Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back and forth, or pace, while some may just have an uneasy feeling in their body. The most severe cases may result in aggression, violence or suicidal thoughts.
The term was first used by Czech neuropsychiatrist Ladislav Haškovec, who described the phenomenon in 1901. It is from Greeka-, meaning "not", and καθίζεινkathízein, meaning "to sit", or in other words an "inability to sit".
Classification
Akathisia is usually grouped as a medication-induced movement disorder but is also seen to be a neuropsychiatric concern as it can be experienced purely subjectively with no apparent movement abnormalities. Akathisia is generally associated with antipsychotics but it was already described in Parkinson's disease, and other neuropsychiatric disorders. It also presents with the use of non-psychiatric medications, including calcium channel blockers, antibiotics, anti-nausea and anti-vertigo drugs.
Signs and symptoms
Symptoms
of akathisia are often described in vague terms such as feeling
nervous, uneasy, tense, twitchy, restless, and an inability to relax. Reported symptoms also include insomnia, a sense of discomfort, motor restlessness, marked anxiety, and panic. Symptoms have also been said to resemble symptoms of neuropathic pain that are similar to fibromyalgia and restless legs syndrome.
When due to psychiatric drugs, the symptoms are side effects that
usually disappear quickly and remarkably when the medication is reduced
or stopped. However, tardive akathisia which has a late onset, may go on long after the medication is discontinued, for months and sometimes years.
When misdiagnosis occurs in antipsychotic-induced akathisia, more
antipsychotic may be prescribed, potentially worsening the symptoms. If symptoms are not recognised and identified akathisia can increase in severity and lead to suicidal thoughts, aggression and violence.
Visible signs of akathisia include repetitive movements such as
crossing and uncrossing the legs, and constant shifting from one foot to
the other. Other noted signs are rocking back and forth, fidgeting and pacing.
However not all observable restless motion is akathisia. For example,
mania, agitated depression, and attention deficit hyperactivity disorder
may look like akathisia, but the movements feel voluntary and not due
to restlessness.
Jack Henry Abbott,
who was diagnosed with akathisia, described the sensation in 1981 as:
“You ache with restlessness, so you feel you have to walk, to pace. And
then as soon as you start pacing, the opposite occurs to you; you must
sit and rest. Back and forth, up and down you go … you cannot get relief
…“
Medication-induced akathisia is termed acute akathisia and is frequently associated with the use of antipsychotics. Antipsychotics block dopamine receptors, but the pathophysiology
is poorly understood. Additionally, drugs with successful therapeutic
effects in the treatment of medication-induced akathisia have provided
additional insight into the involvement of other transmitter systems.
These include benzodiazepines, β-adrenergic blockers, and serotonin antagonists. Another major cause of the syndrome is the withdrawal observed in drug-dependent
individuals. Since dopamine deficiency (or disruptions in dopamine
signalling) appears to play an important role in the development of RLS,
a form of akathisia focused in the legs,
the sudden withdrawal or rapidly decreased dosage of drugs which
increase dopamine signalling may create similar deficits of the chemical
which mimic dopamine antagonism and thus can precipitate RLS. This is
why sudden cessation of opioids, cocaine, serotonergics, and other
euphoria-inducing substances commonly produce RLS as a side-effect.
Akathisia involves increased levels of the neurotransmitter norepinephrine, which is associated with mechanisms that regulate aggression, alertness, and arousal. It has been correlated with Parkinson's disease and related syndromes, and descriptions of akathisia predate the existence of pharmacologic agents.
Akathisia can be miscoded in side effect reports from antidepressant clinical trials as "agitation, emotional lability, and hyperkinesis (overactivity)"; misdiagnosis of akathisia as simple motor restlessness occurred, but was more properly classed as dyskinesia.
Diagnosis
The presence and severity of akathisia can be measured using the Barnes Akathisia Scale, which assesses both objective and subjective criteria.
Precise assessment of akathisia is problematic, as there are various
types making it difficult to differentiate from disorders with similar
symptoms.
The primary distinguishing features of akathisia in comparison
with other syndromes are primarily subjective characteristics, such as
the feeling of inner restlessness and tension. Akathisia can commonly be mistaken for agitation secondary to psychotic symptoms or mood disorder, antipsychotic dysphoria, restless legs syndrome (RLS), anxiety, insomnia, drug withdrawal states, tardive dyskinesia, or other neurological and medical conditions.
