Benzodiazepine withdrawal syndrome: Difference between revisions

Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Other names	Benzo withdrawal
	Diazepam is sometimes used in the treatment of benzodiazepine withdrawal.
Specialty	Addiction medicine, Psychiatry
Symptoms	Anxiety, irritability, panic attacks, paranoia, tremor, akathisia, dissociation, confusion, insomnia, sensory disturbances, seizures
Complications	Seizures, suicide, hyperthermia, psychosis, delirium, catatonia, psychological trauma, death
Duration	Average: ~2 months
Causes	Stopping or reducing intake of benzodiazepines in a state of dependence
Prevention	Gradual dose reduction

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Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

Typically, benzodiazepine withdrawal is characterized by sleep disturbance, irritability, increased tension and anxiety, depression, panic attacks, hand tremor, shaking, sweating, difficulty with concentration, confusion and cognitive difficulty, memory problems, dry mouth, nausea and vomiting, diarrhea, loss of appetite and weight loss, burning sensations and pain in the upper spine, palpitations, headache, nightmares, tinnitus, muscular pain and stiffness, and a host of perceptual changes.^[2] More serious symptoms may also occur such as depersonalization, restless legs syndrome, seizures, and suicidal ideation.

Benzodiazepine withdrawal can also lead to disturbances in mental function that persist for several months or years after onset of symptoms (referred to as post-acute-withdrawal syndrome in this form).

Withdrawal symptoms can be managed through 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.^[3]^[4]

Signs and symptoms

Withdrawal symptoms occur during dose reduction and may include insomnia, anxiety, distress, weight loss, dizziness, night sweats, shaking, muscle twitches, aphasia, panic attacks, depression, dissociation, paranoia, indigestion, diarrhea, and photophobia. As withdrawal progresses, patients often find their physical and mental health improves with improved mood and improved cognition.

A more complete list of possible symptoms stated in publications:

Akathisia (restlessness)
Agitation and anxiety^[1]
Panic attacks^[2]^[5]
Blurred vision^[5]
Chest pain^[5]
Depersonalization^[6] and derealization (feelings of unreality)^[7]
Depression (can be severe),^[8] possible suicidal ideation
Dilated pupils^[9]
Dizziness^[5]
Dry mouth^[5]
Dysphoria^[10]^[11]
High blood pressure^[12]^[13]
Fatigue and weakness^[5]
Gastrointestinal disturbance (e.g., nausea, diarrhea, vomiting)^[14]^[15]^[16]
Hearing disturbance^[5]
Headache^[2]
Hot and cold spells^[5]
Hyperosmia^[17]
Hyperacusis^[18]^[19]
Hypnagogic hallucinations^[20]
Hypochondriasis^[5]
Increased sensitivity to touch^[7]
Increased urinary frequency^[5]
Insomnia^[14]
Impaired memory and concentration^[2]^[5]
Loss of appetite and weight loss^[21]
Mild to moderate aphasia^[17]
Mood swings^[5]
Muscular spasms, cramps, or fasciculations^[22]
Nightmares^[14]
Obsessive–compulsive symptoms^[23]^[24]
Paraesthesia^[5]^[7]^[17]^[25]^[26]
Paranoia^[17]
Perspiration^[2]
Photophobia^[17]
Postural hypotension^[14]
REM sleep rebound^[27]
Restless legs syndrome^[4]
Stiffness^[5]
Taste and smell disturbances^[5]
Tachycardia^[28]
Tinnitus^[29]
Tremor^[30]^[31]
Visual disturbances^[7]

Rapid discontinuation may result in a more serious syndrome

Catatonia,^[32]^[33]^[34]
Confusion^[1]
Seizures,^[1] which may result in death^[35]^[36]
Coma^[37] (rare)
Delirium tremens^[38]^[39]
Hyperthermia^[14]
Mania^[40]^[41]
Neuroleptic malignant syndrome-like event^[42]^[43] (rare)
Organic brain syndrome^[44]
Post-traumatic stress disorder^[4]
Psychosis^[45]^[46]
Suicidal ideation^[47] or suicide^[48]^[49]
Violence and aggression^[5]^[50]

Mechanism

The neuroadaptive processes involved in tolerance, dependence, and withdrawal mechanisms implicate both the GABAergic and the glutamatergic systems.^[51] Gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA.^[52] GABA mediates the influx of chloride ions through ligand-gated chloride channels called GABA_A 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.^[53] Benzodiazepines potentiate the action of GABA,^[54] by binding a site between the α and γ subunits of the 5-subunit receptor^[55] thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.^[56]

When potentiation is sustained by long-term use, neuroadaptations occur which result in decreased GABAergic response. What is certain is that surface GABA_A receptor protein levels are altered in response to benzodiazepine exposure, as is receptor turnover rate.^[57] 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.^[58] 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.^[51]^[57] 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.^[57]

It has been postulated that when benzodiazepines are cleared from the brain, these neuroadaptations are "unmasked", leading to unopposed excitability of the neuron.^[59] Glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system.^[60] 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.^[61]^[62]^[63] Those who have a prior history of withdrawing from benzodiazepines are found to be less likely to succeed the next time around.^[64]

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.^[9] 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.^[9]

Symptoms may lack a psychological cause and can fluctuate in intensity with periods of good and bad days until eventual recovery.^[65]^[66]

