Benzodiazepine withdrawal syndrome - often abbreviated as benzo withdrawal - is a group of symptoms that arise when a person has taken benzodiazepines, either medically or recreately, and has developed a physical dependence on subtraction or termination of dose. The development of physical dependence and/or addiction and withdrawal symptoms generated, some of which may last for years, may result from drug seeking behavior or from taking the drug as prescribed. Benzodiazepine withdrawal is characterized by sleep disturbances, irritability, increased tension and anxiety, panic attacks, hand tremors, tremors, sweats, difficulty with concentration, confusion and cognitive difficulties, memory problems, vomiting and nausea, weight loss, palpitations, headaches, muscle pain and stiffness, a number of changes in perception, hallucinations, seizures, psychosis, and suicide (see "Signs and Symptoms" below for a complete list). Furthermore, these symptoms are important for the way in which they wax and decrease and vary in severity from day to day or week to week instead of continuing to decline in a direct monotonous way.
This is a potentially serious, complex and often protracted condition in the course of time. Long-term use, defined as daily use for at least three months, is undesirable because it is associated with an increased risk of dependence, dose escalation, loss of efficacy, increased risk of accidents and falls, especially for the elderly, as well as cognitive, neurological, and intellectual disorders. The use of short-lived hypnotics, while effective at the start of sleep, worsens the second half of sleep due to withdrawal effects. Nevertheless, long-term benzodiazepine users should not be forced to cancel their desires.
Withdrawal of benzodiazepines can be severe and can trigger life-threatening withdrawal symptoms, such as seizures, especially with sudden or excessive dose reduction from high doses or old users. However, severe withdrawal responses can still occur despite gradual dose reduction, or from relatively low doses in short-time users, even after a large dose in animal models. A small percentage of individuals will experience a protracted withdrawal syndrome whose symptoms can persist at sub-acute levels for months, or years after the cessation of benzodiazepines. The likelihood of developing a protracted withdrawal syndrome can be minimized by slow gradual slow dose reduction.
Chronic exposure to benzodiazepines causes neural adaptations that negate the effects of drugs, which leads to tolerance and dependence. Although taking a constant therapeutic dose, long-term use of benzodiazepines may lead to the appearance of withdrawal-like symptoms, especially between doses. When the drug is stopped or the dose is reduced, withdrawal symptoms may appear and remain until the body reverses physiological adaptations. These rebound symptoms may be identical to the symptoms in which the drug was initially taken, or may be part of the symptoms of cessation. In severe cases, withdrawal reactions may worsen or mimic serious psychiatric and medical conditions, such as mania, schizophrenia, and, especially at high doses, seizure disorders. Failure to recognize symptoms of discontinuation may lead to false evidence for the need to take benzodiazepines, which in turn leads to failure of withdrawal and recovery of benzodiazepines, often to higher doses.
Awareness of withdrawal reactions, individual taper strategies according to the severity of withdrawal, the addition of alternative strategies such as guarantees and referrals to benzodiazepine withdrawal support groups, all increase the success rate of withdrawal.
Video Benzodiazepine withdrawal syndrome
Signs and symptoms
Withdrawal effects caused by the cessation of hypnotic tranquilizers, such as benzodiazepines, barbiturates, or alcohol, can cause serious medical complications. They are cited as more dangerous to withdraw than opioids. Users usually receive little advice and support for termination. Some withdrawal symptoms are identical to the symptoms prescribed by the drug, and may be acute or protracted in duration. The onset of symptoms from long-term benzodiazepines may be delayed for up to three weeks, although withdrawal symptoms from short acts often appear earlier, usually within 24-48 hours. There may be no fundamental differences in symptoms either from high or low doses, but symptoms tend to be more severe than higher doses.
