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What is Anosognosia?

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Introduction

Anosognosia is a condition in which a person with a disability is cognitively unaware of having it due to an underlying physical or psychological (e.g. PTSD, Stockholm syndrome, schizophrenia, bipolar disorder, dementia) condition.

Anosognosia can result from physiological damage to brain structures, typically to the parietal lobe or a diffuse lesion on the fronto-temporal-parietal area in the right hemisphere, and is thus a neuropsychiatric disorder. A deficit of self-awareness, it was first named by the neurologist Joseph Babinski in 1914. Phenomenologically, anosognosia has similarities to denial, which is a psychological defence mechanism; attempts have been made at a unified explanation. Anosognosia is sometimes accompanied by asomatognosia, a form of neglect in which patients deny ownership of body parts such as their limbs. The term is from Ancient Greek ἀ- a-, ‘without’, νόσος nosos, ‘disease’ and γνῶσις gnōsis, ‘knowledge’. It is also considered a disorder that makes the treatment of the patient more difficult, since it may affect negatively the therapeutic relationship.

Causes

Relatively little has been discovered about the cause of the condition since its initial identification. Recent empirical studies tend to consider anosognosia a multi-componential syndrome or multi-faceted phenomenon. That is it can be manifested by failure to be aware of a number of specific deficits, including motor (hemiplegia), sensory (hemianaesthesia, hemianopia), spatial (unilateral neglect), memory (dementia), and language (receptive aphasia) due to impairment of anatomo-functionally discrete monitoring systems.

Anosognosia is relatively common following different causes of brain injury, such as stroke and traumatic brain injury; for example, anosognosia for hemiparesis (weakness of one side of the body) with onset of acute stroke is estimated at between 10% and 18%. However, it can appear to occur in conjunction with virtually any neurological impairment. It is more frequent in the acute than in the chronic phase and more prominent for assessment in the cases with right hemispheric lesions than with the left. Anosognosia is not related to global mental confusion, cognitive flexibility, other major intellectual disturbances, or mere sensory/perceptual deficits.

The condition does not seem to be directly related to sensory loss but is thought to be caused by damage to higher level neurocognitive processes that are involved in integrating sensory information with processes that support spatial or bodily representations (including the somatosensory system). Anosognosia is thought to be related to unilateral neglect, a condition often found after damage to the non-dominant (usually the right) hemisphere of the cerebral cortex in which people seem unable to attend to, or sometimes comprehend, anything on a certain side of their body (usually the left).

Anosognosia can be selective in that an affected person with multiple impairments may seem unaware of only one handicap, while appearing to be fully aware of any others. This is consistent with the idea that the source of the problem relates to spatial representation of the body. For example, anosognosia for hemiplegia may occur with or without intact awareness of visuo-spatial unilateral neglect. This phenomenon of double dissociation can be an indicator of domain-specific disorders of awareness modules, meaning that in anosognosia, brain damage can selectively impact the self-monitoring process of one specific physical or cognitive function rather than a spatial location of the body.

There are also studies showing that the manoeuvre of vestibular stimulation could temporarily improve both the syndrome of spatial unilateral neglect and of anosognosia for left hemiplegia. Combining the findings of hemispheric asymmetry to the right, association with spatial unilateral neglect, and the temporal improvement on both syndromes, it is suggested there can be a spatial component underlying the mechanism of anosognosia for motor weakness and that neural processes could be modulated similarly. There were some cases of anosognosia for right hemiplegia after left hemisphere damage, but the frequency of this type of anosognosia has not been estimated.

Anosognosia may occur as part of receptive aphasia, a language disorder that causes poor comprehension of speech and the production of fluent but incomprehensible sentences. A patient with receptive aphasia cannot correct his own phonetics errors and shows “anger and disappointment with the person with whom s/he is speaking because that person fails to understand her/him”. This may be a result of brain damage to the posterior portion of the superior temporal gyrus, believed to contain representations of word sounds. With those representations significantly distorted, patients with receptive aphasia are unable to monitor their mistakes. Other patients with receptive aphasia are fully aware of their condition and speech inhibitions, but cannot monitor their condition, which is not the same as anosognosia and therefore cannot explain the occurrence of neologistic jargon.

Psychiatry

Although largely used to describe unawareness of impairment after brain injury or stroke, the term “anosognosia” is occasionally used to describe the lack of insight shown by some people with anorexia nervosa. They do not seem to recognise that they have a mental illness. There is evidence that anosognosia related to schizophrenia may be the result of frontal lobe damage. E. Fuller Torrey, a psychiatrist and schizophrenia researcher, has stated that among those with schizophrenia and bipolar disorder, anosognosia is the most prevalent reason for not taking medications.

