; HRT reduces the severity of vocal tics, and results in enduring improvement of tics when compared with supportive therapy. HRT has been shown to be more effective than supportive therapy and, in some studies, medication. HRT is not yet proven or widely accepted, but large-scale trials are ongoing and should provide better information about its efficacy in treating Tourette syndrome. Studies through 2006 are:

“characterized by a number of design limitations, including relatively small sample sizes, limited characterization of study participants, limited data on children and adolescents, lack of attention to the assessment of treatment integrity and adherence, and limited attention to the identification of potential clinical and neurocognitive mechanisms and predictors of treatment response”. (Piacentini & Chang, 2006, p.227).

Additional controlled studies of HRT are needed to address whether HRT, medication, or a combination of both is most effective, but in the interim, “HRT either alone or in combination with medication should be considered as a viable treatment” for tic disorders.

Comprehensive Behavioural Intervention for Tics

Comprehensive Behavioural Intervention for Tics (CBIT), based on HRT, is a first-line treatment for Tourette syndrome and tic disorders. With a high level of confidence, CBIT has been shown to be more likely to lead to a reduction in tics than other supportive therapies or psychoeducation. Some limitations are: children younger than ten may not understand the treatment, people with severe tics or ADHD may not be able to suppress their tics or sustain the required focus to benefit from behavioural treatments, there is a lack of therapists trained in behavioural interventions, finding practitioners outside of specialty clinics can be difficult, and costs may limit accessibility. Whether increased awareness of tics through HRT/CBIT (as opposed to moving attention away from them) leads to further increases in tics later in life is a subject of discussion among TS experts.

Reference

Piacentini, J.C. & Chang, S.W. (2006) Behavioral Treatments for Tic Suppression: Habit Reversal Training. Advances in Neurology. 99, pp.227-233.

What is Flualprazolam?

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Introduction

Flualprazolam is a tranquiliser of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

Background

It was first synthesised in 1976, but was never marketed. It has subsequently been sold as a designer drug, first being definitively identified as such in Sweden in 2018. It can be described as the 2′-fluoro derivative of alprazolam, or the fluoro instead of chloro analogue of triazolam, and has similar sedative and anxiolytic effects.

Flualprazolam is banned in Sweden, also is illegal in the UK. In December 2019, the World Health Organisation recommended flualprazolam for international scheduling as a Schedule IV medication under the Convention on Psychotropic Substances.

What is Clonazolam?

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Introduction

Clonazolam (also known as clonitrazolam) is a drug of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

It has had very little research done about its effects and metabolism, and has been sold online as a designer drug. The synthesis of clonazolam was first reported in 1971 and the drug was described as the most active compound in the series tested.

Clonazolam is reported to be highly potent and concerns have been raised that it and flubromazolam in particular may pose comparatively higher risk than other designer benzodiazepines due to their ability to produce strong sedation and amnesia at as little as 0.5 mg.

Legality

United Kingdom

In the UK, clonazolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.

United States

It is an unscheduled medicine and not FDA approved. Virginia State Law has declared all of the following medications are now schedule I: clonazolam, etizolam, flualprazolam, flubromazolam, and flubromazepam. Minnesota declared clonazolam a Schedule I drug in August 2020.

Australia

In Australia, clonazolam is classified as a controlled substance in some states.

Sweden

Sweden’s public health agency suggested classifying clonazolam as a hazardous substance on 01 June 2015.

Effects

Clonazolam’s effects are similar to other benzodiazepines, such as anxiolysis, disinhibition, lethargy, muscle relaxation, and euphoria. While no dose of clonazolam is considered “safe” due to its lack of research and extreme potency, doses higher than 0.5 mg can cause benzodiazepine overdose in some individuals. The effects of a benzodiazepine overdose include sedation, confusion, insufficient breathing, loss of consciousness, and death. Because dependence can occur in a short period of time, or even with a large initial dose, withdrawal symptoms (including seizures and death) may occur acutely following the period of intoxication.

What is Flubromazolam?

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Introduction

Flubromazolam (JYI-73) is a triazolobenzodiazepine (TBZD), which are benzodiazepine (BZD) derivatives.

