Clinical Institute Withdrawal Assessment for Alcohol?

Introduction

The Clinical Institute Withdrawal Assessment for Alcohol, commonly abbreviated as CIWA or CIWA-Ar (revised version), is a 10-item scale used in the assessment and management of alcohol withdrawal.

Each item on the scale is scored independently, and the summation of the scores yields an aggregate value that correlates to the severity of alcohol withdrawal, with ranges of scores designed to prompt specific management decisions such as the administration of benzodiazepines. The maximum score is 67; Mild alcohol withdrawal is defined with a score less than or equal to 10, moderate with scores 11 to 15, and severe with any score equal to or greater than 16.

CIWA-Ar

The CIWA-Ar is actually a shortened, improved version of the CIWA, geared towards objectifying alcohol withdrawal symptom severity. It retains validity, usefulness and reliability between rater’s. This revised version is the most commonly used scale in alcohol withdrawal, and was developed at the Addiction Research Foundation (now Centre for Addiction and Mental Health).

Scale

The ten items evaluated on the scale are common symptoms and signs of alcohol withdrawal, and are as follows:

  • Nausea and vomiting.
  • Tremor.
  • Paroxysmal sweats.
  • Anxiety.
  • Agitation.
  • Tactile disturbances.
  • Auditory disturbances.
  • Visual disturbances.
  • Headache.
  • Orientation and clouded sensorium.

Scoring

All items are scored from 0-7, with the exception of the orientation category, scored from 0-4. The CIWA scale is validated and has high inter-rater reliability. A randomised, double blind trial published in JAMA in 1994 showed that management for alcohol withdrawal that was guided by the CIWA scale resulted in decreased treatment duration and total use of benzodiazepines. The goal of the CIWA scale is to provide an efficient and objective means of assessing alcohol withdrawal. Studies have shown that use of the scale in management of alcohol withdrawal leads to decreased frequency of over-sedation with benzodiazepines in patients with milder alcohol withdrawal than would otherwise be detected without use of the scale, and decreased frequency of under-treatment in patients with greater severity of withdrawal than would otherwise be determined without the scale.

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

What is Climazolam?

Introduction

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

Background

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

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

What is Midazolam?

Introduction

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

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

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

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

Brief History

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

Medical Uses

Seizures

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

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

Procedural Sedation

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

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

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

Agitation

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

End of Life Care

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

Administration

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

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

Contraindications

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

Side Effects

Refer to Long-Term Effects of Benzodiazepines.

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

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

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

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

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

Pregnancy and Breastfeeding

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

Elderly

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

Tolerance, Dependence, and Withdrawal

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

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

Overdose

Refer to Benzodiazepine Overdose.

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

Symptoms of midazolam overdose can include:

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

Detection in Body Fluids

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

Interactions

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

Pharmacology

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

Pharmacokinetics

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

Society and Culture

Cost

Midazolam is available as a generic medication.

Availability

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

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

Legal Status

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

Marketing Authorisation

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

Use in Executions

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

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

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

Notable Incidents

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

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

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

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

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

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

Legal Challenges

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

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

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

What is Physical Dependence?

Introduction

Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms.

Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes.

Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or “PAWS”, is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular mis-association with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

Symptoms

Physical dependence can manifest itself in the appearance of both physical and psychological symptoms which are caused by physiological adaptions in the central nervous system and the brain due to chronic exposure to a substance. Symptoms which may be experienced during withdrawal or reduction in dosage include increased heart rate and/or blood pressure, sweating, and tremors.[9] More serious withdrawal symptoms such as confusion, seizures, and visual hallucinations indicate a serious emergency and the need for immediate medical care.

Sedative hypnotic drugs such as alcohol, benzodiazepines, and barbiturates are the only commonly available substances that can be fatal in withdrawal due to their propensity to induce withdrawal convulsions. Abrupt withdrawal from other drugs, such as opioids can cause an extremely painful withdrawal that is very rarely fatal in patients of general good health and with medical treatment, but is more often fatal in patients with weakened cardiovascular systems; toxicity is generally caused by the often-extreme increases in heart rate and blood pressure (which can be treated with clonidine), or due to arrhythmia due to electrolyte imbalance caused by the inability to eat, and constant diarrhoea and vomiting (which can be treated with loperamide and ondansetron respectively) associated with acute opioid withdrawal, especially in longer-acting substances where the diarrhoea and emesis can continue unabated for weeks, although life-threatening complications are extremely rare, and nearly non-existent with proper medical management.

Treatment

Treatment for physical dependence depends upon the drug being withdrawn and often includes administration of another drug, especially for substances that can be dangerous when abruptly discontinued or when previous attempts have failed. Physical dependence is usually managed by a slow dose reduction over a period of weeks, months or sometimes longer depending on the drug, dose and the individual. A physical dependence on alcohol is often managed with a cross tolerant drug, such as long acting benzodiazepines to manage the alcohol withdrawal symptoms.