The controversial diagnosis of "pseudoakathisia" is sometimes given.
As of 2007, published epidemiological data for akathisia was mostly limited to studies before the availability of second-generation antipsychotics. Prevalence rates may be lower for modern treatment as second-generation antipsychotics carry a lower risk of akathisia.
Approximately one out of four individuals treated with first-generation antipsychotics have akathisia.
History
The term was first used by Czech neuropsychiatrist Ladislav Haškovec, who described the phenomenon in a non-medication induced presentation in 1901.
Reports of medication-induced akathisia from chlorpromazine appeared in 1954. Later in 1960 there were reports of akathisia in response to phenothiazines (a related drug). Akathisia is classified as an extrapyramidal side effect along with other movement disorders that can be caused by antipsychotics.
In 2020 clinical psychologist and professor of psychologyJordan Peterson was diagnosed with akathisia after being treated for insomnia and depression with Benzodiazepines that was associated with an autoimmune disorder and was subsequently treated in Russia.
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
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
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 misassociation 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. 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 diarrhea and vomiting (which can be
treated with loperamide and ondansetron
respectively) associated with acute opioid withdrawal, especially in
longer-acting substances where the diarrhea 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.
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 generalize 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).
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal or BZD withdrawal —is the cluster of signs and symptoms that emerge when a person who has been taking benzodiazepines, either medically or recreationally, and has developed a physical dependence,
undergoes dosage reduction or discontinuation. Development of physical
dependence and the resulting withdrawal symptoms, some of which may last
for years, may result from taking the medication as prescribed.
Benzodiazepine withdrawal is characterized by sleep disturbance,
irritability, increased tension and anxiety, panic attacks,
hand tremor, shaking, sweating, difficulty with concentration,
confusion and cognitive difficulty, memory problems, dry retching and
nausea, weight loss, palpitations, headache, muscular pain and stiffness, a host of perceptual changes, hallucinations, seizures, psychosis, and increased risk of suicide
(see "signs and symptoms" section below for full list). Further, these
symptoms are notable for the manner in which they wax and wane and vary
in severity from day to day or week by week instead of steadily
decreasing in a straightforward monotonic manner. This phenomenon is often referred to as "waves" and "windows".
It is a potentially serious condition, and is complex and often protracted in its course. Long-term benzodiazepine use, defined as daily use for at least three months, is not desirable because of the associated increased risk of dependence, dose escalation, loss of efficacy, increased risk of accidents and falls, particularly for the elderly, as well as cognitive, neurological, and intellectual impairments. Use of short-acting hypnotics, while being effective at initiating sleep, worsens the second half of sleep due to withdrawal effects.
Benzodiazepine withdrawal can be severe and can provoke life-threatening withdrawal symptoms, such as seizures, particularly with abrupt or overly rapid dosage reduction from high doses or long-time use.
A severe withdrawal response can nevertheless occur despite gradual
dose reduction, or from relatively low doses in short-time users; even after a single large dose in animal models. A minority of individuals will experience a protracted withdrawal syndrome,
whose symptoms may persist at a sub-acute level for months or years
after cessation of benzodiazepines. The likelihood of developing a
protracted withdrawal syndrome can be minimized by a slow, gradual
reduction in dosage.
Chronic exposure to benzodiazepines causes neural adaptations that counteract the drug's effects, leading to tolerance and dependence.
Despite taking a constant therapeutic dose, long-term use of
benzodiazepines may lead to the emergence of withdrawal-like symptoms,
particularly between doses, when patients are treated with
shorter-acting benzodiazepines.
When the drug is discontinued or the dosage reduced, withdrawal
symptoms may appear and remain until the body has reversed the long-term
physiological adaptations.
These [[Rebound effect|rebound symptoms may be identical to the
symptoms for which the drug was initially taken, or may be part of
discontinuation symptoms. In severe cases, the withdrawal reaction may exacerbate or resemble serious psychiatric and medical conditions, such as mania, schizophrenia, and, especially at high doses, seizure disorders.
Failure to recognize discontinuation symptoms can lead to false
evidence for the need to take benzodiazepines, which in turn leads to
withdrawal failure and reinstatement of benzodiazepines, often at higher
doses.
Awareness of the withdrawal reactions, individualized taper
strategies according to withdrawal severity, the addition of alternative
strategies such as reassurance and referral to benzodiazepine
withdrawal support groups, all increase the success rate of withdrawal.