Flubromazolam is reputed to be highly potent, and concerns have been raised that clonazolam and flubromazolam in particular may pose comparatively higher risks than other designer benzodiazepines, due to their ability to produce strong sedation and amnesia at oral doses of as little as 0.5 mg. Life-threatening adverse reactions have been observed at doses of only 3 mg of flubromazolam.

Sweden

Flubromazolam has been classified as an illegal substance in Sweden after seizures by customs and police, as well as indications from the EMCDDA of wider use as a recreational drug.

Switzerland

Flubromazolam is illegal in Switzerland as of December 2015.

United Kingdom

In the UK, flubromazolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.

What is Eszopiclone?

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Introduction

Eszopiclone, sold under the brand-name Lunesta among others, is a medication used in the treatment of insomnia.

Evidence supports slight to moderate benefit up to six months. It is taken orally. Common side effects include headache, dry mouth, nausea, and dizziness. Severe side effects may include suicidal thoughts, unhealthy non-medical use, hallucinations, and angioedema. Greater care is recommended in those with liver problems and older people. Rapid decreasing of the dose may result in withdrawal. Eszopiclone is classified as a nonbenzodiazepine sedative hypnotic and as a cyclopyrrolone. It is the S-stereoisomer of zopiclone. It works by interacting with the GABA receptors.

Approved for medical use in the United States in 2004, eszopiclone is available as generic medication. In 2017, it was the 214th most commonly prescribed medication in the United States, with more than two million prescriptions. Eszopiclone is not sold in the European Union, as in 2009 the EMA ruled that it was too similar to zopiclone to be considered a new patentable product.

Brief History

In a controversial 2009 article in the New England Journal of Medicine, “Lost in Transmission — FDA Drug Information That Never Reaches Clinicians”, it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta “was superior to placebo” while it only shortened initial time falling asleep by 15 minutes on average. “Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning.”

Availability in Europe

On 11 September 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell eszopiclone (under the name Lunivia rather than Lunesta) in Europe. Sepracor was expected to receive approximately $155 million if the deal went through. In 2008 Sepracor submitted an application to the EMA (the European Union’s equivalent to the US FDA) for authorisation to market the drug in the EU, and initially received a favourable response. However, Sepracor withdrew its authorization application in 2009 after the EMA stated it would not be granting eszopiclone ‘new active substance’ status, as it was essentially pharmacologically and therapeutically too similar to zopiclone to be considered a new patentable product. Since the patent on zopiclone has expired, this ruling would have allowed rival companies to also legally produce cheaper generic versions of eszopiclone for the European market. As of November 2012, Sepracor has not resubmitted its authorisation application and eszopiclone is not available in Europe. The deal with GSK fell through, and GSK instead launched a $3.3 billion deal to market Actelion’s almorexant sleeping tablet, which entered phase 3 medical trials before development was abandoned due to side effects.

Medical Uses

A 2018 Cochrane review found that it produced moderate improvement in sleep onset and maintenance. The authors suggest that where preferred non-pharmacological treatment strategies have been exhausted, eszopiclone provides an efficient treatment for insomnia. In 2014, the USFDA asked that the starting dose be lowered from 2 milligrams to 1 milligram after it was observed in a study that even 8 hours after taking the drug at night, some people were not able to cope with their next-day activities like driving and other activities that require full alertness.

Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response. It is not recommended for chronic use in the elderly.

Elderly

Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.

In 2015, the American Geriatrics Society reviewed the safety information about eszopiclone and similar drugs and concluded that the “nonbenzodiazepine, benzodiazepine receptor agonist hypnotics (eszopiclone, zaleplon, zolpidem) are to be avoided without consideration of duration of use because of their association with harms balanced with their minimal efficacy in treating insomnia.”

The review made this determination both because of the relatively large dangers to elderly individuals from zolpidem and other “z-drugs” together with the fact the drugs have “minimal efficacy in treating insomnia.” This was a change from the 2012 AGS recommendation, which suggested limiting use to 90 days or less. The review stated: “the 90‐day‐use caveat [was] removed from nonbenzodiazepine, benzodiazepine receptor agonist hypnotics, resulting in an unambiguous ‘avoid’ statement (without caveats) because of the increase in the evidence of harm in this area since the 2012 update.”

An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

A 2009 meta-analysis found a higher rate of infections.