Daytime reheergy and rebound withdrawal symptoms, sometimes confused with interdose withdrawal, may occur after the dependency has been established. 'Reemergence' is the return of symptoms that were originally prescribed drugs, in contrast, 'rebound' symptoms are the return of symptoms to which the benzodiazepine was initially taken, but at a more intense level than before; whereas the 'interdose withdrawal' is when the previous dose of the drug runs out and the beginning of the withdrawal cycle is completely new, the symptoms disappear while taking the next dose but after that the complete recall cycle begins when the dose is exhausted, a new onset of withdrawal between each dose is called ' interdosis withdrawal' and if not properly treated can recur indefinitely in a vicious circle (which assumes benzo with a long half-life (eg Valium) so the drug is not lost between dose). Withdrawal symptoms may appear for the first time during dose reduction, and include insomnia, anxiety, distress, weight loss, dizziness, night sweats, shakes, muscle twitch, aphasia, panic attacks, depression, derealization, paranoia, etc., and more generally related with the termination of short-acting benzodiazepines, such as triazolam. Daytime symptoms may occur after a few days to weeks of administration of benzodiazepine or z-night medication such as zopiclone; withdrawal-related insomnia rebound is worse than the baseline even when benzodiazepine is used intermittently.
The following symptoms may occur during a gradual or abrupt dose reduction:
The immediate termination may result in a more serious syndrome
As withdrawals take place, patients often find their physical and mental health improves with improved mood and increased cognition.
Maps Benzodiazepine withdrawal syndrome
Mechanism
The neuroadaptive processes involved in tolerance, dependence, and withdrawal mechanisms involve both GABAergic and glutamatergic systems. Gamma-Aminobutyric Acid (GABA) is a major inhibitory neurotransmitter of the central nervous system; approximately one quarter to one-third of synapses using GABA. GABA mediates the entry of chloride ions through a chloride-lated-gated channel called GABA A receptor. When chloride enters the nerve cell, the cell membrane has the potential of hyperpolarizes to inhibit depolarization, or a reduction in the rate of firing of the post-synaptic nerve cells. Benzodiazepines potentiate GABA action, by binding intermediate sites? and? subunit of 5-subunit receptors thereby increasing the frequency of GABA chloride channel opening in presence of GABA.
When potentiation is sustained by long-term use, neuroadaptations occur which results in a decrease in GABAergic response. What is certain is that the GABA A surface of the receptor protein level is altered in response to benzodiazepine exposure, such as the rate at which the receptor is replaced. The exact reasons for reducing the response are not explained but down-regulation of the number of receptors has only been observed at several receptor sites including in pars reticulata of substansia nigra; down-regulation of the number of receptors or internalization does not seem to be the primary mechanism in other locations. There is evidence for other hypotheses including changes in receptor conformation, change of turn, recycle, or level of production, degree of phosphorylation and expression of receptor gene, subunit composition, reduction of the merging mechanism between GABA and benzodiazepine sites, decreased GABA production, and compensation increases gutamatergic activity. An integrated model hypothesis involves a combination of receptor internalization, followed by preferential degradation of certain receptor sub-units, which provides nuclear activation for alterations in transcription of receptor gene.
It has been postulated that when benzodiazepines are cleansed from the brain, these neuroadaptations "mask", leading to the stimulation of neurons that can not be resisted. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Increased activity of glutamate stimulation during withdrawal may cause CNS sensitization or seepage, possibly leading to worsening of cognition and symptomatology and making each subsequent withdrawal period worse. Those with a history of previous withdrawal from benzodiazepines were found to be less successful the next time.
Diagnosis
In severe cases, a protracted withdrawal or withdrawal reaction may worsen or mimic serious psychiatric and medical conditions, such as mania, schizophrenia, anxiety depression, panic disorder, general anxiety disorder, and complex partial seizures and, especially at high doses, seizure disorder. Failure to recognize symptoms of discontinuation may lead to false evidence for the need to take benzodiazepines, which in turn leads to failure of withdrawal and recovery of benzodiazepines, often to higher doses. Pre-existing disorders or other causes usually do not improve, whereas dotted symptoms gradually improve over the next few months. For this reason at least six months must have elapsed after the cessation of benzodiazepines before re-evaluating the symptoms and updating the diagnosis.
