Category: Mental Health Treatment

What is Schema Therapy?

Published on by Andrew Marshall2 Comments

Introduction

Schema therapy was developed by Jeffrey E. Young for use in treatment of personality disorders and chronic DSM Axis I disorders, such as when patients fail to respond or relapse after having been through other therapies (for example, traditional cognitive behavioural therapy, CBT). Schema therapy is an integrative psychotherapy combining theory and techniques from previously existing therapies, including CBT, psychoanalytic object relations theory, attachment theory, and Gestalt therapy.

Concepts

Four main theoretical concepts in schema therapy are early maladaptive schemas (or simply schemas), coping styles, modes, and basic emotional needs:

  1. In cognitive psychology, a schema is an organised pattern of thought and behaviour. It can also be described as a mental structure of preconceived ideas, a framework representing some aspect of the world, or a system of organizing and perceiving new information. In schema therapy, a schema specifically refers to an early maladaptive schema, defined as a pervasive self-defeating or dysfunctional theme or pattern of memories, emotions, and physical sensations, developed during childhood or adolescence and elaborated throughout one’s lifetime. Often they have the form of a belief about the self or the world. For instance, a person with an Abandonment schema could be hypersensitive (have an “emotional button” or “trigger”) about their perceived value to others, which in turn could make them feel sad and panicky in their interpersonal relationships.
  2. Coping styles are a person’s behavioural responses to schemas. There are three potential coping styles. In “avoidance” the person tries to avoid situations that activate the schema. In “surrender” the person gives into the schema, doesn’t try to fight against it, and changes their behaviour in expectation that the feared outcome is inevitable. In “counterattack”, also called “overcompensation”, the person puts extra work into not allowing the schema’s feared outcome to happen. These maladaptive coping styles (overcompensation, avoidance, or surrender) very often wind up reinforcing the schemas. Continuing the Abandonment example: having imagined a threat of abandonment in a relationship and feeling sad and panicky, a person using an avoidance coping style might then behave in ways to limit the closeness in the relationship to try to protect themselves from being abandoned. The resulting loneliness or even actual loss of the relationship could easily reinforce the person’s Abandonment schema. Another example can be given for the Defectiveness schema: A person using an avoidance coping style might avoid situations that make them feel defective, or might try to numb the feeling with addictions or distractions. A person using a surrender coping style might tolerate unfair criticism without defending themselves. A person using the counterattack/overcompensation coping style might put extra effort into being superhuman.
  3. Modes are mind states that cluster schemas and coping styles into a temporary “way of being” that a person can shift into occasionally or more frequently. For example, a Vulnerable Child mode might be a state of mind encompassing schemas of Abandonment, Defectiveness, Mistrust/Abuse and a coping style of surrendering (to the schemas).
  4. If a patient’s basic emotional needs are not met in childhood, then schemas, coping styles, and modes can develop. Some basic needs that have been identified are: connection, mutuality, reciprocity, flow, and autonomy. For example, a child with unmet needs around connection – perhaps due to parental loss to death, divorce, or addiction – might develop an Abandonment schema.

The goal of schema therapy is to help patients meet their basic emotional needs by helping the patient learn how to:

  • Heal schemas by diminishing the intensity of emotional memories comprising the schema and the intensity of bodily sensations, and by changing the cognitive patterns connected to the schema; and
  • Replace maladaptive coping styles and responses with adaptive patterns of behaviour.

Techniques used in schema therapy including limited reparenting and Gestalt therapy psychodrama techniques such as imagery re-scripting and empty chair dialogues (Refer to techniques in schema therapy, below).

There is a growing literature of outcome studies on schema therapy, where schema therapy has shown impressive results (Refer to outcome studies on schema therapy, below).

Early Maladaptive Schemas

Refer to List of Maladaptive Schemas.

Early maladaptive schemas are self-defeating emotional and cognitive patterns established from childhood and repeated throughout life. They may be made up of emotional memories of past hurt, tragedy, fear, abuse, neglect, unmet safety needs, abandonment, or lack of normal human affection in general. Early maladaptive schemas can also include bodily sensations associated with such emotional memories. Early maladaptive schemas can have different levels of severity and pervasiveness: the more severe the schema, the more intense the negative emotion when the schema is triggered and the longer it lasts; the more pervasive the schema, the greater the number of situations that trigger it.

Schema Domains

Schema domains are five broad categories of unmet needs into which are grouped 18 early maladaptive schemas identified by Young, Klosko & Weishaar (2003):

  • Disconnection/Rejection includes 5 schemas:
    • Abandonment/Instability.
    • Mistrust/Abuse.
    • Emotional Deprivation.
    • Defectiveness/Shame.
    • Social Isolation/Alienation.
  • Impaired Autonomy and/or Performance includes 4 schemas:
    • Dependence/Incompetence.
    • Vulnerability to Harm or Illness.
    • Enmeshment/Undeveloped Self.
    • Failure.
  • Impaired Limits includes 2 schemas:
    • Entitlement/Grandiosity.
    • Insufficient Self-Control and/or Self-Discipline.
  • Other-Directedness includes 3 schemas:
    • Subjugation.
    • Self-Sacrifice.
    • Approval-Seeking/Recognition-Seeking.
  • Over-vigilance/Inhibition includes 4 schemas:
    • Negativity/Pessimism.
    • Emotional Inhibition.
    • Unrelenting Standards/Hypercriticalness.
    • Punitiveness.

Schema Modes

Schema modes are momentary mind states which every human being experiences at one time or another. A schema mode consists of a cluster of schemas and coping styles. Life situations that a person finds disturbing or offensive, or arouse bad memories, are referred to as “triggers” that tend to activate schema modes. In psychologically healthy persons, schema modes are mild, flexible mind states that are easily pacified by the rest of their personality. In patients with personality disorders, schema modes are more severe, rigid mind states that may seem split off from the rest of their personality.

Identified Schema Modes

Young, Klosko & Weishaar (2003) identified 10 schema modes grouped into four categories. The four categories are: Child modes, Dysfunctional Coping modes, Dysfunctional Parent modes, and the Healthy Adult mode. The four Child modes are: Vulnerable Child, Angry Child, Impulsive/Undisciplined Child, and Happy Child. The three Dysfunctional Coping modes are: Compliant Surrenderer, Detached Protector, and Overcompensator. The two Dysfunctional Parent modes are: Punitive Parent and Demanding Parent.