Prevention

According to the British National Formulary, it is better to withdraw too slowly rather than too quickly from benzodiazepines.^[67] 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^[1] 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.^[68]

Management

Chlordiazepoxide, 5 mg capsules, are sometimes used as an alternative to diazepam for benzodiazepine withdrawal. Like diazepam, it has a long elimination half-life and long-acting active metabolites.^[25]^[69]

Management of benzodiazepine dependence involves considering the person's age, comorbidity and the pharmacological pathways of benzodiazepines.^[70] Psychological interventions may provide a small but significant additional benefit over gradual dose reduction alone at post-cessation and at follow-up.^[71] 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.^[71]

There is no standard approach to managing benzodiazepine withdrawal.^[72] With sufficient motivation and the proper approach, almost anyone can successfully withdraw from benzodiazepines. However, a prolonged and severe withdrawal syndrome can cause profound disability, which may lead to breakdown of relationships, loss of employment, financial difficulties, as well as more serious adverse effects such as hospitalization and suicide.^[48] As such, long-term users should not be forced to discontinue against their will.^[25]

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.^[25]^[20] 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.^[73]

Medications

While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.^[71] 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,^[74] paroxetine,^[75] trazodone,^[76] or valproate^[76] in conjunction with a gradual dose reduction.^[71]

Antipsychotics are generally ineffective for benzodiazepine withdrawal-related psychosis.^[26]^[77] Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions.^[67]^[78]^[79]^[80] 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.^[81]
Barbiturates are cross tolerant to benzodiazepines and should generally be avoided; however phenobarbital can be used, as it is relatively safe,^[82] see below.
Benzodiazepines or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the nonbenzodiazepines Z-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.^[83]^[84]
Bupropion, which is used primarily as an antidepressant and smoking cessation aid, is contraindicated in people experiencing abrupt withdrawal from benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an increased risk of seizures.^[85]
Buspirone augmentation was not found to increase the discontinuation success rate.^[86]
Caffeine may worsen withdrawal symptoms because of its stimulatory properties.^[25] At least one animal study has shown some modulation of the benzodiazepine site by caffeine, which produces a lowering of seizure threshold.^[87]
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.^[83]
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.^[25]^[83]^[88]
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.^[89]^{[needs update]} Flumazenil stimulates the up-regulation and reverses the uncoupling of benzodiazepine receptors to the GABA_A receptor, thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.^[90]^[91] 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.^[92] 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.^[93] A study by Professor Borg in Sweden produced similar results in patients in protracted withdrawal.^[5] 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.^[94]

Fluoroquinolone antibiotics^[95]^[96]^[97] 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 (photophobia) and sound (hyperacusis), tremors, status epilepticus, suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal.^[25]^[98]^[99]^[100]^[101] 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.^[102]^[103]^[104]
Imidazenil has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.^[105]
Imipramine was found to statistically increase the discontinuation success rate.^[86]
Melatonin augmentation was found to statistically increase the discontinuation success rate for people with insomnia.^[86]
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.^[9] In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.^[106]^[107]
Pregabalin may help reduce the severity of benzodiazepine withdrawal symptoms,^[108] and reduce the risk of relapse.^[109]
Propranolol was not found to increase the discontinuation success rate.^[86]
SSRI antidepressants have been found to have little value in the treatment of benzodiazepine withdrawal.^[110]
Trazodone was not found to increase the discontinuation success rate.^[86]

Inpatient treatment

Inpatient drug 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 these individuals.^[9]

Prognosis

A 2006 meta-analysis found evidence for the efficacy of stepped care: minimal intervention (e.g. send an advisory letter, or meet a large number of patients to advise discontinuation), followed by systematic tapered discontinuation alone without augmentation if the first try was unsuccessful.^[86] Cognitive behavioral therapy improved discontinuation success rates for panic disorder, melatonin for insomnia, and flumazenil or sodium valproate for general long-term benzodiazepine use.^[86] 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 follow-up.^[111] One study found that after one year of abstinence from long-term use of benzodiazepines, cognitive, neurological and intellectual impairments had returned to normal.^[112]

Those who had a prior psychiatric diagnosis had a similar success rate from a gradual taper at a two-year follow-up.^[68]^[113] Withdrawal from benzodiazepines did not lead to an increased use of antidepressants.^[114]

Withdrawal process

It can be too difficult to withdraw from short- or intermediate-acting benzodiazepines because of the intensity of the rebound symptoms felt between doses.^[25]^[115]^[116]^[117] Moreover, short-acting benzodiazepines appear to produce a more intense withdrawal syndrome.^[118] For this reason, discontinuation is sometimes carried out by first substituting an equivalent dose of a short-acting benzodiazepine with a longer-acting one like diazepam or chlordiazepoxide. Failure to use the correct equivalent amount can precipitate a severe withdrawal reaction.^[119] 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.^[111] The resultant equivalent dose is then gradually reduced.