Symptoms may be less of a psychological cause and may fluctuate in intensity with periods of good and bad days until eventually recovery.
Prevention
According to the British National Formulary, it is better to draw too slowly than too soon from benzodiazepines. The dose reduction rate is best done to minimize the intensity and severity of symptoms. Anecdotally, a slow rate of reduction can reduce the risk of developing severe syndrome.
The long half-life of benzodiazepines such as diazepam or chlordiazepoxide is preferred to minimize the rebound effect and be available in the form of low-potency doses. Some people may not be completely stable between dose reductions, even when the rate of reduction is slowed. Such people sometimes just need to survive because they may not feel better until they are completely withdrawn from them for a certain period of time.
Management
Benzodiazepine dependency management involves considering a person's age, comorbidity and pharmacological pathways from benzodiazepines. Psychological interventions may provide a small but significant additional benefit of gradual dose reduction in post-termination and follow-up. The psychological interventions studied are relaxation training, cognitive-behavioral treatment of insomnia, and self-monitoring of consumption and symptoms, goal setting, management of withdrawal and overcoming anxiety.
With enough motivation and the right approach, almost anyone can successfully withdraw from benzodiazepines. However, prolonged and severe syndrome can lead to collapsing marriages, business failures, bankruptcies, hospital commitments, and the most serious adverse effects, suicide. Thus, long-term users should not be forced to stop their desires. Excessive withdrawal, lack of explanation, and failure to convince individuals that they have temporary withdrawal symptoms cause some people to experience increased panic and their fears become insane, with some developing a condition similar to post-traumatic stress disorder as a result. A slow withdrawal regimen, coupled with guarantees from family, friends, and peers increases the outcome.
Drugs and interactions
The minimal success rate of intervention in which the first rapid withdrawal is attempted, followed by a systematic tapered stoppage if the first experiment fails, ranging from 25 to 100% with a median of 58%. Cognitive behavioral therapy is useful for improving the success rate of panic disorder, melatonin for insomnia, such as flumazenil and sodium valproate. Ten years of follow-up found that more than half of those who managed to withdraw from long-term use were still fasting two years later, and that if they were able to maintain this situation for two years, they would likely keep this declared on a ten-year follow-up. One study found that after a year of abstinence from long-term use of benzodiazepines, cognitive, neurological and intellectual disorders have returned to normal.
Those with previous psychiatric diagnoses had similar success rates of gradual taper on two years of follow-up. Withdrawal from benzodiazepines does not lead to increased use of antidepressants.
Withdrawal Process
It would be very difficult to withdraw from short or medium benzodiazepines due to the intensity of the perceived rebound symptoms between doses. In addition, short-acting benzodiazepines seem to produce a stronger withdrawal syndrome. For this reason, discontinuation is sometimes performed by first replacing the equivalent dose of short-acting benzodiazepines with longer-acting ones such as diazepam or chlordiazepoxide. Failure to use the correct equivalent amount can trigger a severe withdrawal reaction. Benzodiazepines with a half-life of more than 24 hours include chlordiazepoxide, diazepam, clobazam, clonazepam, chlorazepinic acid, ketazolam, medazepam, nordazepam, and prazepam. Benzodiazepines with a half-life of less than 24 hours include alprazolam, bromazepam, brotizolam, flunitrazepam, loprazolam, lorazepam, lormetazepam, midazolam, nitrazepam, oxazepam, and temazepam. The resulting equivalent dose is then gradually reduced. The reduction rate used in the Heather Ashton protocol calls for the removal of 10% of the remaining doses every two to four weeks, depending on the severity and response to reduction with the final dose at a dose of 0.5m diazepam or 5 mg dose of chlordiazepoxide.