Adverse Effects

Sleeping pills, including eszopiclone, have been associated with an increased risk of death.

Hypersensitivity to eszopiclone is a contra-indication to its use. Some side effects are more common than others. Recommendations around use of eszopiclone may be altered by other health conditions. These conditions or circumstances may occur in people that have lowered metabolism and other conditions. The presence of liver impairment, lactation and activities requiring mental alertness (e.g. driving) may be considered when determining frequency and dosage.

  • Unpleasant taste.
  • Headache.
  • Peripheral oedema.
  • Chest pain.
  • Abnormal thinking.
  • Behaviour changes.
  • Depression.
  • Hallucinations.
  • Sleep driving and sleepwalking.
  • Dry mouth.
  • Rash.
  • Altered sleep patterns.
  • Impaired coordination.
  • Dizziness.
  • Daytime drowsiness.
  • Itching.
  • Painful or frequent urination.
  • Back pain.
  • Aggressive behaviour.
  • Confusion.
  • Agitation.
  • Suicidal thoughts.
  • Depersonalisation.
  • Amnesia.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking eszopiclone or other hypnotic drugs compared to those taking a placebo.

Dependence

In the United States eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of eszopiclone may lead to physical and psychological dependence. The risk of non-medical use and dependence increases with the dose and duration of usage and concomitant use of other psychoactive substances. The risk is also greater in patients with a history of alcohol use disorder or other substance use disorder or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks.

A study funded and carried out by Sepracor, the manufacturer of eszopiclone, found no signs of tolerance or dependence in a group of patients followed for up to six months.

Non-Medical Use

A study of non-medical use potential of eszopiclone found that in persons with a known history of non-medical benzodiazepine use, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia, sedation, sleepiness, and hallucinations was observed for both eszopiclone (Lunesta) as well as for diazepam (Valium).

Overdose

According to the US Prescribing Information, overdoses of eszopiclone up to 90 times the recommended dose have been reported in which the patient fully recovered. According to the May 2014 edition of the official US Prescribing Information, fatalities have been reported only in cases in which eszopiclone was combined with other drugs or alcohol.

Poison control centres reported that between 2005 and 2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts.

If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage.

Interactions

There is an increased risk of central nervous system depression when eszopiclone is taken together with other CNS depressant agents, including antipsychotics, sedative hypnotics (like barbiturates or benzodiazepines), antihistamines, opioids, phenothiazines, and some antidepressants. There is also increased risk of central nervous system depression with other medications that inhibit the metabolic activities of the CYP3A4 enzyme system of the liver. Medications that inhibit this enzyme system include nelfinavir, ritonavir, ketoconazole, itraconazole and clarithromycin. Alcohol also has an additive effect when used concurrently with eszopiclone. Eszopiclone is most effective if it is not taken after a heavy meal with high fat content.

Pharmacology

Eszopiclone acts on benzodiazepine binding site situated on GABAA neurons as a positive allosteric modulator. Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between .45 and 1.3 hours. The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.

What is Estazolam?

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Introduction

Estazolam, sold under the brand name Prosom among others, is a tranquiliser medication of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring.

It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine. It is used for short-term treatment of insomnia.

It was patented in 1968 and came into medical use in 1975.

Medical Uses

Estazolam is prescribed for the short-term treatment of certain sleep disorders. It is an effective hypnotic drug showing efficacy in increasing the time spent asleep as well as reducing awakenings during the night. Combination with non-pharmacological options for sleep management results in long-term improvements in sleep quality after discontinuation of short-term estazolam therapy. Estazolam is also sometimes used as a preoperative sleep aid. It was found to be superior to triazolam in side effect profile in preoperative patients in a trial. Estazolam also has anxiolytic properties and due to its long half life can be an effective short-term treatment for insomnia associated with anxiety.

Side Effects

A hang-over effect commonly occurs with next day impairments of mental and physical performance. Other side effects of estazolam include somnolence, dizziness, hypokinesia, and abnormal coordination.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance and Dependence

The main safety concern of benzodiazepines such as estazolam is a benzodiazepine dependence and the subsequent benzodiazepine withdrawal syndrome which can occur upon discontinuation of the estazolam. A review of the literature found that long-term use of benzodiazepines such as estazolam is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. Estazolam should only be used short term and at the lowest effective dose to avoid complications related to long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality. The short-term benefits of benzodiazepines on sleep begin to reduce after a few days due to tolerance to the hypnotic effects of benzodiazepines in the elderly.