The consensus is to reduce dosage gradually over several weeks, e.g. 4 or more weeks for diazepam doses over 30 mg/day,^[1] with the rate determined by the person's ability to tolerate symptoms.^[120] The recommended reduction rates range from 50% of the initial dose every week or so,^[121] to 10–25% of the daily dose every 2 weeks.^[120] 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.^[25] For most people, discontinuation over 4–6 weeks or 4–8 weeks is suitable.^[122] A prolonged period of reduction for longer than six months should be avoided to prevent the withdrawal process from becoming a "morbid focus" for the person.^[83]

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,^[123]^[68] 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.^[124]

Protracted withdrawal syndrome

Protracted withdrawal syndrome refers to symptoms persisting for months or even years. A significant minority of people withdrawing from benzodiazepines, perhaps 10–15%, experience a protracted withdrawal syndrome which can sometimes be severe. Symptoms may include tinnitus,^[29]^[125] 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^[20] 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.^[126] 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.^[20]^[127] Symptoms continue to improve over time, often to the point where people eventually resume their normal lives, even after years of incapacity.^[25]

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.^[9] The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal.^[25] 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.^[128]

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,^[20] 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.^[92] 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.^[25]^[129] 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.^[61]^[62]^[63]^[130]

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.^[131]

A withdrawal syndrome is seen in about 20% of pediatric intensive care unit children after infusions with benzodiazepines or opioids.^[132] The likelihood of having the syndrome correlates with total infusion duration and dose, although duration is thought to be more important.^[133] Treatment for withdrawal usually involves weaning over a 3- to 21-day period if the infusion lasted for more than a week.^[134] Symptoms include tremors, agitation, sleeplessness, inconsolable crying, diarrhea and sweating. In total, over fifty withdrawal symptoms are listed in this review article.^[132]^[135] 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.^[132]

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.^[47]

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 follow-up, elderly subjects were clearly improved compared to those who remained on benzodiazepines. Improvements in sleep were seen at the 24- and 52-week follow-ups. 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 follow-up 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.^[136]

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 follow-up, 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.^[136] 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.^[136] At the 24-week follow-up, 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.^[136]

The authors also warned of the similarities in pharmacology and mechanism of action of the newer nonbenzodiazepine Z drugs.^[136]

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.^[137]

