Substance use disorder

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Substance_use_disorder 

 

Substance use disorder
Other names	Drug use disorder
Specialty	Psychiatry, clinical psychology
Complications	Drug overdose

Substance use disorder (SUD) is the persistent use of drugs (including alcohol) despite substantial harm and adverse consequences. Substance use disorders are characterized by an array of mental/emotional, physical, and behavioral problems such as chronic guilt; an inability to reduce or stop consuming the substance(s) despite repeated attempts; driving while intoxicated; and physiological withdrawal symptoms. Drug classes that are involved in SUD include: alcohol; cannabis; phencyclidine and other hallucinogens, such as arylcyclohexylamines; inhalants; opioids; sedatives, hypnotics, or anxiolytics; stimulants; tobacco; and other or unknown substances.

In the Diagnostic and Statistical Manual of Mental Disorders 5th edition (2013), also known as DSM-5, the DSM-IV diagnoses of substance abuse and substance dependence were merged into the category of substance use disorders. The severity of substance use disorders can vary widely; in the DSM-5 diagnosis of a SUD, the severity of an individual's SUD is qualified as mild, moderate, or severe on the basis of how many of the 11 diagnostic criteria are met. The International Classification of Diseases 11th revision (ICD-11) divides substance use disorders into two categories: (1) harmful pattern of substance use; and (2) substance dependence.

In 2017, globally 271 million people (5.5% of adults) were estimated to have used one or more illicit drugs. Of these, 35 million had a substance use disorder. An additional 237 million men and 46 million women have alcohol use disorder as of 2016. In 2017, substance use disorders from illicit substances directly resulted in 585,000 deaths. Direct deaths from drug use, other than alcohol, have increased over 60 percent from 2000 to 2015. Alcohol use resulted in an additional 3 million deaths in 2016.

Causes

This section divides substance use disorder causes into categories consistent with the biopsychosocial model. However, it is important to bear in mind that these categories are used by scientists partly for convenience; the categories often overlap (for example, adolescents and adults whose parents had (or have) an alcohol use disorder display higher rates of alcohol problems, a phenomenon that can be due to genetic, observational learning, socioeconomic, and other causal factors); and these categories are not the only ways to classify substance use disorder etiology.

Similarly, most researchers in this and related areas (such as the etiology of psychopathology generally), emphasize that various causal factors interact and influence each other in complex and multifaceted ways.

Social determinants

Among older adults, being divorced, separated, or single; having more financial resources; lack of religious affiliation; bereavement; involuntary retirement; and homelessness are all associated with alcohol problems, including alcohol use disorder.

Psychological determinants

Psychological causal factors include cognitive, affective, and developmental determinants, among others. For example, individuals who begin using alcohol or other drugs in their teens are more likely to have a substance use disorder as adults. Other common risk factors are being male, being under 25, having other mental health problems (with the latter two being related to symptomatic relapse, impaired clinical and psychosocial adjustment, reduced medication adherence, and lower response to treatment), and lack of familial support and supervision. (As mentioned above, some of these causal factors can also be categorized as social or biological). Other psychological risk factors include high impulsivity, sensation seeking, neuroticism and openness to experience in combination with low conscientiousness.

Biological determinants

Children born to parents with SUDs have roughly a two-fold increased risk in developing a SUD compared to children born to parents without any SUDs.

Diagnosis

Addiction and dependence glossary
addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake) drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose drug withdrawal – symptoms that occur upon cessation of repeated drug use physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens) psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia) reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach sensitization – an amplified response to a stimulus resulting from repeated exposure to it substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

Individuals whose drug or alcohol use cause significant impairment or distress may have a substance use disorder (SUD). Diagnosis usually involves an in-depth examination, typically by psychiatrist, psychologist, or drug and alcohol counselor. The most commonly used guidelines are published in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). There are 11 diagnostic criteria which can be broadly categorized into issues arising from substance use related to loss of control, strain to one's interpersonal life, hazardous use, and pharmacologic effects.

DSM-5 guidelines for the diagnosis of a substance use disorder require that the individual have significant impairment or distress from their pattern of drug use, and at least two of the symptoms listed below in a given year.