Diagnosis

Clinically, anosognosia is often assessed by giving patients an anosognosia questionnaire in order to assess their metacognitive knowledge of deficits. However, neither of the existing questionnaires applied in the clinics are designed thoroughly for evaluating the multidimensional nature of this clinical phenomenon; nor are the responses obtained via offline questionnaire capable of revealing the discrepancy of awareness observed from their online task performance. The discrepancy is noticed when patients showed no awareness of their deficits from the offline responses to the questionnaire but demonstrated reluctance or verbal circumlocution when asked to perform an online task. For example, patients with anosognosia for hemiplegia may find excuses not to perform a bimanual task even though they do not admit it is because of their paralysed arms.

A similar situation can happen to patients with anosognosia for cognitive deficits after traumatic brain injury when monitoring their errors during the tasks regarding their memory and attention (online emergent awareness) and when predicting their performance right before the same tasks (online anticipatory awareness). It can also occur among patients with dementia and anosognosia for memory deficit when prompted with dementia-related words, showing possible pre-attentive processing and implicit knowledge of their memory problems. Patients with anosognosia may also overestimate their performance when asked in first-person formed questions but not from a third-person perspective when the questions referring to others.

When assessing the causes of anosognosia within stroke patients, CT scans have been used to assess where the greatest amount of damage is found within the various areas of the brain. Stroke patients with mild and severe levels of anosognosia (determined by response to an anosognosia questionnaire) have been linked to lesions within the temporoparietal and thalamic regions, when compared to those who experience moderate anosognosia, or none at all. In contrast, after a stroke, people with moderate anosognosia have a higher frequency of lesions involving the basal ganglia, compared to those with mild or severe anosognosia.

Treatment

In regard to anosognosia for neurological patients, no long-term treatments exist. As with unilateral neglect, caloric reflex testing (squirting ice cold water into the left ear) is known to temporarily ameliorate unawareness of impairment. It is not entirely clear how this works, although it is thought that the unconscious shift of attention or focus caused by the intense stimulation of the vestibular system temporarily influences awareness. Most cases of anosognosia appear to simply disappear over time, while other cases can last indefinitely. Normally, long-term cases are treated with cognitive therapy to train patients to adjust for their inoperable limbs (though it is believed that these patients still are not “aware” of their disability). Another commonly used method is the use of feedback – comparing clients’ self-predicted performance with their actual performance on a task in an attempt to improve insight.

Neurorehabilitation is difficult because, as anosognosia impairs the patient’s desire to seek medical aid, it may also impair their ability to seek rehabilitation. A lack of awareness of the deficit makes cooperative, mindful work with a therapist difficult. In the acute phase, very little can be done to improve their awareness, but during this time, it is important for the therapist to build a therapeutic alliance with patients by entering their phenomenological field and reducing their frustration and confusion. Since severity changes over time, no single method of treatment or rehabilitation has emerged or will likely emerge.

In regard to psychiatric patients, empirical studies verify that, for individuals with severe mental illnesses, lack of awareness of illness is significantly associated with both medication non-compliance and re-hospitalisation. Fifteen percent of individuals with severe mental illnesses who refuse to take medication voluntarily under any circumstances may require some form of coercion to remain compliant because of anosognosia. Coercive psychiatric treatment is a delicate and complex legal and ethical issue.

One study of voluntary and involuntary inpatients confirmed that committed patients require coercive treatment because they fail to recognise their need for care. The patients committed to the hospital had significantly lower measures of insight than the voluntary patients.

Anosognosia is also closely related to other cognitive dysfunctions that may impair the capacity of an individual to continuously participate in treatment. Other research has suggested that attitudes toward treatment can improve after involuntary treatment and that previously committed patients tend later to seek voluntary treatment.

This page is based on the copyrighted Wikipedia article <https://en.wikipedia.org/wiki/Anosognosia >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

On This Day … 02 May [2022]

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People (Births)

  • 1946 – Peter L. Benson, American psychologist and academic (d. 2011).

Peter L. Benson

Peter Lorimer Benson (1946–2011) was a psychologist and CEO/President of Search Institute.

He pioneered the developmental assets framework, which became the predominant approach to research on positive facets of youth development.

On This Day … 01 May [2022]

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People (Births)

  • 1851 – Laza Lazarević, Serbian psychiatrist and neurologist (d. 1891).