Drugs That Cause Physical Dependence

  • All µ-opioids with any (even slight) agonist effect, such as (partial list) morphine, heroin, codeine, oxycodone, buprenorphine, nalbuphine, methadone, and fentanyl, but not agonists specific to non-µ opioid receptors, such as salvinorin A (a k-opioid agonist), nor opioid antagonists or inverse agonists, such as naltrexone (a universal opioid inverse agonist).
  • All GABA agonists and positive allosteric modulators of both the GABA-A ionotropic receptor and GABA-B metabotropic receptor subunits, including (partial list):
  • Nicotine (tobacco) (cf. nicotine withdrawal).
  • Gabapentinoids such as gabapentin (Neurontin), pregabalin (Lyrica), and phenibut (Noofen), which are inhibitors of α2δ subunit-containing VDCCs.
  • Antiepileptic drugs such as valproate, lamotrigine, tiagabine, vigabatrin, carbamazepine and oxcarbazepine, and topiramate.
  • Antipsychotic drugs such as clozapine, risperidone, olanzapine, haloperidol, thioridazine, etc.
  • Commonly prescribed antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (cf. SSRI/SNRI withdrawal syndrome).
  • Blood pressure medications, including beta blockers such as propanolol and alpha-adrenergic agonists such as clonidine.
  • Androgenic-anabolic steroids.
  • Glucocorticoids.

Rebound Syndrome

Refer to Rebound Effect.

A wide range of drugs whilst not causing a true physical dependence can still cause withdrawal symptoms or rebound effects during dosage reduction or especially abrupt or rapid withdrawal. These can include caffeine, stimulants, steroidal drugs and antiparkinsonian drugs. It is debated whether the entire antipsychotic drug class causes true physical dependency, a subset, or if none do. But, if discontinued too rapidly, it could cause an acute withdrawal syndrome. When talking about illicit drugs rebound withdrawal, especially with stimulants, it is sometimes referred to as “coming down” or “crashing”.

Some drugs, like anticonvulsants and antidepressants, describe the drug category and not the mechanism. The individual agents and drug classes in the anticonvulsant drug category act at many different receptors and it is not possible to generalise their potential for physical dependence or incidence or severity of rebound syndrome as a group so they must be looked at individually. Anticonvulsants as a group however are known to cause tolerance to the anti-seizure effect. SSRI drugs, which have an important use as antidepressants, engender a discontinuation syndrome that manifests with physical side effects; e.g. there have been case reports of a discontinuation syndrome with venlafaxine (Effexor).

What is Nordazepam?

Introduction

Nordazepam (INN; marketed under brand names Nordaz, Stilny, Madar, Vegesan, and Calmday; also known as nordiazepam, desoxydemoxepam, and desmethyldiazepam) is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

Nordazepam is among the longest lasting (longest half-life) benzodiazepines, and its occurrence as a metabolite is responsible for most cumulative side-effects of its myriad of pro-drugs when they are used repeatedly at moderate-high doses; the nordazepam metabolite oxazepam is also active (and is a more potent, full benzodiazepine-site agonist), which contributes to nordazepam cumulative side-effects but occur too minutely to contribute to the cumulative side-effects of nordazepam pro-drugs (except when they are abused chronically in extremely supra-therapeutic doses).

Side effects

Common side effects of nordazepam include somnolence, which is more common in elderly patients and/or people on high-dose regimens. Hypotonia, which is much less common, is also associated with high doses and/or old age.

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. As with many other drugs, changes in liver function associated with aging or diseases such as cirrhosis, may lead to impaired clearance of nordazepam.

Pharmacology

Nordazepam is a partial agonist at the GABAA receptor, which makes it less potent than other benzodiazepines, particularly in its amnesic and muscle-relaxing effects. Its elimination half life is between 36 and 200 hours, with wide variation among individuals; factors such as age and gender are known to impact it. The variation of reported half-lives are attributed to differences in nordazepam metabolism and that of its metabolites as nordazepam is hydroxylated to active metabolites such as oxazepam, before finally being glucuronidated and excreted in the urine. This can be attributed to extremely variable hepatic and renal metabolic functions among individuals depending upon a number of factors (including age, ethnicity, disease, and current or previous use/abuse of other drugs/medicines).

Pregnancy and Nursing Mothers

Nordazepam, like other benzodiazepines, easily crosses the placental barrier, so the drug should not be administered during the first trimester of pregnancy. In case of serious medical reasons, nordazepam can be given in late pregnancy, but the foetus, due to the pharmacological action of the drug, may experience side effects such as hypothermia, hypotonia, and sometimes mild respiratory depression. Since nordazepam and other benzodiazepines are excreted in breast milk, the substance should not be administered to mothers who are breastfeeding. Discontinuing of breast-feeding is indicated for regular intake by the mother.