Signs and symptoms
Withdrawal effects caused by sedative-hypnotics discontinuation, such as benzodiazepines, barbiturates, or alcohol, can cause serious medical complications. They are cited to be more hazardous to withdraw from than opioids. Users typically receive little advice and support for discontinuation. Some withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed, and can be acute or protracted in duration. Onset of symptoms from long half-life
benzodiazepines might be delayed for up to three weeks, although
withdrawal symptoms from short-acting ones often present early, usually
within 24–48 hours.
There may be no fundamental differences in symptoms from either high or
low dose discontinuation, but symptoms tend to be more severe from
higher doses.
Daytime reemergence and rebound withdrawal symptoms, sometimes
confused with interdose withdrawal, may occur once dependence has set
in. 'Reemergence' is the return of symptoms for which the drug was
initially prescribed, in contrast, 'rebound' symptoms are a return of
the symptoms for which the benzodiazepine was initially taken, but at a
more intense level than before; whereas 'interdose withdrawal' is when a
prior dosage of drug wears off and beginnings of an entirely new cycle
of withdrawal sets in, the symptoms of which dissipate upon taking the
next dosage but after which yet another entirely new cycle of withdrawal
begins when that dosage wears off, a new onset of withdrawal between
each dosage thus called 'interdose withdrawal' and if not
properly treated can recur indefinitely in a vicious circle (for which a
benzo with a long half life, e.g. diazepam, can be substituted so the drug does not wear off between doses).
Withdrawal symptoms may appear for the first time during dose
reduction, and include insomnia, anxiety, distress, weight loss,
dizziness, night sweats, shakes, muscle twitches, aphasia, panic
attacks, depression, derealization, paranoia, indigestion, diarrhea,
photo phobia etc., and are more commonly associated with short-acting
benzodiazepines discontinuation, like triazolam. Daytime symptoms can occur after a few days to a few weeks of administration of nightly benzodiazepines or z-drugs such as zopiclone; withdrawal-related insomnia rebounds worse than baseline, and for rapidly eliminated benzodiazepines, including triazolam and temazepam, this may occur even when used briefly and intermittently, according to a small 1991 study (n=18).
The following symptoms may emerge during gradual or abrupt dosage reduction:
As withdrawal progresses, patients often find their physical and
mental health improves with improved mood and improved cognition.
Mechanism
The neuroadaptive processes involved in tolerance, dependence, and
withdrawal mechanisms implicate both the GABAergic and the glutamatergic
systems. Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA. GABA mediates the influx of chloride ions through ligand-gated chloride channels called GABAA
receptors. When chloride enters the nerve cell, the cell membrane
potential hyperpolarizes thereby inhibiting depolarization, or reduction
in the firing rate of the post-synaptic nerve cell. Benzodiazepines potentiate the action of GABA, by binding a site between the α and γ subunits of the 5-subunit receptor thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.
When potentiation is sustained by long-term use, neuroadaptations
occur which result in decreased GABAergic response. What is certain is
that surface GABAA receptor protein levels are altered in response to benzodiazepine exposure, as is receptor turnover rate.
The exact reason for the reduced responsiveness has not been elucidated
but down-regulation of the number of receptors has only been observed
at some receptor locations including in the pars reticulata of the substantia nigra; down-regulation of the number of receptors or internalization does not appear to be the main mechanism at other locations.
Evidence exists for other hypotheses including changes in the receptor
conformation, changes in turnover, recycling, or production rates,
degree of phosphorylation and receptor gene expression, subunit
composition, decreased coupling mechanisms between the GABA and
benzodiazepine site, decrease in GABA production, and compensatory
increased glutamatergic activity.
A unified model hypothesis involves a combination of internalization of
the receptor, followed by preferential degradation of certain receptor
sub-units, which provides the nuclear activation for changes in receptor
gene transcription.
It has been postulated that when benzodiazepines are cleared from
the brain, these neuroadaptations are "unmasked", leading to unopposed
excitability of the neuron. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system. Increased glutamate excitatory activity during withdrawal may lead to sensitization or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse. Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around.
Diagnosis
In
severe cases, the withdrawal reaction or protracted withdrawal may
exacerbate or resemble serious psychiatric and medical conditions, such
as mania, schizophrenia, agitated depression, panic disorder, generalised anxiety disorder, and complex partial seizures and, especially at high doses, seizure disorders.