Angry ChildThis is fuelled mainly by feelings of victimisation or bitterness, leading towards negativity, pessimism, jealousy, and rage. While experiencing this schema mode, a patient may have urges to yell, scream, throw/break things, or possibly even injure themselves or harm others. The Angry Child schema mode is enraged, anxious, frustrated, self-doubting, feels unsupported in ideas and vulnerable.
Impulsive ChildThis is the mode where anything goes. Behaviours of the Impulsive Child schema mode may include reckless driving, substance abuse, cutting oneself, suicidal thoughts, gambling, or fits of rage, such as punching a wall when “triggered” or laying blame of circumstantial difficulties upon innocent people. Unsafe sex, rash decisions to run away from a situation without resolution, tantrums perceived by peers as infantile, and so forth are a mere few of the behaviours which a patient in this schema mode might display. Impulsive Child is the rebellious and careless schema mode.
Detached ProtectorThis is based in escape. Patients in Detached Protector schema mode withdraw, dissociate, alienate, or hide in some way. This may be triggered by numerous stress factors or feelings of being overwhelmed. When a patient with insufficient skills is in a situation involving excessive demands, it can trigger a Detached Protector response mode. Stated simply, patients become numb in order to protect themselves from the harm or stress of what they fear is to come, or to protect themselves from fear of the unknown in general.
Abandoned ChildThis is the mode in which a patient may feel defective in some way, thrown aside, unloved, obviously alone, or may be in a “me against the world” mindset. The patient may feel as though peers, friends, family, and even the entire world have abandoned them. Behaviours of patients in Abandoned Child mode may include (but are not limited to) falling into major depression, pessimism, feeling unwanted, feeling unworthy of love, and perceiving personality traits as irredeemable flaws. Rarely, a patient’s self-perceived flaws may be intentionally withheld on the inside; when this occurs, instead of showing one’s true self, the patient may appear to others as “egotistical”, “attention-seeking”, selfish, distant, and may exhibit behaviours unlike their true nature. The patient might create a narcissistic alter-ego/persona in order to escape or hide the insecurity from others. Due to fear of rejection, of feeling disconnected from their true self and poor self-image, these patients, who truly desire companionship/affection, may instead end up pushing others away.
Punitive ParentThis is identified by beliefs of a patient that they should be harshly punished, perhaps due to feeling “defective”, or making a simple mistake. The patient may feel that they should be punished for even existing. Sadness, anger, impatience, and judgement are directed to the patient and from the patient. The Punitive Parent has great difficulty in forgiving themselves even under average circumstances in which anyone could fall short of their standards. The Punitive Parent does not wish to allow for human error or imperfection, thus punishment is what this mode seeks.
Healthy AdultThis is the mode that schema therapy aims to help a patient achieve as the long-lasting state of well-being. The Healthy Adult is comfortable making decisions, is a problem-solver, thinks before acting, is appropriately ambitious, sets limits and boundaries, nurtures self and others, forms healthy relationships, takes on all responsibility, sees things through, and enjoys/partakes in enjoyable adult activities and interests with boundaries enforced, takes care of their physical health, and values themselves. In this schema mode the patient focuses on the present day with hope and strives toward the best tomorrow possible. The Healthy Adult forgives the past, no longer sees themselves as a victim (but as a survivor), and expresses all emotions in ways which are healthy and cause no harm.

Techniques in Schema Therapy

Treatment plans in schema therapy generally encompass three basic classes of techniques: cognitive, experiential, and behavioural (in addition to the basic healing components of the therapeutic relationship). Cognitive strategies expand on standard CBT techniques such as listing pros and cons of a schema, testing the validity of a schema, or conducting a dialogue between the “schema side” and the “healthy side”. Experiential and emotion focused strategies expand on standard Gestalt therapy psychodrama and imagery techniques. Behavioural pattern-breaking strategies expand on standard behaviour therapy techniques, such as role playing an interaction and then assigning the interaction as homework. One of the most central techniques in schema therapy is the use of the therapeutic relationship, specifically through a process called “limited reparenting”.

Specific techniques often used in schema therapy include flash cards with important therapeutic messages, created in session and used by the patient between sessions, and the schema diary – a template or workbook that is filled out by the patient between sessions and that records the patient’s progress in relation to all the theoretical concepts in schema therapy.

Schema Therapy and Psychoanalysis

From an integrative psychotherapy perspective, limited reparenting and the experiential techniques, particularly around changing modes, could be seen as actively changing what psychoanalysis has described as object relations. Historically, mainstream psychoanalysis tended to reject active techniques – such as Fritz Perls’ Gestalt therapy work or Franz Alexander’s “corrective emotional experience” – but contemporary relational psychoanalysis (led by analysts such as Lewis Aron, and building on the ideas of earlier unorthodox analysts such as Sándor Ferenczi) is more open to active techniques. It is notable that in a head to head comparison of a psychoanalytic object relations treatment (Otto F. Kernberg’s transference focused psychotherapy) and schema therapy, the latter has been demonstrated to be more effective in treating Borderline Personality Disorder.

Outcome Studies on Schema Therapy

Schema Therapy vs Transference Focused Psychotherapy Outcomes

Dutch investigators, including Josephine Giesen-Bloo and Arnoud Arntz (the project leader), compared schema therapy (also known as schema focused therapy or SFT) with transference focused psychotherapy (TFP) in the treatment of borderline personality disorder. 86 patients were recruited from four mental health institutes in the Netherlands. Patients in the study received two sessions per week of SFT or TFP for three years. After three years, full recovery was achieved in 45% of the patients in the SFT condition, and in 24% of those receiving TFP. One year later, the percentage fully recovered increased to 52% in the SFT condition and 29% in the TFP condition, with 70% of the patients in the SFT group achieving “clinically significant and relevant improvement”. Moreover, the dropout rate was only 27% for SFT, compared with 50% for TFP.

Patients began to feel and function significantly better after the first year, with improvement occurring more rapidly in the SFT group. There was continuing improvement in subsequent years. Thus investigators concluded that both treatments had positive effects, with schema therapy clearly more successful.

Less Intensive Outpatient, Individual Schema Therapy

Dutch investigators, including Marjon Nadort and Arnoud Arntz, assessed the effectiveness of schema therapy in the treatment of borderline personality disorder when utilised in regular mental health care settings. A total of 62 patients were treated in eight mental health centres located in the Netherlands. The treatment was less intensive along a number of dimensions including a shift from twice weekly to once weekly sessions during the second year. Despite this, there was no lessening of effectiveness with recovery rates that were at least as high and similarly low dropout rates.

Pilot Study of Group Schema Therapy for Borderline Personality Disorder

Investigators Joan Farrell, Ida Shaw and Michael Webber at the Indiana University School of Medicine Centre for BPD Treatment & Research tested the effectiveness of adding an eight-month, 30-session schema therapy group to treatment-as-usual (TAU) for borderline personality disorder (BPD) with 32 patients. The dropout rate was 0% for those patients who received group schema therapy in addition to TAU and 25% for those who received TAU alone. At the end of treatment, 94% of the patients who received group schema therapy in addition to TAU compared to 16% of the patients receiving TAU alone no longer met BPD diagnostic criteria. The schema therapy group treatment led to significant reductions in symptoms and global improvement in functioning. The large positive treatment effects found in the group schema therapy study suggest that the group modality may augment or catalyse the active ingredients of the treatment for BPD patients. As of 2014, a collaborative randomised controlled trial is under way at 14 sites in six countries to further explore this interaction between groups and schema therapy.

What is Midazolam?

Published on by Andrew Marshall2 Comments

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 also useful for the treatment of seizures. Midazolam can be given by mouth, intravenously, or 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 for 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.

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.[31] Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur.[32] Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects.[33][34] Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

Side Effects

Refer to Long-term Effects of Benzodiazepine Use.

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 verbalisation, 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% 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.

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 to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner’s breathing and heart, respectively.

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 which drug or drugs caused his death or what quantities of vecuronium bromide and potassium chloride were released 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, 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.[86] 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.

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.

What is Fletazepam?

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Introduction

Fletazepam is a drug which is a benzodiazepine derivative. It has sedative and anxiolytic effects similar to those produced by other benzodiazepine derivatives, but is mainly notable for its strong muscle relaxant properties.