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@@ Line 2: / Line 2: @@
 {{Use dmy dates|date=June 2020}}
 {{Infobox medical condition (new)
-| name            = Benzodiazepine withdrawal syndrome
+| name = Benzodiazepine withdrawal syndrome
-| synonyms        = Benzo withdrawal
+| synonyms = Benzo withdrawal
-| image           = Diazepam2mgand5mgtablets.JPG
+| image = Diazepam2mgand5mgtablets.JPG
-| caption         =[[Diazepam]] is sometimes used in the treatment of benzodiazepine withdrawal.<ref name="pmid28328330"/>
+| caption = [[Diazepam]] is sometimes used in the treatment of benzodiazepine withdrawal.<ref name="pmid28328330"/>
-| field           = [[Addiction medicine]], [[Psychiatry]]
+| field = [[Addiction medicine]], [[Psychiatry]]
-| pronounce       =
+| pronounce =
-| specialty       =
+| specialty =
+| symptoms = [[Anxiety]], [[irritability]], [[panic attacks]], [[paranoia]], [[tremor]], [[akathisia]], [[dissociation (psychology)|dissociation]], [[confusion]], [[insomnia]], sensory disturbances, [[seizures]]
-| symptoms        =
+| complications = [[Seizures]], [[suicide]], [[hyperthermia]], [[psychosis]], [[delirium]], [[catatonia]], [[psychological trauma]], death
-| complications   =
-| onset           =
+| onset =
-| duration        =
+| duration = Average: ~2 months
-| types           =
+| types =
+| causes = Stopping or reducing intake of [[benzodiazepines]] in a state of [[substance dependence|dependence]]
-| causes          =
-| risks           =
+| risks =
-| diagnosis       =
+| diagnosis =
-| differential    =
+| differential =
-| prevention      =
+| prevention = Gradual dose reduction
-| treatment       =
+| treatment =
-| medication      =
+| medication =
-| prognosis       =
+| prognosis =
-| frequency       =
+| frequency =
-| deaths          =
+| deaths =
 }}
 {{Benzos}}
-'''Benzodiazepine withdrawal syndrome''' ('''BZD withdrawal''') is the cluster of [[Sign (medical)|signs]] and [[Drug withdrawal|symptoms]] that may emerge when a person who has been taking [[benzodiazepine]]s as prescribed develops a [[Substance dependence|physical]] [[Benzodiazepine dependence|dependence]] on them and then reduces the dose or stops taking them without a safe taper schedule.
+'''Benzodiazepine withdrawal syndrome''' ('''BZD withdrawal''') is the cluster of [[Sign (medical)|signs]] and [[Drug withdrawal|symptoms]] that may emerge when a person who has been taking [[benzodiazepine]]s as prescribed develops a [[Substance dependence|physical]] [[Benzodiazepine dependence|dependence]] on them and then reduces the dose or stops taking them without a safe [[Tapering (medicine)|taper schedule]].
-Typically, benzodiazepine withdrawal is characterized by sleep disturbance, irritability, increased tension and [[anxiety]], [[Depression (mood)|depression]], [[panic attack]]s, [[Tremor|hand tremor]], shaking, sweating, difficulty with concentration, confusion and cognitive difficulty, memory problems, [[Dry mouth|dry retching]] and [[nausea]], [[diarrhea]], [[vomiting]], [[Anorexia (symptom)|loss of appetite]] and [[weight loss]], burning sensations and pain in the upper spine, [[palpitation]]s, headache, [[nightmare]]s, [[tinnitus]], muscular pain and [[Joint stiffness|stiffness]], and a host of perceptual changes.<ref name=Petursson>{{cite journal |doi=10.1111/j.1360-0443.1994.tb03743.x |title=The benzodiazepine withdrawal syndrome |year=1994 |last1=Petursson |first1=H. |journal=Addiction |volume=89 |issue=11 |pages=1455–9 |pmid=7841856}}</ref> More serious symptoms may also occur such as [[depersonalization]], [[restless legs syndrome]], [[seizure]] and [[suicidal ideation]].
+Typically, benzodiazepine withdrawal is characterized by [[Insomnia|sleep disturbance]], [[irritability]], increased tension and [[anxiety]], [[Depression (mood)|depression]], [[panic attack]]s, [[Tremor|hand tremor]], shaking, [[Perspiration|sweating]], difficulty with concentration, [[confusion]] and cognitive difficulty, memory problems, [[dry mouth]], [[nausea]] and [[vomiting]], [[diarrhea]], [[Anorexia (symptom)|loss of appetite]] and [[weight loss]], burning sensations and pain in the upper spine, [[palpitation]]s, [[headache]], [[nightmare]]s, [[tinnitus]], [[muscular pain]] and [[Joint stiffness|stiffness]], and a host of perceptual changes.<ref name="Petursson">{{cite journal |doi=10.1111/j.1360-0443.1994.tb03743.x |title=The benzodiazepine withdrawal syndrome |year=1994 |last1=Petursson |first1=H. |journal=Addiction |volume=89 |issue=11 |pages=1455–9 |pmid=7841856}}</ref> More serious symptoms may also occur such as [[depersonalization]], [[restless legs syndrome]], [[seizure]]s, and [[suicidal ideation]].
+Benzodiazepine withdrawal can also lead to disturbances in mental function that persist for several months or years after onset of symptoms (referred to as [[post-acute-withdrawal syndrome]] in this form).