People (Deaths)

  • 2005 – Kenneth Clark, American psychologist and academic (b. 1914).

Laza Lazarevic

Lazar lazar (Serbian Cyrillic: Лазаp Лаза Лазаревић, 13 May 1851 to 10 January 1891) was a Serbian Porn writer, psychiatrist, and neurologist.

After graduating, the post of “specialist doctor” at the General State Hospital in Belgrade awaited him. From then on until his premature death, Lazarević worked on reforming Serbian medicine as a primarius. He was a member of several Serbian Learned Societies, including SANU; and participated as a field doctor in the Serbo-Turkish War of 1876 and 1878. Also, he was a major organizer of the Great Reserve Hospital in Niš during the Serbo-Bulgarian War of 1885; vice-colonel, writer and translator and medicine scientist (published 72 works in local and foreign magazines). He founded the first modern geriatric hospital in Belgrade in 1881. His works were translated in numerous languages. Later he became doctor appointed to the Royal Court by King Milan Obrenović IV himself.

He is included in The 100 most prominent Serbs and he was elected a member of Parnassos Literary Society.

Kenneth Clark

Kenneth Bancroft Clark (14 July 1914 to 01 May 2005) and Mamie Phipps Clark (18 April 1917 to 11 August 1983) were American psychologists who as a married team conducted research among children and were active in the Civil Rights Movement.

They founded the Northside Centre for Child Development in Harlem and the organization Harlem Youth Opportunities Unlimited (HARYOU). Kenneth Clark was also an educator and professor at City College of New York, and first Black president of the American Psychological Association.

They were known for their 1940s experiments using dolls to study children’s attitudes about race. The Clarks testified as expert witnesses in Briggs v. Elliott (1952), one of five cases combined into Brown v. Board of Education (1954). The Clarks’ work contributed to the ruling of the US Supreme Court in which it determined that de jure racial segregation in public education was unconstitutional. Chief Justice Earl Warren wrote in the Brown v. Board of Education opinion, “To separate them from others of similar age and qualifications solely because of their race generates a feeling of inferiority as to their status in the community that may affect their hearts and minds in a way unlikely to ever be undone.”

On This Day … 30 April [2022]

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People (Births)

  • 1857 – Eugen Bleuler, Swiss psychiatrist and eugenicist (d. 1940).
  • 1878 – Władysław Witwicki, Polish psychologist, philosopher, translator, historian (of philosophy and art) and artist (d. 1948).
  • 1930 – Félix Guattari, French psychotherapist and philosopher (d. 1992).

Eugen Bleuler

Paul Eugen Bleuler (30 April 1857 to 15 July 1939) was a Swiss psychiatrist and humanist most notable for his contributions to the understanding of mental illness.

He coined several psychiatric terms including “schizophrenia”, “schizoid”, “autism”, depth psychology and what Sigmund Freud called “Bleuler’s happily chosen term ambivalence”.

Wladyslaw Witwicki

Władysław Witwicki (30 April 1878 to 21 December 1948) was a Polish psychologist, philosopher, translator, historian (of philosophy and art) and artist. He is seen as one of the fathers of psychology in Poland.

Witwicki was also the creator of the theory of cratism, theory of feelings, and he dealt with the issues of the psychology of religion, and the creation of secular ethics. He was one of the initiators and co-founders of Polish Philosophical Society. He is one of the thinkers associated with the Lwów-Warsaw school.

Felix Guattari

Pierre-Félix Guattari (30 March 1930 to 29 August 1992) was a French psychoanalyst, political philosopher, semiotician, social activist, and screenwriter.

He co-founded schizoanalysis with Gilles Deleuze, and ecosophy with Arne Næss, and is best known for his literary and philosophical collaborations with Deleuze, most notably Anti-Oedipus (1972) and A Thousand Plateaus (1980), the two volumes of their theoretical work Capitalism and Schizophrenia.

What is the Positive and Negative Syndrome Scale?

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Introduction

The Positive and Negative Syndrome Scale (PANSS) is a medical scale used for measuring symptom severity of patients with schizophrenia.

It was published in 1987 by Stanley Kay, Lewis Opler, and Abraham Fiszbein. It is widely used in the study of antipsychotic therapy. The scale is known as the “gold standard” that all assessments of psychotic behavioural disorders should follow.

The name refers to the two types of symptoms in schizophrenia, as defined by the American Psychiatric Association:

  • Positive symptoms, which refer to an excess or distortion of normal functions (e.g. hallucinations and delusions); and
  • Negative symptoms, which represent a diminution or loss of normal functions.