1. Using more of a substance than planned, or using a substance for a longer interval than desired
2. Inability to cut down despite desire to do so
3. Spending substantial amount of the day obtaining, using, or recovering from substance use
4. Cravings or intense urges to use
5. Repeated usage causes or contributes to an inability to meet important social, or professional obligations
6. Persistent usage despite user's knowledge that it is causing frequent problems at work, school, or home
7. Giving up or cutting back on important social, professional, or leisure activities because of use
8. Using in physically hazardous situations, or usage causing physical or mental harm
9. Persistent use despite the user's awareness that the substance is causing or at least worsening a physical or mental problem
10. Tolerance: needing to use increasing amounts of a substance to obtain its desired effects
11. Withdrawal: characteristic group of physical effects or symptoms that emerge as amount of substance in the body decreases

There are additional qualifiers and exceptions outlined in the DSM. For instance, if an individual is taking opiates as prescribed, they may experience physiologic effects of tolerance and withdrawal, but this would not cause an individual to meet criteria for a SUD without additional symptoms also being present. A physician trained to evaluate and treat substance use disorders will take these nuances into account during a diagnostic evaluation.

Severity

Substance use disorders can range widely in severity, and there are numerous methods to monitor and qualify the severity of an individual's SUD. The DSM-5 includes specifiers for severity of a SUD. Individuals who meet only 2 or 3 criteria are often deemed to have mild SUD. Substance users who meet 4 or 5 criteria may have their SUD described as moderate, and persons meeting 6 or more criteria as severe. In the DSM-5, the term drug addiction is synonymous with severe substance use disorder. The quantity of criteria met offer a rough gauge on the severity of illness, but licensed professionals will also take into account a more holistic view when assessing severity which includes specific consequences and behavioral patterns related to an individual's substance use. They will also typically follow frequency of use over time, and assess for substance-specific consequences, such as the occurrence of blackouts, or arrests for driving under the influence of alcohol, when evaluating someone for an alcohol use disorder. There are additional qualifiers for stages of remission that are based on the amount of time an individual with a diagnosis of a SUD has not met any of the 11 criteria except craving. Some medical systems refer to an Addiction Severity Index to assess the severity of problems related to substance use. The index assesses potential problems in seven categories: medical, employment/support, alcohol, other drug use, legal, family/social, and psychiatric.

Screening tools

There are several different screening tools that have been validated for use with adolescents, such as the CRAFFT, and with adults, such as CAGE, AUDIT and DALI. Laboratory tests to detect alcohol and other drugs in urine and blood may be useful during the assessment process to confirm a diagnosis, to establish a baseline, and later, to monitor progress. However, since these tests measure recent substance use rather than chronic use or dependence, they are not recommended as screening tools.

Mechanisms

Main articles: Addiction § Mechanisms, and Substance dependence § Biomolecular mechanisms

Management

Detoxification

Depending on the severity of use, and the given substance, early treatment of acute withdrawal may include medical detoxification. Of note, acute withdrawal from heavy alcohol use should be done under medical supervision to prevent a potentially deadly withdrawal syndrome known as delirium tremens. See also Alcohol detoxification.

Therapy

Main article: Drug rehabilitation

Therapists often classify people with chemical dependencies as either interested or not interested in changing. About 11% of Americans with substance use disorder seek treatment, and 40–60% of those people relapse within a year. Treatments usually involve planning for specific ways to avoid the addictive stimulus, and therapeutic interventions intended to help a client learn healthier ways to find satisfaction. Clinical leaders in recent years have attempted to tailor intervention approaches to specific influences that affect addictive behavior, using therapeutic interviews in an effort to discover factors that led a person to embrace unhealthy, addictive sources of pleasure or relief from pain.

Treatments
Behavioral pattern	Intervention	Goals
Low self-esteem, anxiety, verbal hostility	Relationship therapy, client centered approach	Increase self-esteem, reduce hostility and anxiety
Defective personal constructs, ignorance of interpersonal means	Cognitive restructuring including directive and group therapies	Insight
Focal anxiety such as fear of crowds	Desensitization	Change response to same cue
Undesirable behaviors, lacking appropriate behaviors	Aversive conditioning, operant conditioning, counter conditioning	Eliminate or replace behavior
Lack of information	Provide information	Have client act on information
Difficult social circumstances	Organizational intervention, environmental manipulation, family counseling	Remove cause of social difficulty
Poor social performance, rigid interpersonal behavior	Sensitivity training, communication training, group therapy	Increase interpersonal repertoire, desensitization to group functioning
Grossly bizarre behavior	Medical referral	Protect from society, prepare for further treatment
Adapted from: Essentials of Clinical Dependency Counseling, Aspen Publishers

From the applied behavior analysis literature and the behavioral psychology literature, several evidence-based intervention programs have emerged, such as behavioral marital therapy, community reinforcement approach, cue exposure therapy, and contingency management strategies. In addition, the same author suggests that social skills training adjunctive to inpatient treatment of alcohol dependence is probably efficacious.