Contraindications and Special Caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Elderly

An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including estazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Pharmacology

Estazolam is classed as a “triazolo” benzodiazepine drug. Estazolam exerts its therapeutic effects via its benzodiazepines receptor agonist properties. Estazolam at high doses decreases histamine turnover via its action at the benzodiazepine-GABA receptor complex in mouse brains.

Pharmacokinetics

Peak plasma levels are achieved within 1-6 hours. Estazolam is an intermediate acting benzodiazepine. The elimination half life of estazolam is an average of 19 hours, with a range of 8-31 hours. The major metabolite of estazolam is 4-hydroxyestazolam. Other identified metabolites include 1-oxo-estazolam, 4′-hydroxy-estazolam, and benzophenone.

Interactions

Alcohol enhances the sedative hypnotic properties of estazolam. In package inserts, the manufacturer clearly warns about an interaction with Ritonavir, and although clinical interactions of Ritonavir with estazolam have not yet been described, the lack of clinical descriptions of the interactions does not negate the seriousness of the interaction.

EEG Effects in Rabbits

An animal study in rabbits demonstrated that estazolam induces a drowsy pattern of spontaneous EEG including high voltage slow waves and spindle bursts increase in the cortex and amygdala, while the hippocampal theta rhythm is desynchronised. Also low voltage fast waves occur particularly in the cortical EEG. The EEG arousal response to auditory stimulation and to electric stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus is significantly suppressed. The photic driving response elicited by a flash light in the visual cortex is significantly suppressed by estazolam.

Abuse

Refer to Benzodiazepine Use Disorder.

A primate study found that estazolam has abuse potential. Estazolam is a drug with the potential for misuse. Two types of drug misuse can occur; recreational misuse, where the drug is taken to achieve a high or when the drug is continued long term against medical advice. Estazolam became notorious in 1998 when a large amount of an ‘herbal sleeping mix’ called Sleeping Buddha was recalled from the shelves after the FDA discovered that it contained estazolam. In 2007, a Canadian product called Sleepees was recalled after it was found to contain undeclared estazolam.

What is Chlordiazepoxide?

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Introduction

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.

Chlordiazepoxide has a medium to long half-life but its active metabolite has a very long half-life. The drug has amnesic, anticonvulsant, anxiolytic, hypnotic, sedative and skeletal muscle relaxant properties.

Chlordiazepoxide was patented in 1958 and approved for medical use in 1960. It was the first benzodiazepine to be synthesized and the discovery of chlordiazepoxide was by pure chance. Chlordiazepoxide and other benzodiazepines were initially accepted with widespread public approval but were followed with widespread public disapproval and recommendations for more restrictive medical guidelines for its use.

Brief History

Chlordiazepoxide (initially called methaminodiazepoxide) was the first benzodiazepine to be synthesized in the mid-1950s. The synthesis was derived from work on a class of dyes, quinazolone-3-oxides. It was discovered by accident when in 1957 tests revealed that the compound had hypnotic, anxiolytic, and muscle relaxant effects. “The story of the chemical development of Librium and Valium was told by Sternbach. The serendipity involved in the invention of this class of compounds was matched by the trials and errors of the pharmacologists in the discovery of the tranquilising activity of the benzodiazepines. The discovery of Librium in 1957 was due largely to the dedicated work and observational ability of a gifted technician, Beryl Kappell. For some seven years she had been screening compounds by simple animal tests for muscle relaxant activity…” Three years later chlordiazepoxide was marketed as a therapeutic benzodiazepine medication under the brand name Librium. Following chlordiazepoxide, in 1963 diazepam hit the market under the brand name Valium – and was followed by many further benzodiazepine compounds over the subsequent years and decades.