Failure to recognize discontinuation symptoms can lead to false
evidence for the need to take benzodiazepines, which in turn leads to
withdrawal failure and reinstatement of benzodiazepines, often to higher
doses. Pre-existing disorder or other causes typically do not improve,
whereas symptoms of protracted withdrawal gradually improve over the
ensuing months.
Symptoms may lack a psychological cause and can fluctuate in
intensity with periods of good and bad days until eventual recovery.
Prevention
According to the British National Formulary, it is better to withdraw too slowly rather than too quickly from benzodiazepines.
The rate of dosage reduction is best carried out so as to minimize the
symptoms' intensity and severity. Anecdotally, a slow rate of reduction
may reduce the risk of developing a severe protracted syndrome.
Long half-life benzodiazepines like diazepam or chlordiazepoxide
are preferred to minimize rebound effects and are available in low dose
forms. Some people may not fully stabilize between dose reductions,
even when the rate of reduction is slowed. Such people sometimes simply
need to persist as they may not feel better until they have been fully
withdrawn from them for a period of time.
Management of benzodiazepine dependence involves considering the
person's age, comorbidity and the pharmacological pathways of
benzodiazepines.
Psychological interventions may provide a small but significant
additional benefit over gradual dose reduction alone at post-cessation
and at follow-up.
The psychological interventions studied were relaxation training,
cognitive-behavioral treatment of insomnia, and self-monitoring of
consumption and symptoms, goal-setting, management of withdrawal and
coping with anxiety.
There is no standard approach to managing benzodiazepine withdrawal.
With sufficient motivation and the proper approach, almost anyone can
successfully withdraw from benzodiazepines. However, a prolonged and
severe syndrome can lead to collapsed marriages, business failures,
bankruptcy, hospitalization, and the most serious adverse effect,
suicide. As such, long-term users should not be forced to discontinue against their will.
Over-rapid withdrawal, lack of explanation, and failure to
reassure individuals that they are experiencing temporary withdrawal
symptoms led some people to experience increased panic and fears they
are going mad, with some people developing a condition similar to
post-traumatic stress disorder as a result. A slow withdrawal regimen,
coupled with reassurance from family, friends, and peers improves the
outcome. According to a 2015 Cochrane review, cognitive behavior therapy plus taper was effective in achieving discontinuation in the short-term but the effect was not certain after six months.
Medications
While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.
Some studies found that the abrupt substitution of substitutive
pharmacotherapy was actually less effective than gradual dose reduction
alone, and only three studies found benefits of adding melatonin, paroxetine, trazodone, or valproate in conjunction with a gradual dose reduction.
Antipsychotics are generally ineffective for benzodiazepine withdrawal-related psychosis. Antipsychotics should be avoided during benzodiazepine withdrawal as
they tend to aggravate withdrawal symptoms, including convulsions. Some antipsychotic agents may be riskier than others during withdrawal, especially clozapine, olanzapine or low potency phenothiazines (e.g., chlorpromazine), as they lower the seizure threshold and can worsen withdrawal effects; if used, extreme caution is required.
Barbiturates are cross tolerant to benzodiazepines and should generally be avoided; however phenobarbital can be used, as it is relatively safe, see below.
Benzodiazepines or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the nonbenzodiazepinesZ-drugs,
which have a similar mechanism of action. This is because tolerance to
benzodiazepines has been demonstrated to be still present at four months
to two years after withdrawal depending on personal biochemistry.
Re-exposures to benzodiazepines typically resulted in a reactivation of
the tolerance and benzodiazepine withdrawal syndrome.
Bupropion,
which is used primarily as an antidepressant and smoking cessation aid,
is contraindicated in persons experiencing abrupt withdrawal from
benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an
increased risk of seizures.
Buspirone augmentation was not found to increase the discontinuation success rate.
Caffeine may worsen withdrawal symptoms because of its stimulatory properties. At least one animal study has shown some modulation of the benzodiazepine site by caffeine, which produces a lowering of seizure threshold.
Carbamazepine, an anticonvulsant,
appears to have some beneficial effects in the treatment and management
of benzodiazepine withdrawal; however, research is limited and thus the
ability of experts to make recommendations on its use for
benzodiazepine withdrawal is not possible at present.