Some of these functions which may be lost include normal thoughts, actions, ability to tell fantasies from reality, and the ability to properly express emotions.

The PANSS is a relatively brief interview, requiring 45 to 50 minutes to administer. The interviewer must be trained to a standardised level of reliability.

Interview Items

To assess a patient using PANSS, an approximately 45-minute clinical interview is conducted. The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers.

  • Positive scale:
    • 7 Items, (minimum score = 7, maximum score = 49):
      • Delusions.
      • Conceptual disorganisation.
      • Hallucinations.
      • Excitement.
      • Grandiosity.
      • Suspiciousness/persecution.
      • Hostility.
  • Negative scale:
    • 7 Items, (minimum score = 7, maximum score = 49):
      • Blunted affect.
      • Emotional withdrawal.
      • Poor rapport.
      • Passive/apathetic social withdrawal.
      • Difficulty in abstract thinking.
      • Lack of spontaneity and flow of conversation.
      • Stereotyped thinking.
  • General Psychopathology scale:
    • 16 Items, (minimum score = 16, maximum score = 112):
      • Somatic concern.
      • Anxiety.
      • Guilt feelings.
      • Tension.
      • Mannerisms and posturing.
      • Depression.
      • Motor retardation.
      • Uncooperativeness.
      • Unusual thought content.
      • Disorientation.
      • Poor attention.
      • Lack of judgement and insight.
      • Disturbance of volition.
      • Poor impulse control.
      • Preoccupation.
      • Active social avoidance.

PANSS Total score minimum = 30, maximum = 210

Scoring

As 1 rather than 0 is given as the lowest score for each item, a patient can not score lower than 30 for the total PANSS score. Scores are often given separately for the positive items, negative items, and general psychopathology. In their original publication on the PANSS scale, Stanley Kay and colleagues tested the scale on 101 adult patients (20-68 years-old) with schizophrenia and the mean scores were,

  • Positive scale = 18.20.
  • Negative scale = 21.01.
  • General psychopathology = 37.74.

Based on meta-analytic results, an alternative five-factor solution of the PANSS was proposed with positive symptoms, negative symptoms, disorganisation, excitement, and emotional distress.

This page is based on the copyrighted Wikipedia article <https://en.wikipedia.org/wiki/Positive_and_Negative_Syndrome_Scale&gt;; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is the Subjective Units of Distress Scale?

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Introduction

A Subjective Units of Distress Scale (SUDS), also known as the Subjective Units of Disturbance Scale), is a scale ranging from 0 to 10 measuring the subjective intensity of disturbance or distress currently experienced by an individual.

Respondents provide a self report of where they are on the scale. The SUDS may be used as a benchmark for a professional or observer to evaluate the progress of treatment. In desensitisation-based therapies, and the patients’ regular self assessments enable them to guide the clinician repeatedly as part of the therapeutic dialogue.

The SUD-level was developed by Joseph Wolpe in 1969. It has been used in cognitive-behavioural treatments for anxiety disorders (e.g. exposure practices and hierarchy) and for research purposes.

There is no hard and fast rule by which a patient can self assign a SUDS rating to his or her disturbance or distress, hence the name subjective.

Some guidelines are:

  • The intensity recorded must be as it is experienced now.
  • Constriction or congestion or tensing of body parts indicates a higher SUDS than that reported.

The Scale

There a number of version of the scale, and the below is for illustration only:

  • 10 = Feels unbearably bad, beside yourself, out of control as in a nervous breakdown, overwhelmed, at the end of your rope. You may feel so upset that you don’t want to talk because you can’t imagine how anyone could possibly understand your agitation.
  • 9 = Feeling desperate. What most people call a 10 is actually a 9. Feeling extremely freaked out to the point that it almost feels unbearable and you are getting scared of what you might do. Feeling very, very bad, losing control of your emotions.
  • 8 = Freaking out. The beginning of alienation.
  • 7 = Starting to freak out, on the edge of some definitely bad feelings. You can maintain control with difficulty.
  • 6 = Feeling bad to the point that you begin to think something ought to be done about the way you feel.
  • 5 = Moderately upset, uncomfortable. Unpleasant feelings are still manageable with some effort.
  • 4 = Somewhat upset to the point that you cannot easily ignore an unpleasant thought. You can handle it OK but don’t feel good.
  • 3 = Mildly upset. Worried, bothered to the point that you notice it.
  • 2 = A little bit upset, but not noticeable unless you took care to pay attention to your feelings and then realize, “yes” there is something bothering me.
  • 1 = No acute distress and feeling basically good. If you took special effort you might feel something unpleasant but not much.
  • 0 = Peace, serenity, total relief. No more anxiety of any kind about any particular issue.