Medication

Medication-assisted treatment (MAT) refers to the combination of behavioral interventions and medications to treat substance use disorders. Certain medications can be useful in treating severe substance use disorders. In the United States five medications are approved to treat alcohol and opioid use disorders. There are no approved medications for cocaine, methamphetamine, or other substance use disorders as of 2002.

Medications, such as methadone and disulfiram, can be used as part of broader treatment plans to help a patient function comfortably without illicit opioids or alcohol. Medications can be used in treatment to lessen withdrawal symptoms. Evidence has demonstrated the efficacy of MAT at reducing illicit drug use and overdose deaths, improving retention in treatment, and reducing HIV transmission.

Epidemiology

The disability-adjusted life year, a measure of overall disease burden (number of years lost due to ill-health, disability or early death), from drug use disorders per 100,000 inhabitants in 2004

  no data

  <40

  40-80

  80-120

  120-160

  160-200

  200-240

  240-280

  280-320

  320-360

  360-400

  400–440

  >440

Rates of substance use disorders vary by nation and by substance, but the overall prevalence is high. On a global level, men are affected at a much higher rate than women. Younger individuals are also more likely to be affected than older adults.

United States

In 2017, roughly 7% of Americans aged 12 or older had a SUD in the past year. Rates of alcohol use disorder in the past year were just over 5%. Approximately 3% of people aged 12 or older had an illicit drug use disorder. The highest rates of illicit drug use disorder were among those aged 18 to 25 years old, at roughly 7%.

There were over 72,000 deaths from drug overdose in the United States in 2017, which is a threefold increase from 2002. However the CDC calculates alcohol overdose deaths separately; thus, this 72,000 number does not include the 2,366 alcohol overdose deaths in 2017. Overdose fatalities from synthetic opioids, which typically involve fentanyl, have risen sharply in the past several years to contribute to nearly 30,000 deaths per year. Death rates from synthetic opioids like fentanyl have increased 22-fold in the period from 2002 to 2017. Heroin and other natural and semi-synthetic opioids combined to contribute to roughly 31,000 overdose fatalities. Cocaine contributed to roughly 15,000 overdose deaths, while methamphetamine and benzodiazepines each contributed to roughly 11,000 deaths. Of note, the mortality from each individual drug listed above cannot be summed because many of these deaths involved combinations of drugs, such as overdosing on a combination of cocaine and an opioid.

Deaths from alcohol consumption account for the loss of over 88,000 lives per year. Tobacco remains the leading cause of preventable death, responsible for greater than 480,000 deaths in the United States each year. These harms are significant financially with total costs of more than $420 billion annually and more than $120 billion in healthcare.

Canada

According to Statistics Canada (2018), approximately one in five Canadians aged 15 years and older experience a substance use disorder in their lifetime. In Ontario specifically, the disease burden of mental illness and addiction is 1.5 times higher than all cancers together and over 7 times that of all infectious diseases. Across the country, the ethnic group that is statistically the most impacted by substance use disorders compared to the general population are the Indigenous peoples of Canada. In a 2019 Canadian study, it was found that Indigenous participants experienced greater substance-related problems than non-Indigenous participants.

Statistics Canada's Canadian Community Health Survey (2012) shows that alcohol was the most common substance for which Canadians met the criteria for abuse or dependence. Surveys on Indigenous people in British Columbia show that around 75% of residents on reserve feel alcohol use is a problem in their community and 25% report they have a problem with alcohol use themselves. However, only 66% of First Nations adults living on reserve drink alcohol compared to 76% of the general population. Further, in an Ontario study on mental health and substance use among Indigenous people, 19% reported the use of cocaine and opiates, higher than the 13% of Canadians in the general population that reported using opioids.

Australia

Historical and ongoing colonial practices continue to impact the health of Indigenous Australians, with Indigenous populations being more susceptible to substance use and related harms. For example, alcohol and tobacco are the predominant substances used in Australia. Although tobacco smoking is declining in Australia, it remains disproportionately high in Indigenous Australians with 45% aged 18 and over being smokers, compared to 16% among non-Indigenous Australians in 2014–2015. As for alcohol, while proportionately more Indigenous people refrain from drinking than non-Indigenous people, Indigenous people who do consume alcohol are more likely to do so at high-risk levels. About 19% of Indigenous Australians qualified for risky alcohol consumption (defined as 11 or more standard drinks at least once a month), which is 2.8 times the rate that their non-Indigenous counterparts consumed the same level of alcohol.