In 1959 it was used by over 2,000 physicians and more than 20,000 patients. It was described as “chemically and clinically different from any of the tranquilisers, psychic energizers or other psychotherapeutic drugs now available.” During studies, chlordiazepoxide induced muscle relaxation and a quieting effect on laboratory animals like mice, rats, cats, and dogs. Fear and aggression were eliminated in much smaller doses than those necessary to produce hypnosis. Chlordiazepoxide is similar to phenobarbital in its anticonvulsant properties. However, it lacks the hypnotic effects of barbiturates. Animal tests were conducted in the Boston Zoo and the San Diego Zoo. Forty-two hospital patients admitted for acute and chronic alcoholism, and various psychoses and neuroses were treated with chlordiazepoxide. In a majority of the patients, anxiety, tension, and motor excitement were “effectively reduced.” The most positive results were observed among alcoholic patients. It was reported that ulcers and dermatologic problems, both of which involved emotional factors, were reduced by chlordiazepoxide.

In 1963, approval for use was given to diazepam (Valium), a “simplified” version of chlordiazepoxide, primarily to counteract anxiety symptoms. Sleep-related problems were treated with nitrazepam (Mogadon), which was introduced in 1972, temazepam (Restoril), which was introduced in 1979, and flurazepam (Dalmane), which was introduced in 1975.

Medical Uses

Chlordiazepoxide is 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.

It can sometimes be prescribed to ease symptoms of irritable bowel syndrome combined with clidinium bromide as a fixed dose medication, Librax.

Contraindications

Use of chlordiazepoxide should be avoided in individuals with the following conditions:

  • Myasthenia gravis.
  • Acute intoxication with alcohol, narcotics, or other psychoactive substances.
  • Ataxia.
  • Severe hypoventilation.
  • Acute narrow-angle glaucoma.
  • Severe liver deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of 2).
  • Severe sleep apnoea.
  • Hypersensitivity or allergy to any drug in the benzodiazepine class.

Chlordiazepoxide is generally considered an inappropriate benzodiazepine for the elderly due to its long elimination half-life and the risks of accumulation. Benzodiazepines require special precaution if used in the elderly, pregnancy, children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Pregnancy

The research into the safety of benzodiazepines during pregnancy is limited and it is recommended that use of benzodiazepines during pregnancy should be based on whether the benefits outweigh the risks. If chlordiazepoxide is used during pregnancy the risks can be reduced via using the lowest effective dose and for the shortest time possible. Benzodiazepines should generally be avoided during the first trimester of pregnancy. Chlordiazepoxide and diazepam are considered to be among the safer benzodiazepines to use during pregnancy in comparison to other benzodiazepines. Possible adverse effects from benzodiazepine use during pregnancy include, abortion, malformation, intrauterine growth retardation, functional deficits, carcinogenesis and mutagenesis. Caution is also advised during breast feeding as chlordiazepoxide passes into breast milk.

Adverse Effects

Sedative drugs and sleeping pills, including chlordiazepoxide, have been associated with an increased risk of death. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications. Common side-effects of chlordiazepoxide include:

  • Confusion.
  • Constipation.
  • Drowsiness.
  • Fainting.
  • Altered sex drive.
  • Liver problems.
  • Lack of muscle coordination.
  • Minor menstrual irregularities.
  • Nausea.
  • Skin rash or eruptions.
  • Swelling due to fluid retention.
  • Yellow eyes and skin.

Chlordiazepoxide in laboratory mice studies impairs latent learning. Benzodiazepines impair learning and memory via their action on benzodiazepine receptors, which causes a dysfunction in the cholinergic neuronal system in mice. It was later found that scopolamine impairment in learning was caused by an increase in benzodiazepine/GABA activity (and that benzodiazepines were not associated with the cholinergic system). In tests of various benzodiazepine compounds, chlordiazepoxide was found to cause the most profound reduction in the turnover of 5HT (serotonin) in rats. Serotonin is closely involved in regulating mood and may be one of the causes of feelings of depression in rats using chlordiazepoxide or other benzodiazepines.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Tolerance

Chronic use of benzodiazepines, such as chlordiazepoxide, leads to the development of tolerance, with a decrease in number of benzodiazepine binding sites in mouse forebrain. The Committee of Review of Medicines, who carried out an extensive review of benzodiazepines including chlordiazepoxide, found – and were in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the US National Institute on Drug Abuse – that there was little evidence that long-term use of benzodiazepines were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3-14 days of continuous use, and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months’ continuous use due to the development of tolerance.