Ethanol, the primary alcohol in alcoholic beverages, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its cross tolerance with benzodiazepines.
Flumazenil
has been found to stimulate the reversal of tolerance and the
normalization of receptor function. However, further research is needed
in the form of randomised trials to demonstrate its role in the
treatment of benzodiazepine withdrawal. Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABAA receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.
Because of limited research and experience compared to the possible
risks involved, the flumazenil detoxification method is controversial
and can only be done as an inpatient procedure under medical
supervision.
Flumazenil was found to be more effective than placebo in
reducing feelings of hostility and aggression in patients who had been
free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
A study into the effects of the benzodiazepine receptor
antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting
after withdrawal was carried out by Lader and Morton. Study subjects
had been benzodiazepine-free for between one month and five years, but
all reported persisting withdrawal effects to varying degrees.
Persistent symptoms included clouded thinking, tiredness, muscular
symptoms such as neck tension, depersonalisation, cramps and shaking and the characteristic perceptual
symptoms of benzodiazepine withdrawal, namely, pins and needles
feeling, burning skin, pain and subjective sensations of bodily
distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo-controlled
study. This is of interest as benzodiazepine receptor antagonists are
neutral and have no clinical effects. The author of the study suggested
the most likely explanation is past benzodiazepine use and subsequent
tolerance had locked the conformation of the GABA-BZD receptor complex
into an inverse agonist conformation, and the antagonist
flumazenil resets benzodiazepine receptors to their original
sensitivity. Flumazenil was found in this study to be a successful
treatment for protracted benzodiazepine withdrawal syndrome, but further
research is required. A study by Professor Borg in Sweden produced similar results in patients suffering from protracted withdrawal. In 2007, Hoffmann–La Roche
the makers of flumazenil, acknowledged the existence of protracted
benzodiazepine withdrawal syndromes, but did not recommended flumazenil
to treat the condition.
Fluoroquinolone antibiotics
have been noted to increase the incidence of a CNS toxicity from 1% in
the general population, to 4% in benzodiazepine-dependent population or
in those undergoing withdrawal from them. This is probably the result of
their GABA antagonistic effects as they have been found to
competitively displace benzodiazepines from benzodiazepine receptor
sites. This antagonism can precipitate acute withdrawal symptoms, that
can persist for weeks or months before subsiding. The symptoms include
depression, anxiety, psychosis, paranoia, severe insomnia, paresthesia, tinnitus, hypersensitivity to light and sound, tremors,
status epilepticus, suicidal thoughts and suicide attempt.
Fluoroquinolone antibiotics should be contraindicated in patients who
are dependent on or in benzodiazepine withdrawal. NSAIDs
have some mild GABA antagonistic properties and animal research
indicate that some may even displace benzodiazepines from their binding
site. However, NSAIDs taken in combination with fluoroquinolones cause a
very significant increase in GABA antagonism, GABA toxicity, seizures,
and other severe adverse effects.
Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.
Imipramine was found to statistically increase the discontinuation success rate.
Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia.
Phenobarbital, (a barbiturate), is used at "detox" or other inpatient facilities to prevent seizures during rapid withdrawal or cold turkey. The phenobarbital is followed by a one- to two-week taper, although a slow taper from phenobarbital is preferred. In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.
Pregabalin may help reduce the severity of benzodiazepine withdrawal symptoms, and reduce the risk of relapse.
Propranolol was not found to increase the discontinuation success rate.
SSRI antidepressants have been found to have little value in the treatment of benzodiazepine withdrawal.
Trazodone was not found to increase the discontinuation success rate.
Inpatient treatment
Inpatientdrug detox or rehabilitation
facilities may be inappropriate for those who have become tolerant or
dependent while taking the drug as prescribed, as opposed to
recreational use. Such inpatient referrals may be traumatic for
non-abusers.
Prognosis
A 2006 meta-analysis
found evidence for the efficacy of stepped care: minimal intervention
(e.g. send an advisory letter, or meet large number of patients to
advise discontinuation), followed by systematic tapered discontinuation
alone without augmentation if the first try was unsuccessful.
Cognitive behavioral therapy improved discontinuation success rates for
panic disorder, melatonin for insomnia, and flumazenil or sodium
valproate for general long-term benzodiazepine use.
A ten-year follow-up found that more than half of those who had
successfully withdrawn from long-term use were still abstinent two years
later, and that if they were able to maintain this state at two years,
they were likely to maintain this state at the ten-year followup.