Fletazepam is most closely related to other N-trifluoroethyl substituted benzodiazepines such as halazepam and quazepam.

What is Clobazam?

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Introduction

Clobazam, sold under the brand name Frisium among others, is a benzodiazepine class medication that was patented in 1968.

Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

Refer to Triflubazam.

Brief History

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969; Maestretti was acquired by Roussel Uclaf which became part of Sanofi.

Medical Uses

Clobazam is used for its anxiolytic effect, and as an adjunctive therapy in epilepsy.

Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam is approved for adjunctive therapy in complex partial seizures, certain types of status epilepticus, specifically the mycolonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. It is also approved for the treatment of anxiety.

In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam (Frisium) is approved for short-term (2-4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until 25 October 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.

As an adjunctive therapy in epilepsy, it is used in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy or other epileptic syndromes. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need. In addition to epilepsy and severe anxiety, clobazam is also approved as a short-term (2-4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.

Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due to drug tolerance which may render long-term therapy less effective. Other antiepileptic drugs may therefore be preferred for the long-term management of epilepsy. Furthermore, benzodiazepines may have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.

Contraindications

Clobazam should be used with great care in patients with the following disorders:

  • Myasthenia gravis.
  • Sleep apnoea.
  • Severe liver diseases such as cirrhosis and hepatitis.
  • Severe respiratory failure.

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

Side Effects

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.

Refer to Effects of Long-Term Benzodiazepine Use.

Common

Common side effects include fever, drooling, and constipation.

Post-Marketing Experience

  • Hives.
  • Rashes.

Warnings and Precautions

In December 2013, the FDA added warnings to the label for clobazam, that it can cause serious skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis, especially in the first eight weeks of treatment.

Drug Interactions

  • Alcohol increases bioavailability by 50%; compounded depressant effect may precipitate life-threatening toxicity.
  • Cimetidine increases the effects of clobazam.
  • Valproate.

Overdose

Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.

Abuse Potential and Addiction

Refer to Benzodiazepine Use Disorder.

Classic (non-anxioselective) benzodiazepines in animal studies have been shown to increase reward-seeking behaviours which may suggest an increased risk of addictive behavioural patterns. Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation (WHO) report.

Dependence and Withdrawal

In humans, tolerance to the anticonvulsant effects of clobazam may occur and withdrawal seizures may occur during abrupt or over rapid withdrawal.

Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction, and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dosage and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should only be discontinued via a slow and gradual dose reduction regimen.

Pharmacology

Clobazam is predominantly a positive allosteric modulator at the GABAA receptor with some speculated additional activity at sodium channels and voltage-sensitive calcium channels.

Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, or CP-1414S), the active metabolite N-desmethylclobazam has less affinity for the α1 subunit of the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for α2 containing receptors, where it has positive modulatory activity.

In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg of clobazam was shown to be less sedative than either 0.5 mg or 1 mg of clonazepam.

The α1 subtype of the GABAA receptor, was shown to be responsible for the sedative effects of diazepam by McKernan et al. in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α1 receptors were insensitive to diazepam.

In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride influx at GABAA receptors, creating a hyperpolarizing, inhibitory postsynaptic potential. It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue.

Metabolism

Clobazam has two major metabolites: N-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active. The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.

Chemistry

Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4).

It is not soluble in water and is available in oral form only.

What is Halazepam?

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Introduction

Halazepam is a benzodiazepine derivative that was marketed under the brand names Paxipam in the United States, Alapryl in Spain, and Pacinone in Portugal.

Medical Uses

Halazepam was used for the treatment of anxiety.

Adverse Effects

Adverse effects include drowsiness, confusion, dizziness, and sedation. Gastrointestinal side effects have also been reported including dry mouth and nausea.

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics and pharmacodynamics were listed in Current Psychotherapeutic Drugs published on 15 June 1998 as follows:

  • Onset of action: Intermediate to slow.
  • Plasma half life: 14 hours for parent drug and 30-100 hours for its metabolite.
  • Peak plasma levels: 1-3 hours for parent drug and 3-6 hours for its metabolite.
  • Metabolism: Metabolised into desmethyldiazepam and 3-hydroxyhalazepam (in the liver).
  • Excretion: Excreted through kidneys.
  • Protein binding: 98% bound to plasma protein.

Regulatory Information

Halazepam is classified as a schedule 4 controlled substance with a corresponding code 2762 by the Drug Enforcement Administration (DEA).

Commercial Production

Halazepam was invented by Schlesinger Walter in the US. It was marketed as an anti-anxiety agent in 1981. However, Halazepam is not commercially available in the United States because it was withdrawn by its manufacturer for poor sales.

What is Imidazenil?

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Introduction

Imidazenil is an experimental anxiolytic drug which is derived from the benzodiazepine family, and is most closely related to other imidazobenzodiazepines such as midazolam, flumazenil, and bretazenil.

Outline

Imidazenil is a highly potent benzodiazepine receptor partial agonist with an unusual profile of effects, producing some of the effects associated with normal benzodiazepines such as anticonvulsant and anxiolytic effects, yet without any notable sedative or amnestic effects. In fact, imidazenil blocks the sedative effects of diazepam, yet without lowering the convulsion threshold, and so potentially could be a more flexible antidote than the antagonist flumazenil which is commonly used to treat benzodiazepine overdose at present.

As of August 2021, Imidazenil has not yet been developed commercially for use in humans, however it has been suggested as a safe and effective treatment for anxiety, a potent yet non-sedating anticonvulsant which might be particularly useful in the treatment of poisoning with organophosphate nerve agents, and as a novel treatment for schizophrenia.

What is Loprazolam?

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Introduction

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication.

It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

It was patented in 1975 and came into medical use in 1983.

Medical Uses

Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis.

Dose

The dose of loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half-life is much more prolonged in the elderly than in younger patients. A half-life of 19.8 hours has been reported in elderly patients. Patients and prescribing physicians should, however, bear in mind that higher doses of loprazolam may impair long-term memory functions.

Side Effects

Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam.[5] The most significant difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half-life of loprazolam is considered to be intermediate whereas diazepam has a very long half-life. The side effects of loprazolam are the following:

  • Drowsiness.
  • Paradoxical increase in aggression.
  • Lightheadedness.
  • Confusion.
  • Muscle weakness.
  • Ataxia (particularly in the elderly).
  • Amnesia.
  • Headache.
  • Vertigo.
  • Hypotension.
  • Salivation changes.
  • Gastro-intestinal disturbances.
  • Visual disturbances.
  • Dysarthria.
  • Tremor.
  • Changes in libido.
  • Incontinence.
  • Urinary retention.
  • Blood disorders and jaundice.
  • Skin reactions.
  • Dependence and withdrawal reactions.

Residual ‘hangover’ effects after night-time administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may increase risks of falls and hip fractures.

Tolerance, Dependence and Withdrawal

Loprazolam, like all other benzodiazepines, is recommended only for the short-term management of insomnia in the UK, owing to the risk of serious adverse effects such as tolerance, dependence and withdrawal, as well as adverse effects on mood and cognition. Benzodiazepines can become less effective over time, and patients can develop increasing physical and psychological adverse effects, e.g. agoraphobia, gastrointestinal complaints, and peripheral nerve abnormalities such as burning and tingling sensations.