Duration
After the last dose has been taken, the acute phase of withdrawal usually lasts for about two months although withdrawal symptoms, even from low dose use, can last for six to twelve months gradually improves over that period; however, clinically significant withdrawal symptoms may persist over the years, though gradually decreased.
A clinical trial of patients taking alprazolam benzodiazepine for as little as eight weeks triggered a protracted symptom of memory deficits that remained until eight weeks after the cessation of alprazolam.
Prolonged withdrawal syndrome
The prolonged withdrawal syndrome refers to symptoms lasting for months or even years. A significant minority of people who withdraw from benzodiazepines, perhaps 10 to 15%, have a prolonged withdrawal syndrome that can sometimes be severe. Symptoms may include tinnitus, psychosis, cognitive deficits, gastrointestinal complaints, insomnia, paresthesia (tingling and numbness), pain (usually in limbs and extremities), muscle aches, weakness, tension, painful tremors, trembling attacks, jerks, dizziness and blepharospasm and can occur even without a history of pre-existing symptoms. Tinnitus occurs during dose reduction or cessation of benzodiazepines reduced by restarting benzodiazepines. Dizziness is often reported as the longest withdrawal symptoms.
A study examining neuropsychological factors found a psychophysiological marker different from the norm, and concluded that the prolonged withdrawal syndrome was the original iatrogenic condition caused by prolonged use. The cause of persistent symptoms is a combination of pharmacological factors such as persistent drug-induced receptor changes, drug-induced and drug-induced psychological factors and, in some cases, particularly high-dose users, structural brain damage or structural nerve damage. Symptoms continue to improve over time, often to the point where people end up resuming their normal lives, even after years of disability.
A slow withdrawal rate significantly reduces the risk of a protracted and/or severe withdrawal. The protracted withdrawal symptoms can be interspersed by periods of good days and bad days. When symptoms increase periodically during prolonged termination, physiological changes may be present, including dilated pupils as well as increased blood pressure and heart rate. Symptom changes have been proposed due to changes in receptor sensitivity for GABA during the inversion tolerance process. A meta-analysis found cognitive impairment because benzodiazepine use showed improvement after six months of withdrawal, but the remaining cognitive impairment may be permanent or may require more than six months to retreat.
Prolonged symptoms continue to fade for several months or years. No known cure for the prolonged benzodiazepine withdrawal syndrome except time, however, the flumazenil drug was found to be more effective than placebo in reducing hostile feelings and aggression in patients who had been free of benzodiazepines for 4-266 weeks. This may indicate the role of flumazenil in treating withdrawal symptoms of benzodiazepine drugs.
Epidemiology
The severity and length of the withdrawal syndrome may be determined by a variety of factors, including rate of reduction, duration of use and dose size, and possible genetic factors. Those with a history of withdrawal from benzodiazepines may have a sensitive or disturbed central nervous system leading to worsening of cognition and symptomatology, and make any subsequent withdrawal periods worse.
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Pediatrics
The neonatal withdrawal syndrome, sometimes severe, can occur when the mother has taken benzodiazepines, especially during the third trimester. Symptoms include hypotonia, apnoeic spells, cyanosis, and metabolic response disorders to stress and cold spasms. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hour to month after birth.
The withdrawal syndrome is seen in about 20% of intensive care units of children after infusion with benzodiazepines or opioids. The likelihood of having a syndrome correlates with duration and total infusion dose, although duration is considered more important. Treatment for withdrawal typically involves weaning over a period of 3 to 21 days if the infusion lasts for more than one week. Symptoms include tremor, agitation, insomnia, inconsolable crying, diarrhea and sweating. In total, more than fifty withdrawal symptoms are listed in this review article. Environmental measures aimed at reducing neonatal symptoms with severe abstinent syndrome have little impact, but providing a quiet sleeping environment helps in mild cases.