One study found that after one year of abstinence from long-term use of
benzodiazepines, cognitive, neurological and intellectual impairments
had returned to normal.
Those who had a prior psychiatric diagnosis had a similar success rate from a gradual taper at a two-year follow-up. Withdrawal from benzodiazepines did not lead to an increased use of antidepressants.
The consensus is to reduce dosage gradually over several weeks, e.g. 4 or more weeks for diazepam doses over 30 mg/day,
with the rate determined by the person's ability to tolerate symptoms.
The recommended reduction rates range from 50% of the initial dose every week or so,
to 10-25% of the daily dose every 2 weeks.
For example, the reduction rate used in the Heather Ashton protocol
calls for eliminating 10% of the remaining dose every two to four weeks,
depending on the severity and response to reductions with the final
dose at 0.5 mg dose of diazepam or 2.5 mg dose of chlordiazepoxide.
For most people, discontinuation over 4-6 weeks or 4-8 weeks is suitable.
Prolonged period of reduction over many months should be avoided to
prevent the withdrawal process from becoming a "morbid focus" for the
person.
Duration
After
the last dose has been taken, the acute phase of the withdrawal
generally lasts for about two months although withdrawal symptoms, even
from low-dose use, can persist for six to twelve months gradually
improving over that period, however, clinically significant withdrawal symptoms may persist for years, although gradually declining.
A clinical trial of patients taking the benzodiazepine alprazolam
for as short as eight weeks triggered protracted symptoms of memory
deficits which were still present up to eight weeks after cessation of
alprazolam.
Protracted withdrawal syndrome
Protracted
withdrawal syndrome refers to symptoms persisting for months or even
years. A significant minority of people withdrawing from
benzodiazepines, perhaps 10% to 15%, experience a protracted withdrawal syndrome which can sometimes be severe. Symptoms may include tinnitus, psychosis, cognitive deficits, gastrointestinal complaints,
insomnia, paraesthesia (tingling and numbness), pain (usually in limbs
and extremities), muscle pain, weakness, tension, painful tremor,
shaking attacks, jerks, dizziness and blepharospasm
and may occur even without a pre-existing history of these symptoms.
Tinnitus occurring during dose reduction or discontinuation of
benzodiazepines is alleviated by recommencement of benzodiazepines.
Dizziness is often reported as being the withdrawal symptom that lasts
the longest.
A study testing neuropsychological factors found
psychophysiological markers differing from normals, and concluded that
protracted withdrawal syndrome was a genuine iatrogenic condition caused
by the long-term use.
The causes of persisting symptoms are a combination of pharmacological
factors such as persisting drug induced receptor changes, psychological
factors both caused by the drug and separate from the drug and possibly
in some cases, particularly high dose users, structural brain damage or
structural neuronal damage.
Symptoms continue to improve over time, often to the point where people
eventually resume their normal lives, even after years of incapacity.
A slow withdrawal rate significantly reduces the risk of a
protracted or severe withdrawal state. Protracted withdrawal symptoms
can be punctuated by periods of good days and bad days. When symptoms
increase periodically during protracted withdrawal, physiological
changes may be present, including dilated pupils as well as an increase in blood pressure and heart rate.
The change in symptoms has been proposed to be due to changes in
receptor sensitivity for GABA during the process of tolerance reversal. A meta-analysis
found cognitive impairments in many areas due to benzodiazepine use
show improvements after six months of withdrawal, but significant
impairments in most areas may be permanent or may require more than six
months to reverse.
Protracted symptoms continue to fade over a period of many months
or several years. There is no known cure for protracted benzodiazepine
withdrawal syndrome except time,
however, the medication flumazenil was found to be more effective than
placebo in reducing feelings of hostility and aggression in patients who
had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
Epidemiology
The
severity and length of the withdrawal syndrome is likely determined by
various factors, including rate of tapering, length of use and dosage
size, and possible genetic factors. Those who have a prior history of withdrawing from benzodiazepines may have a sensitized or kindled central nervous system leading to worsening cognition and symptomatology, and making each subsequent withdrawal period worse.
Special populations
Pediatrics
A neonatal withdrawal syndrome, sometimes severe, can occur when the mother had taken benzodiazepines, especially during the third trimester. Symptoms include hypotonia, apnoeic spells, cyanosis, impaired metabolic responses to cold stress, and seizures. The neonatal benzodiazepine withdrawal syndrome has been reported to persist from hours to months after birth.