Loprazolam has a low risk of physical dependence and withdrawal if it is used for less than 4 weeks or very occasionally. However, one placebo-controlled study comparing 3 weeks of treatment for insomnia with either loprazolam or triazolam showed rebound anxiety and insomnia occurring 3 days after discontinuing loprazolam therapy, whereas with triazolam the rebound anxiety and insomnia was seen the next day. The differences between the two are likely due to the differing elimination half-lives of the two drugs. These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1-2 weeks rather than 2-4 weeks to reduce the risk of physical dependence, withdrawal, and rebound phenomenon.

Withdrawal Symptoms

Slow reduction of the dosage over a period of months at a rate that the individual can tolerate greatly minimises the severity of the withdrawal symptoms. Individuals who are benzodiazepine dependent often cross to an equivalent dose of diazepam to taper gradually, as diazepam has a longer half-life and small dose reductions can be achieved more easily.

  • Anxiety and panic attacks.
  • Sweating.
  • Nightmares.
  • Insomnia.
  • Headache.
  • Tremor.
  • Nausea and vomiting.
  • Feelings of unreality.
  • Abnormal sensation of movement.
  • Hypersensitivity to stimuli.
  • Hyperventilation.
  • Flushing.
  • Sweating.
  • Palpitations.
  • Dimensional distortions of rooms and television pictures.
  • Paranoid thoughts and feelings of persecution.
  • Depersonalisation.
  • Fears of going mad.
  • Heightened perception of taste, smell, sound, and light; photophobia.
  • Agoraphobia.
  • Clinical depression.
  • Poor memory and concentration.
  • Aggression.
  • Excitability.
  • Somatic symptoms.
  • Numbness.
  • Altered sensations of the skin.
  • Pain.
  • Stiffness.
  • Weakness in the neck, head, jaw, and limbs.
  • Muscle fasciculation, ranging from twitches to jerks, affecting the legs or shoulders.
  • Ataxia.
  • Paraesthesia.
  • Influenza-like symptoms.
  • Blurred double vision.
  • Menorrhagia.
  • Loss of or dramatic gain in appetite.
  • Thirst with polyuria.
  • Urinary incontinence.
  • Dysphagia.
  • Abdominal pain.
  • Diarrhoea.
  • Constipation.

Major complications can occur after abrupt or rapid withdrawal, especially from high doses, producing symptoms such as:

  • Psychosis.
  • Confusion.
  • Visual and auditory hallucinations.
  • Delusions.
  • Epileptic seizures (which may be fatal).
  • Suicidal thoughts or actions.
  • Abnormal, often severe, drug seeking behaviour.

It has been estimated that between 30% and 50% of long-term users of benzodiazepines will experience withdrawal symptoms. However, up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, but the rate of taper was very fast at 25% of dose per week. Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10-15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasionally several years.

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. Loprazolam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.

Mechanism of Action

Loprazolam is a benzodiazepine, which acts via positively modulating the GABAA receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABAA receptors. This action enhances the effect of the neurotransmitter GABA on the GABAA receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces such effects as; muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant action. These properties can be used for therapeutic benefit in clinical practice. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation.

Pharmacokinetics

After oral administration of loprazolam on an empty stomach, it takes 2 hours for serum concentration levels to peak, significantly longer than other benzodiazepine hypnotics. This delay brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics (particularly when the major complaint is difficulty falling asleep instead of difficulty maintaining sleep for the entire night), although some studies show that loprazolam may induce sleep within half an hour, indicating rapid penetration into the brain. The peak plasma delay of loprazolam, therefore, may not be relevant to loprazolam’s efficacy as a hypnotic. If taken after a meal it can take even longer for loprazolam plasma levels to peak and peak levels may be lower than normal. Loprazolam significantly alters electrical activity in the brain as measured by EEG, with these changes becoming more pronounced as the dose increases. Roughly half of each dose is metabolized in humans to produce an active metabolite, (a piperazine with lesser potency), the other half is excreted unchanged. The half-life of the active metabolite is about the same as the parent compound loprazolam.

What is Flumazenil?

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Introduction

Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through competitive inhibition.

It was first characterised in 1981, and was first marketed in 1987 by Hoffmann-La Roche under the trade name Anexate. However, it did not receive US Food and Drug Administration (FDA) approval until 20 December 1991. The developer lost its exclusive patent rights in 2008; so at present, generic formulations of this drug are available. Intravenous flumazenil is primarily used to treat benzodiazepine overdoses and to help reverse anaesthesia. Administration of flumazenil by sublingual lozenge and topical cream has also been tested.

Medical Uses

Flumazenil benefits patients who become excessively drowsy after use of benzodiazepines for either diagnostic or therapeutic procedures.

The drug has been used as an antidote in the treatment of benzodiazepine overdoses. It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine (BZ) recognition site on the GABA/benzodiazepine receptor complex. There are many complications that must be taken into consideration when used in the acute care setting. These include lowered seizure threshold, agitation, and anxiousness. Flumazenil’s short half-life requires multiple doses. Because of the potential risks of withdrawal symptoms and the drug’s short half-life, patients must be carefully monitored to prevent recurrence of overdose symptoms or adverse side effects.

Flumazenil is also sometimes used after surgery to reverse the sedative effects of benzodiazepines. This is similar to naloxone’s application to reverse the effect of opiates and opioids following surgery. Administration of the drug requires careful monitoring by an anaesthesiologist due to potential side effects and serious risks associated with over-administration. Likewise, post-surgical monitoring is also necessary because flumazenil can mask the apparent metabolisation (“wearing off”) of the drug after removal of patient life-support and monitoring equipment.

Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone (also known as “Z-drugs”).

It may also be effective in reducing excessive daytime sleepiness while improving vigilance in primary hypersomnias, such as idiopathic hypersomnia.

The drug has also been used in hepatic encephalopathy. It may have beneficial short‐term effects in people with cirrhosis, but there is no evidence for long-term benefits.

The onset of action is rapid, and effects are usually seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1-2 minutes until the effect is seen, up to a maximum of 3 mg per hour. It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5 mL.

Many benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, in cases of overdose, repeat doses of flumazenil may be required to prevent recurrent symptoms once the initial dose of flumazenil wears off.

It is hepatically metabolised to inactive compounds which are excreted in the urine. Individuals who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon rapid administration of flumazenil.

It is not recommended for routine use in those with a decreased level of consciousness.

In terms of drug enforcement initiatives, diversion control programs and required post-marketing surveillance of adverse events, orders for flumazenil may trigger a prescription audit to the search for benzodiazepine misuse and for clinically significant adverse reactions related to their use.

PET Radioligand

Radiolabeled with the radioactive isotope carbon-11, flumazenil may be used as a radioligand in neuroimaging with positron emission tomography to visualize the distribution of GABAA receptors in the human brain.

Treatment for Benzodiazepine Dependence & Tolerance

Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil. Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7-8 days of treatment with flumazenil.

Flumazenil has been tested against placebo in benzo-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms. Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomised, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.

In vitro studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed. After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.[20]

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

Low-dose, slow subcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency. It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8-10 days of low-dose, slowly infused flumazenil. One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic’s most common patients.

Clinical Pharmacology

Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-type monomers; the clinical relevance of this is unknown.