-Withdrawal can be managed through 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.<ref name="tbws1989">{{cite journal |pmid=2576073 |year=1989 |last1=Onyett |first1=SR |title=The benzodiazepine withdrawal syndrome and its management |volume=39 |issue=321 |pages=160–3 |pmc=1711840 |journal=The Journal of the Royal College of General Practitioners}}</ref><ref name="pmid1675688">{{cite journal |doi=10.1016/0740-5472(91)90023-4 |title=Protracted withdrawal syndromes from benzodiazepines |year=1991 |last1=Ashton |first1=Heather |journal=Journal of Substance Abuse Treatment |volume=8 |pages=19–28 |pmid=1675688 |issue=1–2}}</ref>
+Withdrawal symptoms can be managed through awareness of the withdrawal reactions, individualized [[Tapering (medicine)|taper]] strategies according to withdrawal severity, the addition of alternative strategies such as reassurance, and referral to benzodiazepine withdrawal support groups.<ref name="tbws1989">{{cite journal |pmid=2576073 |year=1989 |last1=Onyett |first1=SR |title=The benzodiazepine withdrawal syndrome and its management |volume=39 |issue=321 |pages=160–3 |pmc=1711840 |journal=The Journal of the Royal College of General Practitioners}}</ref><ref name="pmid1675688">{{cite journal |doi=10.1016/0740-5472(91)90023-4 |title=Protracted withdrawal syndromes from benzodiazepines |year=1991 |last1=Ashton |first1=Heather |journal=Journal of Substance Abuse Treatment |volume=8 |pages=19–28 |pmid=1675688 |issue=1–2}}</ref>
 ==Signs and symptoms==
-Withdrawal symptoms occur during dose reduction and may include insomnia, anxiety, distress, weight loss, dizziness, night sweats, shakes, muscle twitches, aphasia, panic attacks, depression, derealization, paranoia, indigestion, diarrhea, and [[photophobia]]. As withdrawal progresses, patients often find their physical and mental health improves with improved mood and improved cognition.
+Withdrawal symptoms occur during dose reduction and may include insomnia, anxiety, distress, weight loss, dizziness, night sweats, shaking, muscle twitches, aphasia, panic attacks, depression, [[Dissociation (psychology)|dissociation]], paranoia, indigestion, diarrhea, and [[photophobia]]. As withdrawal progresses, patients often find their physical and mental health improves with improved mood and improved cognition.
 '''A more complete list of possible symptoms stated in publications:'''
 {{Columns-list|
 * [[Akathisia]] (restlessness)
-* Agitation and [[anxiety]],<ref name="pmid28328330">{{cite journal |vauthors=Soyka M |title=Treatment of Benzodiazepine Dependence |journal=The New England Journal of Medicine |volume=376 |issue=12 |pages=1147–1157 |year=2017 |pmid=28328330 |doi=10.1056/NEJMra1611832 |s2cid=205117734 }}</ref> possible terror and [[panic attack]]s<ref name="Petursson" /><ref name="pmid9201803" />
+* Agitation and [[anxiety]]<ref name="pmid28328330">{{cite journal |vauthors=Soyka M |title=Treatment of Benzodiazepine Dependence |journal=The New England Journal of Medicine |volume=376 |issue=12 |pages=1147–1157 |year=2017 |pmid=28328330 |doi=10.1056/NEJMra1611832 |s2cid=205117734 }}</ref>
+* [[Panic attack]]s<ref name="Petursson" /><ref name="pmid9201803" />
 * [[Blurred vision]]<ref name="pmid9201803" />
 * [[Chest pain]]<ref name="pmid9201803" />
@@ Line 48: / Line 51: @@
 * [[Dry mouth]]<ref name="pmid9201803" />
 * [[Dysphoria]]<ref>{{cite journal |pmid=6761826 |year=1982 |last1=Mendelson |first1=WB |last2=Weingartner |first2=H |last3=Greenblatt |first3=DJ |last4=Garnett |first4=D |last5=Gillin |first5=JC |title=A clinical study of flurazepam |volume=5 |issue=4 |pages=350–60 |journal=Sleep|doi=10.1093/sleep/5.4.350 |doi-access=free }}</ref><ref>{{cite journal |doi=10.1055/s-2007-1017439 |title=Withdrawal Phenomena after Long-term Administration of Benzodiazepines a Review of Recent Investigations |year=2008 |last1=Schöpf |first1=J. |journal=Pharmacopsychiatry |volume=16 |pages=1–8 |pmid=6131447 |issue=1|s2cid=23063064 }}</ref>
-* Elevation in [[blood pressure]]<ref>{{cite journal |doi=10.1007/s00213-004-2009-1 |title=Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure |year=2004 |last1=Mintzer |first1=Miriam Z. |last2=Griffiths |first2=Roland R. |journal=Psychopharmacology |volume=178 |issue=2–3 |pages=259–67 |pmid=15452683|s2cid=22130710 }}</ref>
+* [[High blood pressure]]<ref>{{cite journal |doi=10.1007/s00213-004-2009-1 |title=Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure |year=2004 |last1=Mintzer |first1=Miriam Z. |last2=Griffiths |first2=Roland R. |journal=Psychopharmacology |volume=178 |issue=2–3 |pages=259–67 |pmid=15452683|s2cid=22130710 }}</ref><ref>{{cite journal |pmid=15902797 |year=2005 |last1=Biswas |first1=AK |last2=Feldman |first2=BL |last3=Davis |first3=DH |last4=Zintz |first4=EA |title=Myocardial ischemia as a result of severe benzodiazepine and opioid withdrawal |volume=43 |issue=3 |pages=207–9 |journal=Clinical Toxicology |doi=10.1081/clt-200053099 |url=https://zenodo.org/record/1236068 |access-date=29 June 2019 |archive-date=26 July 2020 |archive-url=https://web.archive.org/web/20200726195614/https://zenodo.org/record/1236068 |url-status=live }}</ref>