However, while alcohol and tobacco usage are declining, use of other substances, such as cannabis and opiates, is increasing in Australia. Cannabis is the most widely used illicit drug in Australia, with cannabis usage being 1.9 times higher than non-Indigenous Australians. Prescription opioids have seen the greatest increase in usage in Australia, although use is still lower that in the US. In 2016, Indigenous persons were 2.3 times more likely to misuse pharmaceutical drugs than non-Indigenous people.

Clonazepam

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Clonazepam 

Clonazepam

Clinical data
Pronunciation	kləˈnazɪpam
Trade names	Klonopin, Rivotril, others
AHFS/Drugs.com	Monograph
MedlinePlus	a682279
License data	US DailyMed: Clonazepam US FDA: Clonazepam
Pregnancy category	AU: B3
Dependence liability	Physical: Moderate to High Psychological: Moderate to High
Addiction liability	Moderate
Routes of administration	By mouth, intramuscular, intravenous, sublingual
Drug class	Benzodiazepine
ATC code	N03AE01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class B1 (Psychoactive drugs) CA: Schedule IV DE: Prescription only (Anlage III for higher doses) NZ: Class C UK: Controlled Drug (Benz) POM US: Schedule IV UN: Psychotropic Schedule IV In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	90%
Protein binding	≈85%
Metabolism	Liver (CYP3A)
Metabolites	7-aminoclonazepam; 7-acetaminoclonazepam; 3-hydroxy clonazepam
Onset of action	Within an hour
Elimination half-life	19–60 hours
Duration of action	6–12 hours
Excretion	Kidney
Identifiers

IUPAC name
CAS Number	1622-61-3
PubChem CID	2802
IUPHAR/BPS	6963
DrugBank	DB01068
ChemSpider	2700
UNII	5PE9FDE8GB
KEGG	D00280
ChEBI	CHEBI:3756
ChEMBL	ChEMBL452
CompTox Dashboard (EPA)	DTXSID1022845
ECHA InfoCard	100.015.088
Chemical and physical data
Formula	C15H10ClN3O3
Molar mass	315.71 g·mol−1
3D model (JSmol)	Interactive image

Clonazepam, sold under the brand Klonopin among others, is a medication used to prevent and treat seizures, panic disorder, anxiety, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class. It is taken by mouth. Effects begin within one hour and last between six and twelve hours.

Common side effects include sleepiness, poor coordination, and agitation. Long-term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. Dependence occurs in one-third of people who take clonazepam for longer than four weeks. There is an increased risk of suicide, particularly in people who are already depressed. If used during pregnancy it may result in harm to the fetus. Clonazepam binds to GABA_A receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid (GABA).

Clonazepam was patented in 1960 and went on sale in 1975 in the United States from Roche. It is available as a generic medication. In 2018, it was the 47th most commonly prescribed medication in the United States, with more than 17 million prescriptions. In many areas of the world it is commonly used as a recreational drug.

Medical uses

Clonazepam is prescribed for short term management of epilepsy, anxiety, and panic disorder with or without agoraphobia.

Seizures

Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.

Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam. As a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms. Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of non-convulsive status epilepticus; however, the benefits tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.

It is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures. A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.

Anxiety disorders

• Panic disorder with or without agoraphobia.
• Clonazepam has also been found effective in treating other anxiety disorders, such as social phobia, but this is an off-label use.

The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo-controlled. Clonazepam is also effective in the management of acute mania.

Muscle disorders

Restless legs syndrome can be treated using clonazepam as a third-line treatment option as the use of clonazepam is still investigational. Bruxism also responds to clonazepam in the short-term. Rapid eye movement sleep behavior disorder responds well to low doses of clonazepam.

• The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics.
• Spasticity related to amyotrophic lateral sclerosis.
• Alcohol withdrawal syndrome

Other

• Benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol or risperidone. The effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.
• Hyperekplexia
• Many forms of parasomnia and other sleep disorders are treated with clonazepam.
• It is not effective for preventing migraines.

Contraindications

Coma; current alcohol use disorder; current substance use disorder; and respiratory depression.

Adverse effects

In September 2020, the U.S. 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.