Recreational Use

Refer to Benzodiazepine Use Disorder.

Nordazepam and other sedative-hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Many drivers have blood levels far exceeding the therapeutic dose range, suggesting benzodiazepines are commonly used in doses higher than the recommended doses.

What is Fosazepam?

Introduction

Fosazepam is a drug which is a benzodiazepine derivative; it is a water soluble derivative of diazepam. It has sedative and anxiolytic effects, and is a derivative of diazepam which has been substituted with a dimethylphosphoryl group to improve solubility in water.

Background

Fosazepam has similar effects on sleep as other benzodiazepines. In a clinical trial it was reported that fosazepam to lead to increased sleep duration with less broken sleep but sleep quality was worsened with suppressed deep sleep and increased light sleep. Adverse effects included feelings of impaired morning vitality and upon discontinuing the drug benzodiazepine withdrawal symptoms of anxiety, impaired concentration and impaired morning vitality were experienced. Another clinical trial also found worsening of sleep while on benzodiazepines as well as during withdrawal with suppression of deep sleep stages including REM (rapid eye movement) sleep, with increased light sleep upon withdrawal. The main metabolites of fosazepam are 3-hydroxyfosazepam and the active metabolite desmethyldiazepam which has a very long elimination half-life of about 3 days. Tolerance to the hypnotic effects of fosazepam starts to develop after about 7 days of use. Due to the very long elimination half-life of the active metabolite of fosazepam it is not recommended for use as a hypnotic. The main pharmacological effects of fosazepam may be due to its metabolite nordiazepam (desmethyldiazepam), rather than the parent drug. The long-acting active metabolite nordazepam (refer to nordiazepam) can cause extended sedative effects at high doses or with prolonged use, and may produce residual sedation upon awakening.

Fosazepam is of relatively low potency compared to other benzodiazepine derivatives, with a 100 mg dose of fosazepam equivalent to 10 mg of nitrazepam. 60 mg of fosazepam has also been estimated to be equivalent to about 5-10 mg of diazepam. Fosazepam has similar effects to nitrazepam, but with a shorter duration of action and less tendency to cause over sedation, motor-impairment, amnesia, rebound insomnia, and morning grogginess.

What is Flutoprazepam?

Introduction

Flutoprazepam (Restas) is a drug which is a benzodiazepine.

It was patented in Japan by Sumitomo in 1972 and its medical use remains mostly confined to that country. Its muscle relaxant properties are approximately equivalent to those of diazepam – however, it has more powerful sedative, hypnotic, anxiolytic and anticonvulsant effects and is around four times more potent by weight compared to diazepam. It is longer acting than diazepam due to its long-acting active metabolites, which contribute significantly to its effects. Its principal active metabolite is n-desalkylflurazepam, also known as norflurazepam, which is also a principal metabolite of flurazepam (trade name Dalmane).

Flutoprazepam is typically used for the treatment of severe insomnia and may also be used for treating stomach ulcers.

Flutoprazepam does not fall under the international Convention on Psychotropic Substances of 1971, and is currently unscheduled in the United States.

  • In Singapore, flutoprazepam is a Class C-Schedule II drug under the Misuse of Drugs Act.
  • In Thailand, flutoprazepam is a Schedule III psychotropic substance.
  • In Hong Kong, flutoprazepam is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance.
    • Flutoprazepam can only be used legally by health professionals and for university research purposes.
    • The substance can be given by pharmacists under a prescription.
    • Anyone who supplies the substance without prescription can be fined $10000 (HKD).
    • The penalty for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment.
    • Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.

What is Flunitrazolam?

Introduction

Flunitrazolam (FNTZ, Flunazolam) is a triazolobenzodiazepine (TBZD), which are benzodiazepine (BZD) derivatives, that has been sold online as a designer drug, and is a potent hypnotic and sedative drug similar to related compounds such as flunitrazepam, clonazolam and flubromazolam.

Background

It was first definitively identified and reported to the EMCDDA Early Warning System, by an analytical laboratory in Germany in October 2016, and had not been described in the scientific or patent literature before this.

It is the triazole analogue of Flunitrazepam (Rohypnol).

The addition of the triazole ring to the scaffold increases potency significantly, this is evident as flunitrazolam is reported anecdotally to be active in the microgram level.

What is Flubromazepam?

Introduction

Flubromazepam is a benzodiazepine derivative which was first synthesized in 1960, but was never marketed and did not receive any further attention or study until late 2012 when it appeared on the grey market as a novel designer drug.

It is a structural analogue of phenazepam in which the chlorine atom has been replaced by a fluorine atom.

An alternative isomer, 5-(2-bromophenyl)-7-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one or “iso-flubromazepam”, may have been sold under the same name.

United Kingdom

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

United States

Flubromazepam, clonazolam, and flubromazolam are Schedule I controlled substances under Virginia State Law.