Flumazenil does not antagonize all of the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, and most anaesthetics) and does not reverse the effects of opioids. It will however antagonize the action of non-benzodiazepine z-drugs, such as zolpidem and zopiclone, because they act via the benzodiazepine site of the GABA receptor – it has been used to successfully treat z-drug overdose.

Pharmacodynamics

Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.

The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil.

Availability

Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon. In India it is manufactured by Roche Bangladesh Pharmaceuticals and USAN Pharmaceuticals.

What are the Effects of Long-Term Benzodiazepine Use?

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Introduction

The effects of long-term benzodiazepine use include drug dependence and neurotoxicity as well as the possibility of adverse effects on cognitive function, physical health, and mental health.

Long term use is sometimes described as use not shorter than three months. Benzodiazepines are generally effective when used therapeutically in the short term, but even then the risk of dependency can be significantly high. There are significant physical, mental and social risks associated with the long-term use of benzodiazepines. Although anxiety can temporarily increase as a withdrawal symptom, there is evidence that a reduction or withdrawal from benzodiazepines can lead in the long run to a reduction of anxiety symptoms. Due to these increasing physical and mental symptoms from long-term use of benzodiazepines, slow withdrawal is recommended for long-term users. Not everyone, however, experiences problems with long-term use.

Some of the symptoms that could possibly occur as a result of a withdrawal from benzodiazepines after long-term use include emotional clouding, flu-like symptoms, suicide, nausea, headaches, dizziness, irritability, lethargy, sleep problems, memory impairment, personality changes, aggression, depression, social deterioration as well as employment difficulties, while others never have any side effects from long-term benzodiazepine use. Abruptly or rapidly stopping benzodiazepines can be dangerous; when withdrawing a gradual reduction in dosage is recommended, under professional supervision.

While benzodiazepines are highly effective in the short term, adverse effects associated with long-term use, including impaired cognitive abilities, memory problems, mood swings, and overdoses when combined with other drugs, may make the risk-benefit ratio unfavourable. In addition, benzodiazepines have reinforcing properties in some individuals and thus are considered to be addictive drugs, especially in individuals that have a “drug-seeking” behaviour; further, a physical dependence can develop after a few weeks or months of use. Many of these adverse effects associated with long-term use of benzodiazepines begin to show improvements three to six months after withdrawal.

Other concerns about the effects associated with long-term benzodiazepine use, in some, include dose escalation, benzodiazepine use disorder, tolerance and benzodiazepine dependence and benzodiazepine withdrawal problems. Both physiological tolerance and dependence can be associated with worsening the adverse effects associated with benzodiazepines. Increased risk of death has been associated with long-term use of benzodiazepines in several studies; however, other studies have not found increased mortality. Due to conflicting findings in studies regarding benzodiazepines and increased risks of death including from cancer, further research in long-term use of benzodiazepines and mortality risk has been recommended; most of the available research has been conducted in prescribed users, even less is known about illicit misusers. The long-term use of benzodiazepines is controversial and has generated significant debate within the medical profession. Views on the nature and severity of problems with long-term use of benzodiazepines differ from expert to expert and even from country to country; some experts even question whether there is any problem with the long-term use of benzodiazepines.

Brief History

Benzodiazepines when introduced in 1961 were widely believed to be safe drugs but as the decades went by increased awareness of adverse effects connected to their long-term use became known. Recommendations for more restrictive medical guidelines followed. Concerns regarding the long-term effects of benzodiazepines have been raised since 1980. These concerns are still not fully answered. A review in 2006 of the literature on use of benzodiazepine and nonbenzodiazepine hypnotics concluded that more research is needed to evaluate the long-term effects of hypnotic drugs. The majority of the problems of benzodiazepines are related to their long-term use rather than their short-term use. There is growing evidence of the harm of long-term use of benzodiazepines, especially at higher doses. In 2007, the Department of Health recommended that individuals on long-term benzodiazepines be monitored at least every 3 months and also recommended against long-term substitution therapy in benzodiazepine drug misusers due to a lack of evidence base for effectiveness and due to the risks of long-term use. The long-term effects of benzodiazepines are very similar to the long-term effects of alcohol consumption (apart from organ toxicity) and other sedative-hypnotics. Withdrawal effects and dependence are not identical. Dependence can be managed, with a medical professional of course, but withdrawal can be fatal. Physical dependence and withdrawal are very much related but not the same thing. A report in 1987 by the Royal College of Psychiatrists in Great Britain reported that any benefits of long-term use of benzodiazepines are likely to be far outweighed by the risks of long-term use. Despite this benzodiazepines are still widely prescribed. The socioeconomic costs of the continued widespread prescribing of benzodiazepines is high.

Political Controversy

In 1980, the UK Medical Research Council (MRC) recommended that research be conducted into the effects of long-term use of benzodiazepines. A 2009 British Government parliamentary inquiry recommended that research into the long-term effects of benzodiazepines must be carried out. The view of the Department of Health is that they have made every effort to make doctors aware of the problems associated with the long-term use of benzodiazepines, as well as the dangers of benzodiazepine drug addiction.

In 1980, the Medicines and Healthcare Products Regulatory Agency’s Committee on the Safety of Medicines issued guidance restricting the use of benzodiazepines to short-term use and updated and strengthened these warnings in 1988. When asked by Phil Woolas in 1999 whether the Department of Health had any plans to conduct research into the long-term effects of benzodiazepines, the Department replied, saying they have no plans to do so, as benzodiazepines are already restricted to short-term use and monitored by regulatory bodies. In a House of Commons debate, Phil Woolas claimed that there had been a cover-up of problems associated with benzodiazepines because they are of too large of a scale for governments, regulatory bodies, and the pharmaceutical industry to deal with. John Hutton stated in response that the Department of Health took the problems of benzodiazepines extremely seriously and was not sweeping the issue under the carpet. In 2010, the All-Party Parliamentary Group on Involuntary Tranquilliser Addiction filed a complaint with the Equality and Human Rights Commission under the Disability Discrimination Act 1995 against the Department of Health and the Department for Work and Pensions alleging discrimination against people with a benzodiazepine prescription drug dependence as a result of denial of specialised treatment services, exclusion from medical treatment, non-recognition of the protracted benzodiazepine withdrawal syndrome, as well as denial of rehabilitation and back-to-work schemes. Additionally the APPGITA complaint alleged that there is a “virtual prohibition” on the collection of statistical information on benzodiazepines across government departments, whereas with other controlled drugs there are enormous volumes of statistical data. The complaint alleged that the discrimination is deliberate, large scale and that government departments are aware of what they are doing.