Common

• Sedation
• Motor impairment

Less common

• Confusion
• Irritability and aggression
• Psychomotor agitation
• Lack of motivation
• Loss of libido
• Impaired motor function
  • Impaired coordination
  • Impaired balance
  • Dizziness
• Cognitive impairments
  • Hallucinations.
  • Short-term memory loss
  • Anterograde amnesia (common with higher doses)
• Some users report hangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up. While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep. After regular use, rebound insomnia may occur when discontinuing clonazepam.
• Benzodiazepines may cause or worsen depression.

Occasional

• Dysphoria
• Induction of seizures or increased frequency of seizures
• Personality changes
• Behavioural disturbances
• Ataxia

Rare

• Suicide through disinhibition
• Psychosis
• Incontinence
• Liver damage
• Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities)
  • Rage
  • Excitement
  • Impulsivity

The long-term effects of clonazepam can include depression, disinhibition, and sexual dysfunction.

Drowsiness

Clonazepam, like other benzodiazepines, may impair a person's ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption, and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.

Withdrawal-related

• Anxiety
• Irritability
• Insomnia
• Tremors
• Headaches
• Stomach pain
• Nausea
• Hallucinations
• Suicidal thoughts or urges
• Depression
• Fatigue
• Dizziness
• Sweating
• Confusion
• Potential to exacerbate existing panic disorder upon discontinuation
• Seizures similar to delirium tremens (with long-term use of excessive doses)

Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behavior. Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal. Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug.

A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.

Tolerance and withdrawal

Main article: Benzodiazepine withdrawal syndrome

Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator. One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of the benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitization, down regulation, receptor decoupling, and alterations in subunit composition and in gene transcription coding.

Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long-term effectiveness as an anticonvulsant.

Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life-threatening condition, status epilepticus. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects. Carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring.

Overdose

Main article: Benzodiazepine overdose

Excess doses may result in:

• Difficulty staying awake
• Mental confusion
• Nausea
• Impaired motor functions
  • Impaired reflexes
  • Impaired coordination
  • Impaired balance
  • Dizziness
• Respiratory depression
• Low blood pressure
• Coma

Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who suffered an overdose of clonazepam. The combination of clonazepam and certain barbiturates (for example, amobarbital), at prescribed doses has resulted in a synergistic potentiation of the effects of each drug, leading to serious respiratory depression.

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.

Detection in biological fluids

Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum, or whole blood in order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses.

Special precautions

The elderly metabolize benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.

The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may have comorbid psychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.

Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam and phenobarbital.

Doses higher than 0.5–1 mg per day are associated with significant sedation.

Clonazepam may aggravate hepatic porphyria.

Clonazepam is not recommended for patients with chronic schizophrenia. A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.

Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.

Interactions

Clonazepam decreases the levels of carbamazepine, and, likewise, clonazepam's level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin (diphenylhydantoin). In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%. Clonazepam increases the levels of primidone and phenobarbital.

Combined use of clonazepam with certain antidepressants, anticonvulsants (such as phenobarbital, phenytoin, and carbamazepine), sedative antihistamines, opiates, and antipsychotics, nonbenzodiazepines (such as zolpidem), and alcohol may result in enhanced sedative effects.

Pregnancy

See also: Long-term effects of benzodiazepines § Neonatal effects

There is some medical evidence of various malformations, (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress.

The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the fetus. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors, or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds, diarrhea and vomiting, and growth retardation. This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolized is usually impaired in newborns. If clonazepam is used during pregnancy or breastfeeding, it is recommended that serum levels of clonazepam are monitored and that signs of central nervous system depression and apnea are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance of caffeine, can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.

Mechanism of action

Clonazepam enhances the activity of the inhibitory neurotransmitter Gamma-Aminobutyric acid (GABA) in the central nervous system to give its anticonvulsant, skeletal muscle relaxant, and anxiolytic effects. It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system.

Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.

Clonazepam's primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABA_A receptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABA_A receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA's inhibitory effects and resultant central nervous system depression. In addition, clonazepam decreases the utilization of 5-HT (serotonin) by neurons and has been shown to bind tightly to central-type benzodiazepine receptors. Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of "highly potent" benzodiazepines. The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in the feline brain and decreases prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid-stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines acted via micromolar benzodiazepine binding sites as Ca²⁺ channel blockers and significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.

Clonazepam is a 2'-chlorinated derivative of nitrazepam, which increases its potency due to electron-attracting effect of the halogen in the ortho-position.

Pharmacokinetics

Clonazepam is lipid-soluble, rapidly crosses the blood–brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine. Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, including CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19–60 hours. Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.