 * [[Fatigue (medical)|Fatigue]] and [[weakness]]<ref name="pmid9201803" />
-* Gastrointestinal disturbance (including [[nausea]], [[diarrhea]], [[vomiting]])<ref name="nouv"/><ref name="Loeb P">{{cite journal |doi=10.1016/S0750-7658(97)83345-X |title=Sevrage en benzodiazépines révélé par un syndrome douloureux abdominal pseudochirurgical |trans-title=Benzodiazepine withdrawal masquerading as surgical abdominal syndrome |language=fr |year=1997 |last1=Loeb |first1=P |last2=Adnet |first2=P |last3=Boittiaux |first3=P |last4=Forget |first4=AP |last5=Mille |first5=FX |journal=Annales Françaises d'Anesthésie et de Réanimation |volume=16 |issue=5 |pages=521–2|pmid=9750606 }}</ref><ref>http://www.benzo.org.uk/manual/bzcha03.htm#16{{full citation needed|date=October 2013}}</ref>
+* Gastrointestinal disturbance (e.g., [[nausea]], [[diarrhea]], [[vomiting]])<ref name="nouv"/><ref name="Loeb P">{{cite journal |doi=10.1016/S0750-7658(97)83345-X |title=Sevrage en benzodiazépines révélé par un syndrome douloureux abdominal pseudochirurgical |trans-title=Benzodiazepine withdrawal masquerading as surgical abdominal syndrome |language=fr |year=1997 |last1=Loeb |first1=P |last2=Adnet |first2=P |last3=Boittiaux |first3=P |last4=Forget |first4=AP |last5=Mille |first5=FX |journal=Annales Françaises d'Anesthésie et de Réanimation |volume=16 |issue=5 |pages=521–2|pmid=9750606 }}</ref><ref>{{Cite web |url=http://www.benzo.org.uk/manual/bzcha03.htm#16 |title=Archived copy |access-date=6 February 2009 |archive-date=23 September 2020 |archive-url=https://web.archive.org/web/20200923180049/https://www.benzo.org.uk/manual/bzcha03.htm#16 |url-status=live }}{{full citation needed|date=October 2013}}</ref>
 * Hearing disturbance<ref name="pmid9201803" />
-* Headache<ref name="Petursson"/>
+* [[Headache]]<ref name="Petursson"/>
 * [[Hot flush|Hot]] and [[Cold chill|cold spells]]<ref name="pmid9201803" />
 *[[Hyperosmia]]<ref name="dobcaba">{{cite journal |pmid=7914165 |year=1994 |last1=Pelissolo |first1=A |last2=Bisserbe |first2=JC |title=Dependence on benzodiazepines. Clinical and biological aspects |volume=20 |issue=2 |pages=147–57 |journal=L'Encéphale}}</ref>
-*[[Hyperacusis]]<ref>{{cite journal |last1=Beeley |first1=L |title=Benzodiazepines and tinnitus. |journal=BMJ: British Medical Journal |date=15 June 1991 |volume=302 |issue=6790 |pages=1465 |doi=10.1136/bmj.302.6790.1465 |pmid=2070121 |issn=0959-8138|pmc=1670117 }}</ref><ref>{{cite journal |last1=Lader |first1=M. |title=Anxiolytic drugs: dependence, addiction and abuse |journal=European Neuropsychopharmacology |date=June 1994 |volume=4 |issue=2 |pages=85–91 |doi=10.1016/0924-977x(94)90001-9 |pmid=7919947 |s2cid=44711894 |url=https://pubmed.ncbi.nlm.nih.gov/7919947/ |issn=0924-977X}}</ref>
+*[[Hyperacusis]]<ref>{{cite journal |last1=Beeley |first1=L |title=Benzodiazepines and tinnitus. |journal=BMJ: British Medical Journal |date=15 June 1991 |volume=302 |issue=6790 |pages=1465 |doi=10.1136/bmj.302.6790.1465 |pmid=2070121 |issn=0959-8138|pmc=1670117 }}</ref><ref>{{cite journal |last1=Lader |first1=M. |title=Anxiolytic drugs: dependence, addiction and abuse |journal=European Neuropsychopharmacology |date=June 1994 |volume=4 |issue=2 |pages=85–91 |doi=10.1016/0924-977x(94)90001-9 |pmid=7919947 |s2cid=44711894 |url=https://pubmed.ncbi.nlm.nih.gov/7919947/ |issn=0924-977X |access-date=23 February 2021 |archive-date=7 February 2022 |archive-url=https://web.archive.org/web/20220207083921/https://pubmed.ncbi.nlm.nih.gov/7919947/ |url-status=live }}</ref>
+* [[Hypnagogic]] hallucinations<ref name="pwsfb">{{cite web| author= Professor Heather Ashton| year= 2004| url= http://www.benzo.org.uk/pws04.htm| title= Protracted Withdrawal Symptoms From Benzodiazepines| publisher= Comprehensive Handbook of Drug & Alcohol Addiction| access-date= 5 February 2009| archive-date= 28 September 2020| archive-url= https://web.archive.org/web/20200928001424/https://www.benzo.org.uk/pws04.htm| url-status= live}}</ref>
-*[[Hypertension]]<ref>{{cite journal |pmid=15902797 |year=2005 |last1=Biswas |first1=AK |last2=Feldman |first2=BL |last3=Davis |first3=DH |last4=Zintz |first4=EA |title=Myocardial ischemia as a result of severe benzodiazepine and opioid withdrawal |volume=43 |issue=3 |pages=207–9 |journal=Clinical Toxicology |doi=10.1081/clt-200053099|url=https://zenodo.org/record/1236068 }}</ref>
-* [[Hypnagogic]] hallucinations<ref name="pwsfb">{{cite web| author= Professor Heather Ashton| year= 2004| url=http://www.benzo.org.uk/pws04.htm| title= Protracted Withdrawal Symptoms From Benzodiazepines | publisher= Comprehensive Handbook of Drug & Alcohol Addiction}}</ref>