Declassified Medical Research Council Meeting

The UK Medical Research Council (MRC) held a closed meeting among top UK medical doctors and representatives from the pharmaceutical industry between the dates of 30 October 1980 and 3 April 1981. The meeting was classified under the Public Records Act 1958 until 2014 but became available in 2005 as a result of the Freedom of Information Act. The meeting was called due to concerns that 10-100,000 people could be dependent; meeting chairman Professor Malcolm Lader later revised this estimate to include approximately half a million members of the British public suspected of being dependent on therapeutic dose levels of benzodiazepines, with about half of those on long-term benzodiazepines. It was reported that benzodiazepines may be the third- or fourth-largest drug problem in the UK (the largest being alcohol and tobacco). The Chairman of the meeting followed up after the meeting with additional information, which was forwarded to the Medical Research Council neuroscience board, raising concerns regarding tests that showed definite cortical atrophy in 2 of 14 individuals tested and borderline abnormality in five others. He felt that, due to the methodology used in assessing the scans, the abnormalities were likely an underestimate, and more refined techniques would be more accurate. Also discussed were findings that tolerance to benzodiazepines can be demonstrated by injecting diazepam into long-term users; in normal subjects, increases in growth hormone occurs, whereas in benzodiazepine-tolerant individuals this effect is blunted. Also raised were findings in animal studies that showed the development of tolerance in the form of a 15% reduction in binding capacity of benzodiazepines after seven days administration of high doses of the partial agonist benzodiazepine drug flurazepam and a 50% reduction in binding capacity after 30 days of a low dose of diazepam. The Chairman was concerned that papers soon to be published would “stir the whole matter up” and wanted to be able to say that the Medical Research Council “had matters under consideration if questions were asked in parliament”. The Chairman felt that it “was very important, politically that the MRC should be ‘one step ahead'” and recommended epidemiological studies be funded and carried out by Roche Pharmaceuticals and MRC sponsored research conducted into the biochemical effects of long-term use of benzodiazepines. The meeting aimed to identify issues that were likely to arise, alert the Department of Health to the scale of the problem and identify the pharmacology and nature of benzodiazepine dependence and the volume of benzodiazepines being prescribed. The World Health Organisation (WHO) was also interested in the problem and it was felt the meeting would demonstrate to the WHO that the MRC was taking the issue seriously. Among the psychological effects of long-term use of benzodiazepines discussed was a reduced ability to cope with stress. The Chairman stated that the “withdrawal symptoms from valium were much worse than many other drugs including, e.g. heroin”. It was stated that the likelihood of withdrawing from benzodiazepines was “reduced enormously” if benzodiazepines were prescribed for longer than four months. It was concluded that benzodiazepines are often prescribed inappropriately, for a wide range of conditions and situations. Dr Mason (DHSS) and Dr Moir (SHHD) felt that, due to the large numbers of people using benzodiazepines for long periods of time, it was important to determine the effectiveness and toxicity of benzodiazepines before deciding what regulatory action to take.

Controversy resulted in 2010 when the previously secret files came to light over the fact that the Medical Research Council was warned that benzodiazepines prescribed to millions of patients appeared to cause cerebral atrophy similar to hazardous alcohol use in some patients and failed to carry out larger and more rigorous studies. The Independent on Sunday reported allegations that “scores” of the 1.5 million members of the UK public who use benzodiazepines long-term have symptoms that are consistent with brain damage. It has been described as a “huge scandal” by Jim Dobbin, and legal experts and MPs have predicted a class action lawsuit. A solicitor said she was aware of the past failed litigation against the drug companies and the relevance the documents had to that court case and said it was strange that the documents were kept ‘hidden’ by the MRC.

Professor Lader, who chaired the MRC meeting, declined to speculate as to why the MRC declined to support his request to set up a unit to further research benzodiazepines and why they did not set up a special safety committee to look into these concerns. Professor Lader stated that he regrets not being more proactive on pursuing the issue, stating that he did not want to be labelled as the guy who pushed only issues with benzos. Professor Ashton also submitted proposals for grant-funded research using MRI, EEG, and cognitive testing in a randomised controlled trial to assess whether benzodiazepines cause permanent damage to the brain, but similarly to Professor Lader was turned down by the MRC.

The MRC spokesperson said they accept the conclusions of Professor Lader’s research and said that they fund only research that meets required quality standards of scientific research, and stated that they were and continue to remain receptive to applications for research in this area. No explanation was reported for why the documents were sealed by the Public Records Act.

Jim Dobbin, who chaired the All-Party Parliamentary Group for Involuntary Tranquilliser Addiction, stated that:

Many victims have lasting physical, cognitive and psychological problems even after they have withdrawn. We are seeking legal advice because we believe these documents are the bombshell they have been waiting for. The MRC must justify why there was no proper follow-up to Professor Lader’s research, no safety committee, no study, nothing to further explore the results. We are talking about a huge scandal here.

The legal director of Action Against Medical Accidents said urgent research must be carried out and said that, if the results of larger studies confirm Professor Lader’s research, the government and MRC could be faced with one of the biggest group actions for damages the courts have ever seen, given the large number of people potentially affected. People who report enduring symptoms post-withdrawal such as neurological pain, headaches, cognitive impairment, and memory loss have been left in the dark as to whether these symptoms are drug-induced damage or not due to the MRC’s inaction, it was reported. Professor Lader reported that the results of his research did not surprise his research group given that it was already known that alcohol could cause permanent brain changes.

Class-Action Lawsuit

Benzodiazepines spurred the largest-ever class-action lawsuit against drug manufacturers in the UK, in the 1980s and early 1990s, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the potential for dependence but intentionally withheld this information from doctors. At the same time, 117 general practitioners and 50 health authorities were sued by patients to recover damages for the harmful effects of dependence and withdrawal. This led some doctors to require a signed consent form from their patients and to recommend that all patients be adequately warned of the risks of dependence and withdrawal before starting treatment with benzodiazepines. The court case against the drug manufacturers never reached a verdict; legal aid had been withdrawn, leading to the collapse of the trial, and there were allegations that the consultant psychiatrists, the expert witnesses, had a conflict of interest. This litigation led to changes in British law, making class-action lawsuits more difficult.

Symptoms

Effects of long-term benzodiazepine use may include disinhibition, impaired concentration and memory, depression, as well as sexual dysfunction. The long-term effects of benzodiazepines may differ from the adverse effects seen after acute administration of benzodiazepines. An analysis of cancer patients found that those who took tranquillisers or sleeping tablets had a substantially poorer quality of life on all measurements conducted, as well as a worse clinical picture of symptomatology. Worsening of symptoms such as fatigue, insomnia, pain, dyspnoea and constipation was found when compared against those who did not take tranquillisers or sleeping tablets. Most individuals who successfully discontinue hypnotic therapy after a gradual taper and do not take benzodiazepines for 6 months have less severe sleep and anxiety problems, are less distressed and have a general feeling of improved health at 6-month follow-up. The use of benzodiazepines for the treatment of anxiety has been found to lead to a significant increase in healthcare costs due to accidents and other adverse effects associated with the long-term use of benzodiazepines.

Cognitive Status

Long-term benzodiazepine use can lead to a generalised impairment of cognition, including sustained attention, verbal learning and memory and psychomotor, visuo-motor and visuo-conceptual abilities. Transient changes in the brain have been found using neuroimaging studies, but no brain abnormalities have been found in patients treated long term with benzodiazepines. When benzodiazepine users cease long-term benzodiazepine therapy, their cognitive function improves in the first six months, although deficits may be permanent or take longer than six months to return to baseline. In the elderly, long-term benzodiazepine therapy is a risk factor for amplifying cognitive decline, although gradual withdrawal is associated with improved cognitive status. A study of alprazolam found that 8 weeks administration of alprazolam resulted in deficits that were detectable after several weeks but not after 3.5 years.

Effect on Sleep

Sleep architecture can be adversely affected by benzodiazepine dependence. Possible adverse effects on sleep include induction or worsening of sleep disordered breathing. Like alcohol, benzodiazepines are commonly used to treat insomnia in the short term (both prescribed and self-medicated), but worsen sleep in the long term. Although benzodiazepines can put people to sleep, while asleep, the drugs disrupt sleep architecture, decreasing sleep time, delayed and decreased REM sleep, increased alpha and beta activity, decreased K complexes and delta activity, and decreased deep slow-wave sleep (i.e. NREM stages 3 and 4, the most restorative part of sleep for both energy and mood).