Clonazepam has plasma protein binding of 85%. Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam. These metabolites are excreted by the kidney.

It is effective for 6–8 hours in children, and 6–12 in adults.

Society and culture

Recreational use

See also: Benzodiazepine misuse

A 2006 US government study of hospital emergency department (ED) visits found that sedative-hypnotics were the most frequently implicated pharmaceutical drug in visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits. Alcohol alone was responsible for over twice as many ED visits as clonazepam in the same study. The study examined the number of times the non-medical use of certain drugs was implicated in an ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.

Formulations

Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available as tablets and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.

Brand names

Brand name clonazepam tablets

It is marketed under the trade name Rivotril by Roche in Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia, Germany, Hungary, Iceland, Ireland, Italy, China, Mexico, the Netherlands, Norway, Portugal, Peru, Romania, Serbia, South Africa, South Korea, Spain, Turkey, and the United States; Emcloz, Linotril and Clonotril in India and other parts of Europe; under the name Riklona in Indonesia and Malaysia; and under the trade name Klonopin by Roche in the United States. Other names, such as Clonoten, Ravotril, Rivotril, Iktorivil, Clonex, Paxam, Petril, Naze, Zilepam and Kriadex, are known throughout the world.

• 

  Klonopin 0.5 mg tablet

• 

  Klonopin 1 mg tablet

• 

  Klonopin 2 mg tablet

• 

  Clonazepam orally disintegrating tablet, 0.25 mg

 

Hypochondriasis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Hypochondriasis 

Hypochondriasis
Other names	Hypochondria, health anxiety (HA), illness anxiety disorder, somatic symptom disorder
Specialty	Psychiatry, psychology
Symptoms	Excessive and persistent fear of, or preoccupation with, having or developing a severe illness
Usual onset	Anytime from early childhood
Differential diagnosis	Actual serious medical condition, panic disorder, obsessive-compulsive disorder, generalized anxiety disorder
Treatment	Cognitive behavioral therapy (CBT)
Medication	SSRI, antidepressants
Prognosis	~50% meet criteria after ~1-5 yrs
Frequency	~5%

Hypochondriasis or hypochondria is a condition in which a person is excessively and unduly worried about having a serious illness. An old concept, the meaning of hypochondria has repeatedly changed. It has been claimed that this debilitating condition results from an inaccurate perception of the condition of body or mind despite the absence of an actual medical diagnosis. An individual with hypochondriasis is known as a hypochondriac. Hypochondriacs become unduly alarmed about any physical or psychological symptoms they detect, no matter how minor the symptom may be, and are convinced that they have, or are about to be diagnosed with, a serious illness.

Often, hypochondria persists even after a physician has evaluated a person and reassured them that their concerns about symptoms do not have an underlying medical basis or, if there is a medical illness, their concerns are far in excess of what is appropriate for the level of disease. It is also referred to hypochondriaism which is the act of being in a hypochondriatic state, acute hypochondriaism. Many hypochondriacs focus on a particular symptom as the catalyst of their worrying, such as gastro-intestinal problems, palpitations, or muscle fatigue. To qualify for the diagnosis of hypochondria the symptoms must have been experienced for at least 6 months.

International Classification of Diseases (ICD-10) classifies hypochondriasis as a mental and behavioral disorder. In the Diagnostic and Statistical Manual of Mental Disorders, DSM-IV-TR defined the disorder, "Hypochondriasis", as a somatoform disorder and one study has shown it to affect about 3% of the visitors to primary care settings. The 2013 DSM-5 replaced the diagnosis of hypochondriasis with the diagnoses of somatic symptom disorder (75%) and illness anxiety disorder (25%).

Hypochondria is often characterized by fears that minor bodily or mental symptoms may indicate a serious illness, constant self-examination and self-diagnosis, and a preoccupation with one's body. Many individuals with hypochondriasis express doubt and disbelief in the doctors' diagnosis, and report that doctors’ reassurance about an absence of a serious medical condition is unconvincing, or short-lasting. Additionally, many hypochondriacs experience elevated blood pressure, stress, and anxiety in the presence of doctors or while occupying a medical facility, a condition known as "white coat syndrome". Many hypochondriacs require constant reassurance, either from doctors, family, or friends, and the disorder can become a debilitating challenge for the individual with hypochondriasis, as well as their family and friends. Some hypochondriacal individuals completely avoid any reminder of illness, whereas others frequently visit medical facilities, sometimes obsessively. Some sufferers may never speak about it.