Pregnancy
Stopping benzodiazepines or antidepressants abruptly because of concerns of teratogenic effects of the drug have a high risk of causing serious complications, so it is not recommended. For example, the sudden withdrawal of benzodiazepines or antidepressants has a high risk of causing extreme withdrawal symptoms, including suicidal ideas and severe rebound effects from the return of the underlying disorder if present. This can lead to hospitalization and potentially, suicide. One study reported a third of mothers who suddenly stopped or tapered quickly their drugs became very keen to commit suicide due to 'unbearable symptoms'. A woman has a medical abortion, because she feels she can no longer handle it, and other women use alcohol in an attempt to combat withdrawal symptoms from benzodiazepines. Spontaneous abortion can also be caused by the withdrawal of psychotropic drugs suddenly, including benzodiazepines. The study reported that physicians are generally unaware of the severe consequences of sudden withdrawal of psychotropic drugs such as benzodiazepines or antidepressants.
Elderly
A study of elderly dependent on benzodiazepines found that withdrawal can be done with few complications and may lead to increased sleep and cognitive abilities. At 52 weeks after successful withdrawal, a 22% increase in cognitive status was found, as well as an increase in social function. Those who remained in benzodiazepines had a 5% decrease in cognitive abilities, which seemed to be faster than those seen in normal aging, indicating the longer the intake of benzodiazepines, the worse the cognitive effects. Some of the worsening symptoms were seen in the first few months of abstinent benzodiazepine, but at 24 weeks follow-up, the elderly subjects clearly improved compared with those who continued to take benzodiazepines. Sleep improvements were seen at 24 and 52 weeks follow-up. The authors conclude that benzodiazepines are not effective in the long term for sleep problems except in suppressing rebound insomnia associated withdrawal. Improvements were seen between 24 and 52 weeks after withdrawal in many factors, including increased sleep and some cognitive and performance abilities. Some cognitive abilities, which are sensitive to benzodiazepines, as well as age, such as episodic memory do not improve. The authors, however, cite a study in younger patients who at 3.5 years of follow-up showed no memory impairment and speculated that certain memory functions took longer to recover from the use of chronic benzodiazepines and further improvement in cognitive function of the parents can occur beyond 52 weeks after withdrawal. The reason it took 24 weeks for the improvements to be seen after discontinuation of benzodiazepine was due to the time it took the brain to adapt to the benzodiazepine-free environment.
At 24 weeks, significant improvements were found, including improved information processing accuracy, but a noticeable reduction in those who continued to take benzodiazepines. Further improvements were recorded at 52 weeks of follow-up, showing continuous improvement with benzodiazepine abstinence. Younger people on benzodiazepines also experience cognitive impairment in visual spatial memory, but are not as vulnerable as parents to cognitive effects. Increased reaction time was recorded at 52 weeks in elderly patients free of benzodiazepines. This is an important function in the elderly, especially if they drive a car due to the increased risk of traffic accidents in benzodiazepine users. At 24-week follow-up, 80% of people managed to withdraw from benzodiazepines. Part of that success was attributed to a placebo method used for part of an experiment that solved psychological dependence on benzodiazepines when elderly patients realized they had completed a gradual decline a few weeks earlier, and only took placebo tablets. It helps convince them that they can sleep without their pills.
The authors also warned about the similarity in pharmacology and the mechanism of action of newer nonbenzodiazepine Z drugs.
The elimination half-life of diazepam and chlordiazepoxide, as well as other long-term benzodiazepines, is twice as long in older people as compared to younger individuals. Many doctors do not adjust the dose of benzodiazepine by age in elderly patients.
Inpatient care
Detoxification and/or inpatient rehabilitation facilities may not be suitable for those who have become tolerant or dependent on taking the drug as prescribed, not for recreational use. Such inpatient referral may be traumatic for non-abusers.
See also
References
External links
- Benzodiazepines: How it works and how to withdraw by Professor Heather Ashton
- The Minor Tranquillizer Project, For support, Camden, UK
- Benzodiazepine withdrawal syndrome in Curlie (based on DMOZ)
Source of the article : Wikipedia
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