Mental and Physical Health

The long-term use of benzodiazepines may have a similar effect on the brain as alcohol, and is also implicated in depression, anxiety, post-traumatic stress disorder (PTSD), mania, psychosis, sleep disorders, sexual dysfunction, delirium, and neurocognitive disorders. However a 2016 study found no association between long-term usage and dementia. As with alcohol, the effects of benzodiazepine on neurochemistry, such as decreased levels of serotonin and norepinephrine, are believed to be responsible for their effects on mood and anxiety. Additionally, benzodiazepines can indirectly cause or worsen other psychiatric symptoms (e.g. mood, anxiety, psychosis, irritability) by worsening sleep (i.e. benzodiazepine-induced sleep disorder).

Long-term benzodiazepine use may lead to the creation or exacerbation of physical and mental health conditions, which improve after six or more months of abstinence. After a period of about 3 to 6 months of abstinence after completion of a gradual-reduction regimen, marked improvements in mental and physical wellbeing become apparent. For example, one study of hypnotic users gradually withdrawn from their hypnotic medication reported after six months of abstinence that they had less severe sleep and anxiety problems, were less distressed, and had a general feeling of improved health. Those who remained on hypnotic medication had no improvements in their insomnia, anxiety, or general health ratings. A study found that individuals having withdrawn from benzodiazepines showed a marked reduction in use of medical and mental health services.

Approximately half of patients attending mental health services for conditions including anxiety disorders such as panic disorder or social phobia may be the result of alcohol or benzodiazepine dependence. Sometimes anxiety disorders precede alcohol or benzodiazepine dependence but the alcohol or benzodiazepine dependence often acts to keep the anxiety disorders going and often progressively makes them worse. Many people who are addicted to alcohol or prescribed benzodiazepines decide to quit when it is explained to them they have a choice between ongoing ill mental health or quitting and recovering from their symptoms. It was noted that because every individual has an individual sensitivity level to alcohol or sedative hypnotic drugs, what one person can tolerate without ill health will cause another to suffer very ill health, and that even moderate drinking in sensitive individuals can cause rebound anxiety syndromes and sleep disorders. A person who is suffering the toxic effects of alcohol or benzodiazepines will not benefit from other therapies or medications as they do not address the root cause of the symptoms. Recovery from benzodiazepine dependence tends to take a lot longer than recovery from alcohol, but people can regain their previous good health. A review of the literature regarding benzodiazepine hypnotic drugs concluded that these drugs cause an unjustifiable risk to the individual and to public health. The risks include dependence, accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep.

Daily users of benzodiazepines are also at a higher risk of experiencing psychotic symptomatology such as delusions and hallucinations. A study found that of 42 patients treated with alprazolam, up to a third of long-term users of the benzodiazepine drug alprazolam (Xanax) develop depression. Studies have shown that long-term use of benzodiazepines and the benzodiazepine receptor agonist nonbenzodiazepine Z drugs are associated with causing depression as well as a markedly raised suicide risk and an overall increased mortality risk.

A study of 50 patients who attended a benzodiazepine withdrawal clinic found that, after several years of chronic benzodiazepine use, a large portion of patients developed health problems including agoraphobia, irritable bowel syndrome, paraesthesia, increasing anxiety, and panic attacks, which were not pre-existing. The mental health and physical health symptoms induced by long-term benzodiazepine use gradually improved significantly over a period of a year following completion of a slow withdrawal. Three of the 50 patients had wrongly been given a preliminary diagnosis of multiple sclerosis when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken drug overdoses whilst on benzodiazepines, despite the fact that only two of the patients had any prior history of depressive symptomatology. After withdrawal, no patients took any further overdoses after one year post-withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal-type symptoms emerged, despite the administration of stable prescribed doses. Another theory is that chronic benzodiazepine use causes subtle increasing toxicity, which in turn leads to increasing psychopathology in long-term users of benzodiazepines.

Long-term use of benzodiazepines can induce perceptual disturbances and depersonalisation in some people, even in those taking a stable daily dosage, and it can also become a protracted withdrawal feature of the benzodiazepine withdrawal syndrome.

In addition, chronic use of benzodiazepines is a risk factor for blepharospasm. Drug-induced symptoms that resemble withdrawal-like effects can occur on a set dosage as a result of prolonged use, also documented with barbiturate-like substances, as well as alcohol and benzodiazepines. This demonstrates that the effects from chronic use of benzodiazepine drugs are not unique but occur with other GABAergic sedative hypnotic drugs, i.e. alcohol and barbiturates.

Immune System

Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department. Diazepam and clonazepam have been found to have long-lasting, but not permanent, immunotoxic effects in fetuses of rats. However, single very high doses of diazepam have been found to cause lifelong immunosuppression in neonatal rats. No studies have been done to assess the immunotoxic effects of diazepam in humans; however, high prescribed doses of diazepam, in humans, have been found to be a major risk of pneumonia, based on a study of people with tetanus. It have been proposed that diazepam may cause long-lasting changes to the GABAA receptors with resultant long-lasting disturbances to behaviour, endocrine function and immune function.

Suicide and Self-Harm

Use of prescribed benzodiazepines is associated with an increased rate of attempted and completed suicide. The prosuicidal effects of benzodiazepines are suspected to be due to a psychiatric disturbance caused by side effects or withdrawal symptoms. Because benzodiazepines in general may be associated with increased suicide risk, care should be taken when prescribing, especially to at-risk patients. Depressed adolescents who were taking benzodiazepines were found to have a greatly increased risk of self-harm or suicide, although the sample size was small. The effects of benzodiazepines in individuals under the age of 18 requires further research. Additional caution is required in using benzodiazepines in depressed adolescents. Benzodiazepine dependence often results in an increasingly deteriorating clinical picture, which includes social deterioration leading to comorbid alcohol use disorder and substance use disorder. Benzodiazepine misuse or misuse of other CNS depressants increases the risk of suicide in drug misusers. Benzodiazepine has several risks based on its biochemical function and symptoms associated with this medication like exacerbation of sleep apnoea, sedation, suppression of self-care functions, amnesia and disinhibition are suggested as a possible explanation to the increase in mortality. Studies also demonstrate that an increased mortality associated with benzodiazepine use has been clearly documented among ‘drug misusers’.

Carcinogenicity

There has been some controversy around the possible link between benzodiazepine use and development of cancer; early cohort studies in the 1980s suggested a possible link, but follow-up case-control studies have found no link between benzodiazepines and cancer. In the second US national cancer study in 1982, the American Cancer Society conducted a survey of over 1.1 million participants. A markedly increased risk of cancer was found in users of sleeping pills, mainly benzodiazepines. Fifteen epidemiologic studies have suggested that benzodiazepine or nonbenzodiazepine hypnotic drug use is associated with increased mortality, mainly due to increased cancer death. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. It has been hypothesised that benzodiazepines depress immune function and increase viral infections and could be the cause or trigger of the increased rate of cancer. While initially US Food and Drug Administration (FDA) reviewers expressed concerns about approving the nonbenzodiazepine Z drugs due to concerns of cancer, ultimately they changed their minds and approved the drugs. A 2017 meta-analysis of multiple observational studies found that benzodiazepine use is associated with increased cancer risk.