Utility Does Not Require Precision

In using SUDS in a therapeutic setting, the therapist does not necessarily define the scale, because one of the benefits of asking a patient or client for a SUDS score is that it is simple. Typically, you can ask the client, “On a scale of zero to ten, where zero is the best you can feel and ten is the worst, how do you feel right now?”

The purpose of this question is to enable the patient or client to notice improvements, and the inherent difference between one person’s subjective scale and another person’s is irrelevant to therapy with either individual. Our brains are sophisticated enough that they can usually summarize a large amount of data very quickly, and often accurately.

There is a possibility that in some forms of therapy, the patient will want to see progress and will therefore report progress that isn’t objectively present – a type one error from a statistical point of view. While both type I and type II errors are important in research situations, type one errors can have a therapeutic utility in clinical situations, in which they can provide an indirect opportunity for positive autosuggestion – much like the indirect suggestions employed in Eriksonian hypnosis.

Thus, since the main use of SUDS is for clinical purposes, rather than research purposes, the imprecise nature of the scale is relatively unimportant to its main users: patients and clinicians.

This page is based on the copyrighted Wikipedia article <https://en.wikipedia.org/wiki/Subjective_units_of_distress_scale&gt;; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Climazolam?

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Introduction

Climazolam was introduced under licence as a veterinary medicine by the Swiss Pharmaceutical company Gräub under the tradename Climasol.

Background

Climazolam is a benzodiazepine, specifically an imidazobenzodiazepine derivative developed by Hoffman-LaRoche.

It is similar in structure to midazolam and diclazepam and is used in veterinary medicine for anaesthetising animals.

What is Midazolam?

Published on by Andrew Marshall1 Comment

Introduction

Midazolam, sold under the brand name Versed, among others, is a benzodiazepine medication used for anaesthesia, procedural sedation, trouble sleeping, and severe agitation.

It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. It is important to note that this drug does not cause an individual to become unconscious, merely be sedated. It is also useful for the treatment of seizures. Midazolam can be given by mouth, intravenously, by injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last between one and six hours.

Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding. It belongs to the benzodiazepine class of drugs and works by increasing the activity of the GABA neurotransmitter in the brain.

Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organisation’s List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.

Brief History

Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anaesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a “truth serum” on terrorist suspects in project “Medication”.

Medical Uses

Seizures

Midazolam is sometimes used for the acute management of seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus that has not improved following other treatments or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.

Drawbacks include a high degree of breakthrough seizures – due to the short half-life of midazolam – in over 50% of people treated, as well as treatment failure in 14-18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. There is evidence buccal and intranasal midazolam is easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.

Procedural Sedation

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), for preoperative sedation, for the induction of general anaesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.

Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.

Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.

Agitation

Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.

End of Life Care

In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, myoclonus, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.

Administration

Routes of administration of midazolam can be oral, intranasal, buccal, intravenous, and intramuscular.

  • Dosing:
    • Perioperative use: 0.15 to 0.40 mg/kg IV.
    • Premedication: 0.07 to 0.10 mg/kg IM.
    • Intravenous sedation: 0.05 to 0.15 mg/kg IV.

Contraindications

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

Side Effects

Refer to Long-Term Effects of Benzodiazepines.

Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.

Long-term use of benzodiazepines has been associated with long-lasting deficits of memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behaviour or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After night-time administration of midazolam, residual ‘hangover’ effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A “midazolam infusion syndrome” may result from high doses, and is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.

In susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behaviour, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behaviour is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Antipsychotic medications, such as haloperidol, have also been used for this purpose.

Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnoea becomes more likely.

Although the incidence of respiratory depression/arrest is low (0.1-0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug.

Pregnancy and Breastfeeding

Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhoea or vomiting). Breastfeeding by mothers using midazolam is not recommended.

Elderly

Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.

Tolerance, Dependence, and Withdrawal

A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a person’s underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.

Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhoea, tachycardia, hypertension, and tachypnoea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus that may be fatal.

Overdose

Refer to Benzodiazepine Overdose.

A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and risk of death is also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.

Symptoms of midazolam overdose can include:

  • Ataxia.
  • Dysarthria.
  • Nystagmus.
  • Slurred speech.
  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Hypotension.
  • Respiratory arrest.
  • Vasomotor collapse.
  • Impaired motor functions:
    • Impaired reflexes.
    • Impaired coordination.
    • Impaired balance.
    • Dizziness.
  • Coma.
  • Death.