Signs and symptoms

Hypochondriasis is categorized as a somatic amplification disorder—a disorder of "perception and cognition"—that involves a hyper-vigilance of situation of the body or mind and a tendency to react to the initial perceptions in a negative manner that is further debilitating. Hypochondriasis manifests in many ways. Some people have numerous intrusive thoughts and physical sensations that push them to check with family, friends, and physicians. For example, a person who has a minor cough may think that they have tuberculosis. Or sounds produced by organs in the body, such as those made by the intestines, might be seen as a sign of a very serious illness to patients dealing with hypochondriasis.

Other people are so afraid of any reminder of illness that they will avoid medical professionals for a seemingly minor problem, sometimes to the point of becoming neglectful of their health when a serious condition may exist and go undiagnosed. Yet others live in despair and depression, certain that they have a life-threatening disease and no physician can help them. Some consider the disease as a punishment for past misdeeds.

Hypochondriasis is often accompanied by other psychological disorders. Bipolar disorder, clinical depression, obsessive-compulsive disorder (OCD), phobias, and somatization disorder are the most common accompanying conditions in people with hypochondriasis, as well as a generalized anxiety disorder diagnosis at some point in their life.

Many people with hypochondriasis experience a cycle of intrusive thoughts followed by compulsive checking, which is very similar to the symptoms of obsessive-compulsive disorder. However, while people with hypochondriasis are afraid of having an illness, patients with OCD worry about getting an illness or of transmitting an illness to others. Although some people might have both, these are distinct conditions.

Patients with hypochondriasis often are not aware that depression and anxiety produce their own physical symptoms, and mistake these symptoms for manifestations of another mental or physical disorder or disease. For example, people with depression often experience changes in appetite and weight fluctuation, fatigue, decreased interest in sex, and motivation in life overall. Intense anxiety is associated with rapid heartbeat, palpitations, sweating, muscle tension, stomach discomfort, dizziness, shortness of breath, and numbness or tingling in certain parts of the body (hands, forehead, etc.).

If a person is ill with a medical disease such as diabetes or arthritis, there will often be psychological consequences, such as depression. Some even report being suicidal. In the same way, someone with psychological issues such as depression or anxiety will sometimes experience physical manifestations of these affective fluctuations, often in the form of medically unexplained symptoms. Common symptoms include headaches; abdominal, back, joint, rectal, or urinary pain; nausea; fever and/or night sweats; itching; diarrhea; dizziness; or balance problems. Many people with hypochondriasis accompanied by medically unexplained symptoms feel they are not understood by their physicians, and are frustrated by their doctors’ repeated failure to provide symptom relief.

Cause

The genetic contribution to hypochondriasis is probably moderate, with heritability estimates around 10-37%. Non-shared environmental factors (i.e., experiences that differ between twins in the same family) explain most of the variance in key components of the condition such as the fear of illness and disease conviction. In contrast, the contribution of shared environmental factors (i.e., experiences shared by twins in the same family) to hypochondriasis is approximately zero.

Although little is known about exactly which non-shared environmental factors typically contribute to causing hypochondriasis, certain factors such as exposure to illness-related information are widely believed to lead to short-term increases in health anxiety and to have contributed to hypochondriasis in individual cases. Overly protective caregivers and an excessive focus on minor health concerns have also been implicated as potential causes of hypochondriasis.

In the media and on the Internet, articles, TV shows, and advertisements regarding serious illnesses such as cancer and multiple sclerosis often portray these diseases as being random, obscure, and somewhat inevitable. In the short term, inaccurate portrayal of risk and the identification of non-specific symptoms as signs of serious illness may contribute to exacerbating fear of illness. Major disease outbreaks or predicted pandemics can have similar effects.

There is anecdotal evidence that it is common for serious illnesses or deaths of family members or friends to trigger hypochondria in certain individuals. Similarly, when approaching the age of a parent's premature death from disease, many otherwise healthy, happy individuals fall prey to hypochondria. These individuals believe they are suffering from the same disease that caused their parent's death, sometimes causing panic attacks with corresponding symptoms.

Diagnosis

The ICD-10 defines hypochondriasis as follows:

A. Either one of the following:

• A persistent belief, of at least six months' duration, of the presence of a minimum of two serious physical diseases (of which at least one must be specifically named by the patient).
• A persistent preoccupation with a presumed deformity or disfigurement (body dysmorphic disorder).

B. Preoccupation with the belief and the symptoms causes persistent distress or interference with personal functioning in daily living and leads the patient to seek medical treatment or investigations (or equivalent help from local healers).