A withdrawal syndrome is seen in about 20% of pediatric intensive care unit children after infusions with benzodiazepines or opioids.
The likelihood of having the syndrome correlates with total infusion
duration and dose, although duration is thought to be more important. Treatment for withdrawal usually involves weaning over a 3- to 21-day period if the infusion lasted for more than a week.
Symptoms include tremors, agitation, sleeplessness, inconsolable
crying, diarrhea and sweating. In total, over fifty withdrawal symptoms
are listed in this review article.
Environmental measures aimed at easing the symptoms of neonates with
severe abstinence syndrome had little impact, but providing a quiet
sleep environment helped in mild cases.
Pregnancy
Discontinuing benzodiazepines or antidepressants abruptly due to concerns of teratogenic
effects of the medications has a high risk of causing serious
complications, so is not recommended. For example, abrupt withdrawal of
benzodiazepines or antidepressants has a high risk of causing extreme
withdrawal symptoms, including suicidal ideation and a severe rebound
effect of the return of the underlying disorder if present. This can
lead to hospitalisation and potentially, suicide. One study reported
one-third of mothers who suddenly discontinued or very rapidly tapered
their medications became acutely suicidal due to 'unbearable symptoms'.
One woman had a medical abortion,
as she felt she could no longer cope, and another woman used alcohol in
a bid to combat the withdrawal symptoms from benzodiazepines. Spontaneous abortions
may also result from abrupt withdrawal of psychotropic medications,
including benzodiazepines. The study reported physicians generally are
not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.
Elderly
A study
of the elderly who were benzodiazepine dependent found withdrawal could
be carried out with few complications and could lead to improvements in
sleep and cognitive abilities. At 52 weeks after successful withdrawal,
a 22% improvement in cognitive status was found, as well as improved
social functioning. Those who remained on benzodiazepines experienced a
5% decline in cognitive abilities, which seemed to be faster than that
seen in normal aging, suggesting the longer the intake of
benzodiazepines, the worse the cognitive effects become. Some worsening
of symptoms were seen in the first few months of benzodiazepine
abstinence, but at a 24-week followup, elderly subjects were clearly
improved compared to those who remained on benzodiazepines. Improvements
in sleep were seen at the 24- and 52-week followups. The authors
concluded benzodiazepines were not effective in the long term for sleep
problems except in suppressing withdrawal-related rebound insomnia.
Improvements were seen between 24 and 52 weeks after withdrawal in many
factors, including improved sleep and several cognitive and performance
abilities. Some cognitive abilities, which are sensitive to
benzodiazepines, as well as age, such as episodic memory
did not improve. The authors, however, cited a study in younger
patients who at a 3.5-year followup showed no memory impairments and
speculated that certain memory functions take longer to recover from
chronic benzodiazepine use and further improvements in elderly people's
cognitive function may occur beyond 52 weeks after withdrawal. The
reason it took 24 weeks for improvements to be seen after cessation of
benzodiazepine use was due to the time it takes the brain to adapt to
the benzodiazepine-free environment.
At 24 weeks, significant improvements were found, including
accuracy of information processing improved, but a decline was seen in
those who remained on benzodiazepines. Further improvements were noted
at the 52-week followup, indicating ongoing improvements with
benzodiazepine abstinence. Younger people on benzodiazepines also
experience cognitive deterioration in visual spatial memory, but are not
as vulnerable as the elderly to the cognitive effects.
Improved reaction times were noted at 52 weeks in elderly patients free
from benzodiazepines. This is an important function in the elderly,
especially if they drive a car due to the increased risk of road traffic
accidents in benzodiazepine users.
At the 24-week followup, 80% of people had successfully withdrawn from
benzodiazepines. Part of the success was attributed to the placebo method used for part of the trial which broke the psychological dependence
on benzodiazepines when the elderly patients realised they had
completed their gradual reduction several weeks previously, and had only
been taking placebo tablets. This helped reassure them they could sleep
without their pills.
The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepineZ drugs.
The elimination half-life
of diazepam and chlordiazepoxide, as well as other long half-life
benzodiazepines, is twice as long in the elderly compared to younger
individuals. Many doctors do not adjust benzodiazepine dosage according
to age in elderly patients.