Dependence

Chlordiazepoxide can cause physical dependence and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from chlordiazepoxide or other benzodiazepines often leads to withdrawal symptoms that are similar to those seen with alcohol and barbiturates. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can, however, occur at standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible through a slow and gradual dose-reduction regime.

Chlordiazepoxide taken during pregnancy can cause a postnatal benzodiazepine withdrawal syndrome.

Overdose

Refer to Benzodiazepine Overdose.

An individual who has consumed excess chlordiazepoxide may display some of the following symptoms:

  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Hypotension.
  • Hypoventilation.
  • Impaired motor functions:
    • Impaired reflexes.
    • Impaired coordination.
    • Impaired balance.
    • Dizziness.
    • Muscle weakness.
  • Coma.

Chlordiazepoxide is a drug that is very frequently involved in drug intoxication, including overdose. Chlordiazepoxide overdose is considered a medical emergency and, in general, requires the immediate attention of medical personnel. The antidote for an overdose of chlordiazepoxide (or any other benzodiazepine) is flumazenil. Flumazenil should be given with caution as it may precipitate severe withdrawal symptoms in benzodiazepine-dependent individuals.

Pharmacology

Chlordiazepoxide acts on benzodiazepine allosteric sites that are part of the GABAA receptor/ion-channel complex and this results in an increased binding of the inhibitory neurotransmitter GABA to the GABAA receptor thereby producing inhibitory effects on the central nervous system and body similar to the effects of other benzodiazepines. Chlordiazepoxide is anticonvulsant. There is preferential storage of chlordiazepoxide in some organs including the heart of the neonate. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate. The withdrawal of chlordiazepoxide during pregnancy and breast feeding is recommended, as chlordiazepoxide rapidly crosses the placenta and also is excreted in breast milk. Chlordiazepoxide also decreases prolactin release in rats. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in animal nerve terminal preparations. Chlordiazepoxide inhibits acetylcholine release in mouse hippocampal synaptosomes in vivo. This has been found by measuring sodium-dependent high affinity choline uptake in vitro after pre-treatment of the mice in vivo with chlordiazepoxide. This may play a role in chlordiazepoxide’s anticonvulsant properties.

Pharmacokinetics

Chlordiazepoxide is a long-acting benzodiazepine drug. The half-life of Chlordiazepoxide is 5-30 hours but has an active benzodiazepine metabolite (desmethyldiazepam), which has a half-life of 36-200 hours. The half-life of chlordiazepoxide increases significantly in the elderly, which may result in prolonged action as well as accumulation of the drug during repeated administration. Delayed body clearance of the long half-life active metabolite also occurs in those over 60 years of age, which further prolongs the effects of the drugs with additional accumulation after repeated dosing.

Despite its name, chlordiazepoxide is not an epoxide; they are formed from different roots.

Recreational Use

Refer to Benzodiazepine Use Disorder.

In 1963, Carl F. Essig of the Addiction Research Centre of the National Institute of Mental Health stated that meprobamate, glutethimide, ethinamate, ethchlorvynol, methyprylon and chlordiazepoxide as drugs whose usefulness “can hardly be questioned.” However, Essig labelled these “newer products” as “drugs of addiction,” like barbiturates, whose habit-forming qualities were more widely known. He mentioned a 90-day study of chlordiazepoxide, which concluded that the automobile accident rate among 68 users was 10 times higher than normal. Participants’ daily dosage ranged from 5 to 100 milligrams.

Chlordiazepoxide is a drug of potential misuse and is frequently detected in urine samples of drug users who have not been prescribed the drug.

Internationally, chlordiazepoxide is a Schedule IV controlled drug under the Convention on Psychotropic Substances.

Toxicity

Animal

Laboratory tests assessing the toxicity of chlordiazepoxide, nitrazepam and diazepam on mice spermatozoa found that chlordiazepoxide produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam, however, caused more profound abnormalities than chlordiazepoxide.

Availability

Chlordiazepoxide is available in various dosage forms, alone or in combination with other drugs, worldwide. In combination with Clidinium as NORMAXIN-CC and in combination with dicyclomine as NORMAXIN for IBS, and with the anti-depressant Amitriptyline as Limbitrol.