C. Persistent refusal to accept medical advice that there is no adequate physical cause for the symptoms or physical abnormality, except for short periods of up to a few weeks at a time immediately after or during medical investigations.

D. Most commonly used exclusion criteria: not occurring only during any of the schizophrenia and related disorders (F20–F29, particularly F22) or any of the mood disorders (F30–F39).

The DSM-IV defines hypochondriasis according to the following criteria:

A. Preoccupation with fears of having, or the idea that one has, a serious disease based on the person's misinterpretation of bodily symptoms.
B. The preoccupation persists despite appropriate medical evaluation and reassurance.
C. The belief in Criterion A is not of delusional intensity (as in Delusional Disorder, Somatic Type) and is not restricted to a circumscribed concern about appearance (as in Body Dysmorphic Disorder).
D. The preoccupation causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
E. The duration of the disturbance is at least 6 months.
F. The preoccupation is not better accounted for by Generalized Anxiety Disorder, Obsessive-Compulsive Disorder, Panic Disorder, a Major Depressive Episode, Separation Anxiety, or another Somatoform Disorder.

In the fifth version of the DSM (DSM-5), most who met criteria for DSM-IV hypochondriasis instead meet criteria for a diagnosis of somatic symptom disorder (SSD) or illness anxiety disorder (IAD).

Classification

The classification of hypochondriasis in relation to other psychiatric disorders has long been a topic of scholarly debate and has differed widely between different diagnostic systems and influential publications.

In the case of the DSM, the first and second versions listed hypochondriasis as a neurosis, whereas the third and fourth versions listed hypochondriasis as a somatoform disorder. The current version of the DSM (DSM-5) lists somatic symptom disorder (SSD) under the heading of "somatic symptom and related disorders", and illness anxiety disorder (IAD) under both this heading and as an anxiety disorder.

The ICD-10, like the third and fourth versions of the DSM, lists hypochondriasis as a somatoform disorder. The ICD-11, however, lists hypochondriasis under the heading of "obsessive-compulsive or related disorders".

There are also numerous influential scientific publications that have argued for other classifications of hypochondriasis. Notably, since the early 1990s, it has become increasingly common to regard hypochondriasis as an anxiety disorder, and to refer to the condition as "health anxiety" or "severe health anxiety".

Treatment

Approximately 20 randomized controlled trials and numerous observational studies indicate that cognitive behavioral therapy (CBT) is an effective treatment for hypochondriasis. Typically, about two-thirds of patients respond to treatment, and about 50% of patients achieve remission, i.e., no longer suffer from hypochondriasis after treatment. CBT for hypochondriasis and health anxiety may be offered in various formats, including as face-to-face individual or group therapy, via telephone, or as guided self-help with information conveyed via a self-help book or online treatment platform. Effects are typically sustained over time.

There is also evidence that antidepressant medications such as selective serotonin reuptake inhibitors can reduce symptoms. In some cases, hypochondriasis responds well to antipsychotics, particularly the newer atypical antipsychotic medications.

Etymology

Among the regions of the abdomen, the hypochondrium is the uppermost part. The word derives from the Greek term ὑποχόνδριος hypokhondrios, meaning "of the soft parts between the ribs and navel" from ὑπό hypo ("under") and χόνδρος khondros, or cartilage (of the sternum). Hypochondria in Late Latin meant "the abdomen".

The term hypochondriasis for a state of disease without real cause reflected the ancient belief that the viscera of the hypochondria were the seat of melancholy and sources of the vapor that caused morbid feelings. Until the early 18th century, the term referred to a "physical disease caused by imbalances in the region that was below your rib cage" (i.e., of the stomach or digestive system). For example, Robert Burton's The Anatomy of Melancholy (1621) blamed it "for everything from 'too much spittle' to 'rumbling in the guts'".

Immanuel Kant discussed hypochondria in his 1798 book, Anthropology from a Pragmatic Point of View, like this:

The disease of the hypochondriac consists in this: that certain bodily sensations do not so much indicate a really existing disease in the body as rather merely excite apprehensions of its existence: and human nature is so constituted – a trait which the animal lacks – that it is able to strengthen or make permanent local impressions simply by paying attention to them, whereas an abstraction – whether produced on purpose or by other diverting occupations – lessens these impressions, or even effaces them altogether.

• Anthropology by Immanuel Kant, 1798 Journal of Speculative Philosophy Vol. XVI edited by William Torrey Harris p. 395-396