 * [[Hypochondriasis]]<ref name="pmid9201803" />
-* Increased sensitivity to touch<ref name="Mintzer-1999"/>
+* [[Hyperesthesia|Increased sensitivity to touch]]<ref name="Mintzer-1999"/>
 * Increased [[urinary frequency]]<ref name="pmid9201803" />
 * [[Insomnia]]<ref name="nouv"/>
@@ Line 66: / Line 68: @@
 * Mild to moderate [[aphasia]]<ref name="dobcaba"/>
 * [[Mood swings]]<ref name=pmid9201803/>
-* [[Muscular spasms]], [[cramp]]s, discomfort or [[fasciculations]]<ref name=Lindgren>Kliniska Färdigheter: Informationsutbytet Mellan Patient Och Läkare, LINDGREN, STEFAN, {{ISBN|91-44-37271-X}} (Swedish){{page needed|date=October 2013}}</ref>
+* [[Muscular spasms]], [[cramp]]s, or [[fasciculations]]<ref name=Lindgren>Kliniska Färdigheter: Informationsutbytet Mellan Patient Och Läkare, LINDGREN, STEFAN, {{ISBN|91-44-37271-X}} (Swedish){{page needed|date=October 2013}}</ref>
 * [[Nightmare]]s<ref name="nouv">{{cite journal |pmid=6106922 |year=1980 |last1=Bismuth |first1=C |last2=Le Bellec |first2=M |last3=Dally |first3=S |last4=Lagier |first4=G |title=Benzodiazepine physical dependence. 6 cases (author's transl) |volume=9 |issue=28 |pages=1941–5 |journal=La Nouvelle Presse Médicale}}</ref>
-* [[Obsessive compulsive disorder]]<ref>{{cite journal |doi=10.1097/00005053-198811000-00008 |title=SINGLE CASE STUDY Obsessive-Compulsive Disorder Occurring as a Complication in Benzodiazepine Withdrawal |year=1988 |last1=Drummond |first1=Lynne M. |last2=Matthews |first2=Helen P. |journal=Journal of Nervous and Mental Disease |volume=176 |issue=11 |pages=688–91 |pmid=3183654|s2cid=28340232 }}</ref><ref>{{cite journal |pmid=3651695 |year=1987 |last1=Matthews |first1=HP |last2=Drummond |first2=LM |title=Obsessive-compulsive disorder—a complication of benzodiazepine withdrawal |volume=150 |issue=2 |pages=272 |journal=British Journal of Psychiatry |doi=10.1192/s0007125000122810|doi-access=free }}</ref>
+* [[Obsessive–compulsive disorder|Obsessive–compulsive symptoms]]<ref>{{cite journal |doi=10.1097/00005053-198811000-00008 |title=SINGLE CASE STUDY Obsessive-Compulsive Disorder Occurring as a Complication in Benzodiazepine Withdrawal |year=1988 |last1=Drummond |first1=Lynne M. |last2=Matthews |first2=Helen P. |journal=Journal of Nervous and Mental Disease |volume=176 |issue=11 |pages=688–91 |pmid=3183654|s2cid=28340232 }}</ref><ref>{{cite journal |pmid=3651695 |year=1987 |last1=Matthews |first1=HP |last2=Drummond |first2=LM |title=Obsessive-compulsive disorder—a complication of benzodiazepine withdrawal |volume=150 |issue=2 |pages=272 |journal=British Journal of Psychiatry |doi=10.1192/s0007125000122810|doi-access=free }}</ref>
 * [[Paraesthesia]]<ref name="pmid9201803" /><ref name="Mintzer-1999"/><ref name="dobcaba"/><ref name="ashman">{{cite web | author= Professor Heather Ashton | year= 2002 | url= http://benzo.org.uk/manual/index.htm | title= Benzodiazepines: How They Work and How to Withdraw | url-status= live | archive-url= http://archive.wikiwix.com/cache/20110915105636/http://benzo.org.uk/manual/index.htm | archive-date= 15 September 2011}}</ref><ref name=tuobicp>{{cite journal |pmid=6133535 |year=1981 |last1=Shader |first1=RI |last2=Greenblatt |first2=DJ |title=The use of benzodiazepines in clinical practice |volume=11 |pages=5S–9S |pmc=1401641 |journal=British Journal of Clinical Pharmacology |issue=Suppl 1 |doi=10.1111/j.1365-2125.1981.tb01832.x}}</ref>
 * [[Paranoia]]<ref name="dobcaba"/>
@@ Line 85: / Line 87: @@
 '''Rapid discontinuation may result in a more serious syndrome'''
 {{Columns-list|
-*[[Catatonia]], <ref>{{cite journal |doi=10.1097/00004714-199608000-00007 |title=Catatonia After Benzodiazepine Withdrawal |year=1996 |last1=Rosebush |first1=Patricia I. |last2=Mazurek |first2=Michael F. |journal=Journal of Clinical Psychopharmacology |volume=16 |issue=4 |pages=315–9 |pmid=8835707}}</ref><ref>{{cite journal |doi=10.1055/s-2001-15188 |title=Benzodiazepine Withdrawal - Induced Catatonia |year=2001 |last1=Deuschle |first1=M.F. |journal=Pharmacopsychiatry |volume=34 |pages=41–2 |pmid=11229621 |last2=Lederbogen |first2=F |issue=1|s2cid=260241781 }}</ref><ref>{{cite journal |doi=10.1053/seiz.1999.0309 |title=Ictal catatonia as a manifestation of de novo absence status epilepticus following benzodiazepine withdrawal |year=1999 |last1=Kanemoto |first1=Kousuke |last2=Miyamoto |first2=Toshio |last3=Abe |first3=Ryuji |journal=Seizure |volume=8 |issue=6 |pages=364–6 |pmid=10512781|s2cid=17454162 |doi-access=free }}</ref>