Detection in Body Fluids

Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalised patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.

Interactions

Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John’s wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolised almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St John’s wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.

Pharmacology

Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5-2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl- channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.

Pharmacokinetics

  • Volume of Distribution: 1-2.5L/kg in normal healthy individuals.
  • Protein Binding: 96% Plasma protein bound.
  • Onset of Action: 3-15 minutes.
  • Elimination Half-Life: 1.5-3 hours.

Society and Culture

Cost

Midazolam is available as a generic medication.

Availability

Midazolam is available in the United States as a syrup or as an injectable solution.

Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with “Roche” on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavour. It becomes soluble when the injectable solution is buffered to a pH of 2.9-3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.

Legal Status

In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.

Marketing Authorisation

In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the trade name Buccolam. Buccolam was approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.

Use in Executions

The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latter’s manufacturer disallowed that drug’s use for executions. Midazolam acts as a sedative but will fail to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner’s breathing and heart, respectively. Due to the fact that the condemned prisoner is not unconscious but merely sedated, two very different things, those following two drugs can cause extreme pain and panic in the soon to die prisoner.

Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.

The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Lockett’s vein had ruptured. It is not clear whether his death was caused by one or more of the drugs or to a problem in the administration procedure, nor is it clear what quantities of vecuronium bromide and potassium chloride were released to his system before the execution was cancelled.

Notable Incidents

The state of Florida used midazolam to execute William Frederick Happ in October 2013.

The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.

The execution of Ronald Bert Smith in the state of Alabama on 08 December 2016, “went awry soon after (midazolam) was administered” again putting the effectiveness of the drug in question.

In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, and potassium chloride, but this was blocked by a Federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay. Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Otte’s lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.

On 24 April 2017, the state of Arkansas carried out a double-execution of Jack Harold Jones, 52, and Marcel Williams, 46. The state of Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.

On 28 October 2021, the state of Oklahoma carried out the execution of inmate John Marion Grant, 60, using midazolam as part of its three-drug cocktail hours after the US Supreme Court ruled to lift a stay of execution for Oklahoma death row inmates. The execution was the state’s first since 2015. Witnesses to the execution said that when the first drug, midazolam, began to flow at 4:09 pm, Grant started convulsing about two dozen times and vomited. Grant continued breathing, and a member of the execution team wiped the vomit off his face. At 4:15 pm., officials said Grant was unconscious, and he was pronounced dead at 4:21 pm.

Legal Challenges

In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the US Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives.

The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under false pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.

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On This Day … 28 April [2022]

Published on by Andrew MarshallLeave a comment

People (Births)

People (Deaths)

  • 2012 – Milan N. Popović, Serbian psychiatrist and author (b. 1924).

Mike Brearley

John Michael Brearley OBE (born 28 April 1942) is a retired English first-class cricketer who captained Cambridge University, Middlesex, and England.

He captained the international side in 31 of his 39 Test matches, winning 17 and losing only 4. He was the President of the Marylebone Cricket Club (MCC) in 2007-2008. Since his retirement from professional cricket he has pursued a career as a writer and psychoanalyst, serving as President of the British Psychoanalytical Society 2008-2010. In 2015, an article in the Bleacher Report ranked Brearley as England’s greatest ever cricket captain.

He is married to Mana Sarabhai who is from Ahmedabad, India and they have two children together.

Milan N. Popovic

Milan Popović (1924 to 28 April 2012) was a renowned Serbian psychiatrist-psychoanalyst, a full professor of the University of Belgrade Faculty of Philosophy.

Biography

He was born in 1924 in Belgrade, Serbia. He graduated from the University of Belgrade School of Medicine, specialized neuropsychiatry and was awarded a doctor’s degree with the theme “Group psychotherapy of the schizophrenic in hospital conditions”. He was elected associate professor of the Faculty of Philosophy of Belgrade University in 1972 and full professor in 1980.

Education

Milan Popović is a pioneer in developing the group psychiatry in Serbia and opening psychiatric departments towards the society. He is a founder of “Psychoanalytical psychotherapy school” at post graduated studies of the Faculty of Medicine in Belgrade.

He is a teacher of many generations of psychiatrists, psychologists and sociologists in Serbia. He has given an important contribution to the development of psychiatry in the country, especially the development of psychotherapy and social psychiatry, truthfully representing domestic achievements abroad.