Brain Damage Evidence

In a study in 1980 in a group of 55 consecutively admitted patients having engaged in non-medical use of exclusively sedatives or hypnotics, neuropsychological performance was significantly lower and signs of intellectual impairment significantly more often diagnosed than in a matched control group taken from the general population. These results suggested a relationship between non-medical use of sedatives or hypnotics and cerebral disorder.

A publication asked in 1981 if lorazepam is more toxic than diazepam.

In a study in 1984, 20 patients having taken long-term benzodiazepines were submitted to brain CT scan examinations. Some scans appeared abnormal. The mean ventricular-brain ratio measured by planimetry was increased over mean values in an age- and sex-matched group of control subjects but was less than that in a group of alcoholics. There was no significant relationship between CT scan appearances and the duration of benzodiazepine therapy. The clinical significance of the findings was unclear.

In 1986, it was presumed that permanent brain damage may result from chronic use of benzodiazepines similar to alcohol-related brain damage.

In 1987, 17 inpatient people who used high doses of benzodiazepines non-medically have anecdotally shown enlarged cerebrospinal fluid spaces with associated cerebral atrophy. Cerebral atrophy reportedly appeared to be dose dependent with low-dose users having less atrophy than higher-dose users.

However, a CT study in 1987 found no evidence of cerebral atrophy in prescribed benzodiazepine users.

In 1989, in a 4- to 6-year follow-up study of 30 inpatient people who used benzodiazepines non-medically, Neuropsychological function was found to be permanently affected in some people long-term high dose non-medical use of benzodiazepines. Brain damage similar to alcoholic brain damage was observed. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike people who consume excessive alcohol, people who use sedative hypnotic agents non-medically showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in people who use high doses of sedative hypnotic benzodiazepines, it is often permanent.

A CT study in 1993 investigated brain damage in benzodiazepine users and found no overall differences to a healthy control group.

A study in 2000 found that long-term benzodiazepine therapy does not result in brain abnormalities.

Withdrawal from high-dose use of nitrazepam anecdotally was alleged in 2001 to have caused severe shock of the whole brain with diffuse slow activity on EEG in one patient after 25 years of use. After withdrawal, abnormalities in hypofrontal brain wave patterns persisted beyond the withdrawal syndrome, which suggested to the authors that organic brain damage occurred from chronic high-dose use of nitrazepam.

Professor Heather Ashton, a leading expert on benzodiazepines from Newcastle University Institute of Neuroscience, has stated that there is no structural damage from benzodiazepines, and advocates for further research into long-lasting or possibly permanent symptoms of long-term use of benzodiazepines as of 1996. She has stated that she believes that the most likely explanation for lasting symptoms is persisting but slowly resolving functional changes at the GABAA benzodiazepine receptor level. Newer and more detailed brain scanning technologies such as PET scans and MRI scans had as of 2002 to her knowledge never been used to investigate the question of whether benzodiazepines cause functional or structural brain damage.

A 2018 review of the research found a likely causative role between the use of benzodiazepines and an increased risk of dementia, but the exact nature of the relationship is still a matter of debate.

Special Populations

Neonatal Effects

Benzodiazepines have been found to cause teratogenic malformations. The literature concerning the safety of benzodiazepines in pregnancy is unclear and controversial. Initial concerns regarding benzodiazepines in pregnancy began with alarming findings in animals but these do not necessarily cross over to humans. Conflicting findings have been found in babies exposed to benzodiazepines. A recent analysis of the Swedish Medical Birth Register found an association with preterm births, low birth weight and a moderate increased risk for congenital malformations. An increase in pylorostenosis or alimentary tract atresia was seen. An increase in orofacial clefts was not demonstrated, however, and it was concluded that benzodiazepines are not major teratogens.

Neurodevelopmental disorders and clinical symptoms are commonly found in babies exposed to benzodiazepines in utero. Benzodiazepine-exposed babies have a low birth weight but catch up to normal babies at an early age, but smaller head circumferences found in benzo babies persists. Other adverse effects of benzodiazepines taken during pregnancy are deviating neurodevelopmental and clinical symptoms including craniofacial anomalies, delayed development of pincer grasp, deviations in muscle tone and pattern of movements. Motor impairments in the babies are impeded for up to 1 year after birth. Gross motor development impairments take 18 months to return to normal but fine motor function impairments persist. In addition to the smaller head circumference found in benzodiazepine-exposed babies mental retardation, functional deficits, long-lasting behavioural anomalies, and lower intelligence occurs.

Benzodiazepines, like many other sedative hypnotic drugs, cause apoptotic neuronal cell death. However, benzodiazepines do not cause as severe apoptosis to the developing brain as alcohol does. The prenatal toxicity of benzodiazepines is most likely due to their effects on neurotransmitter systems, cell membranes and protein synthesis. This, however, is complicated in that neuropsychological or neuropsychiatric effects of benzodiazepines, if they occur, may not become apparent until later childhood or even adolescence. A review of the literature found data on long-term follow-up regarding neurobehavioural outcomes is very limited. However, a study was conducted that followed up 550 benzodiazepine-exposed children, which found that, overall, most children developed normally. There was a smaller subset of benzodiazepine-exposed children who were slower to develop, but by four years of age most of this subgroup of children had normalised. There was a small number of benzodiazepine-exposed children who had continuing developmental abnormalities at 4-year follow-up, but it was not possible to conclude whether these deficits were the result of benzodiazepines or whether social and environmental factors explained the continuing deficits.

Concerns regarding whether benzodiazepines during pregnancy cause major malformations, in particular cleft palate, have been hotly debated in the literature. A meta analysis of the data from cohort studies found no link but meta analysis of case–control studies did find a significant increase in major malformations. (However, the cohort studies were homogenous and the case-control studies were heterogeneous, thus reducing the strength of the case-control results). There have also been several reports that suggest that benzodiazepines have the potential to cause a syndrome similar to foetal alcohol syndrome, but this has been disputed by a number of studies. As a result of conflicting findings, use of benzodiazepines during pregnancy is controversial. The best available evidence suggests that benzodiazepines are not a major cause of birth defects, i.e. major malformations or cleft lip or cleft palate.

Elderly

Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use. Benzodiazepines, along with antihypertensives and drugs affecting the cholinergic system, are the most common cause of drug-induced dementia affecting over 10 percent of patients attending memory clinics. Long-term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including drowsiness, ataxia, fatigue, confusion, weakness, dizziness, vertigo, syncope, reversible dementia, depression, impairment of intellect, psychomotor and sexual dysfunction, agitation, auditory and visual hallucinations, paranoid ideation, panic, delirium, depersonalisation, sleepwalking, aggressiveness, orthostatic hypotension and insomnia. Depletion of certain neurotransmitters and cortisol levels and alterations in immune function and biological markers can also occur. Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of post-operative confusion. Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine hypnotic users without worsening of insomnia.

A review of the evidence has found that whilst long-term use of benzodiazepines impairs memory, its association with causing dementia is not clear and requires further research. A more recent study found that benzodiazepines are associated with an increased risk of dementia and it is recommended that benzodiazepines be avoided in the elderly. A later study, however, found no increase in dementia associated with long-term usage of benzodiazepine.