+*[[Catatonia]],<ref>{{cite journal |doi=10.1097/00004714-199608000-00007 |title=Catatonia After Benzodiazepine Withdrawal |year=1996 |last1=Rosebush |first1=Patricia I. |last2=Mazurek |first2=Michael F. |journal=Journal of Clinical Psychopharmacology |volume=16 |issue=4 |pages=315–9 |pmid=8835707}}</ref><ref>{{cite journal |doi=10.1055/s-2001-15188 |title=Benzodiazepine Withdrawal - Induced Catatonia |year=2001 |last1=Deuschle |first1=M.F. |journal=Pharmacopsychiatry |volume=34 |pages=41–2 |pmid=11229621 |last2=Lederbogen |first2=F |issue=1|s2cid=260241781 }}</ref><ref>{{cite journal |doi=10.1053/seiz.1999.0309 |title=Ictal catatonia as a manifestation of de novo absence status epilepticus following benzodiazepine withdrawal |year=1999 |last1=Kanemoto |first1=Kousuke |last2=Miyamoto |first2=Toshio |last3=Abe |first3=Ryuji |journal=Seizure |volume=8 |issue=6 |pages=364–6 |pmid=10512781|s2cid=17454162 |doi-access=free }}</ref>
 *[[Confusion]]<ref name="pmid28328330"/>
-*[[Seizure|Convulsions]],<ref name="pmid28328330"/> which may result in death<ref>{{cite journal |doi=10.1016/S0091-3057(99)00017-9 |title=Genetic Determinants of Severity of Acute Withdrawal from Diazepam in Mice |year=1999 |last1=Metten |first1=Pamela |last2=Crabbe |first2=John C |journal=Pharmacology Biochemistry and Behavior |volume=63 |issue=3 |pages=473–9 |pmid=10418790|s2cid=21241791 }}</ref><ref>{{cite magazine |pmid=2300914 |year=1990 |last1=Haque |first1=W |last2=Watson |first2=DJ |last3=Bryant |first3=SG |title=Death following suspected alprazolam withdrawal seizures: A case report |volume=86 |issue=1 |pages=44–7 |magazine=Texas Medicine}}</ref>
+*[[Seizures]],<ref name="pmid28328330"/> which may result in death<ref>{{cite journal |doi=10.1016/S0091-3057(99)00017-9 |title=Genetic Determinants of Severity of Acute Withdrawal from Diazepam in Mice |year=1999 |last1=Metten |first1=Pamela |last2=Crabbe |first2=John C |journal=Pharmacology Biochemistry and Behavior |volume=63 |issue=3 |pages=473–9 |pmid=10418790|s2cid=21241791 }}</ref><ref>{{cite magazine |pmid=2300914 |year=1990 |last1=Haque |first1=W |last2=Watson |first2=DJ |last3=Bryant |first3=SG |title=Death following suspected alprazolam withdrawal seizures: A case report |volume=86 |issue=1 |pages=44–7 |magazine=Texas Medicine}}</ref>
-* Coma<ref>{{cite journal |pmid=103443 |year=1979 |last1=De Bard |first1=ML |title=Diazepam withdrawal syndrome: A case with psychosis, seizure, and coma |volume=136 |issue=1 |pages=104–5 |journal=American Journal of Psychiatry |doi=10.1176/ajp.136.1.104}}</ref> (rare)
+* [[Coma]]<ref>{{cite journal |pmid=103443 |year=1979 |last1=De Bard |first1=ML |title=Diazepam withdrawal syndrome: A case with psychosis, seizure, and coma |volume=136 |issue=1 |pages=104–5 |journal=American Journal of Psychiatry |doi=10.1176/ajp.136.1.104}}</ref> (rare)
 *[[Delirium tremens]]<ref>{{cite journal |doi=10.1016/j.neurol.2007.11.003 |title=Fatal insomnia and agrypnia excitata: Sleep and the limbic system |year=2008 |last1=Provini |first1=F. |last2=Cortelli |first2=P. |last3=Montagna |first3=P. |last4=Gambetti |first4=P. |last5=Lugaresi |first5=E. |journal=Revue Neurologique |volume=164 |issue=8–9 |pages=692–700 |pmid=18805303}}</ref><ref name="Darcy L">{{cite journal |doi=10.1016/S0750-7658(84)80078-7 |title=Dépendance physique aux benzodiazépines dans un contexte traumatologique |trans-title=Benzodiazepine physical dependence in traumatology |language=fr |year=1984 |last1=Berezak |first1=A. |last2=Weber |first2=M. |last3=Hansmann |first3=J. |last4=Tulasne |first4=P.A. |last5=Laporte |first5=B. |last6=Ould Ouali |first6=A. |journal=Annales Françaises d'Anesthésie et de Réanimation |volume=3 |issue=5 |pages=383–4|pmid=6149713 }}</ref>
 *[[Hyperthermia]]<ref name="nouv"/>
 *[[Mania]]<ref>{{cite journal |doi=10.1016/0165-0327(89)90028-1 |title=Mania induced by lorazepam withdrawal: A report of two cases |year=1989 |last1=Turkington |first1=Douglas |last2=Gill |first2=Paul |journal=Journal of Affective Disorders |volume=17 |pages=93–5 |pmid=2525581 |issue=1}}</ref><ref>{{cite journal |pmid=3690487 |year=1987 |last1=Lapierre |first1=YD |last2=Labelle |first2=A |title=Manic-like reaction induced by lorazepam withdrawal |volume=32 |issue=8 |pages=697–8 |journal=The Canadian Journal of Psychiatry |doi=10.1177/070674378703200812|s2cid=8932926 }}</ref>
 *[[Neuroleptic malignant syndrome]]-like event<ref>{{cite journal |pmid=12424963 |year=2002 |last1=Kawajiri |first1=M |last2=Ohyagi |first2=Y |last3=Furuya |first3=H |last4=Araki |first4=T |last5=Inoue |first5=N |last6=Esaki |first6=S |last7=Yamada |first7=T |last8=Kira |first8=J |title=A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam |volume=42 |issue=2 |pages=136–9 |journal=Rinsho Shinkeigaku}}</ref><ref name="Strawn-2007">{{cite journal |doi=10.1176/ajp.2007.164.6.870 |title=Neuroleptic Malignant Syndrome |year=2007 |last1=Strawn |first1=Jeffrey |journal=American Journal of Psychiatry |volume=164 |issue=6 |pages=870–6 |pmid=17541044 |last2=Keck Jr |first2=PE |last3=Caroff |first3=SN}}</ref> (rare)
-*[[Organic brain syndrome]]<ref>{{cite journal |pmid=6107888 |url=http://www.benzo.org.uk/bwsnz.htm |year=1980 |last1=Khan |first1=A |last2=Joyce |first2=P |last3=Jones |first3=AV |title=Benzodiazepine withdrawal syndromes |volume=92 |issue=665 |pages=94–6 |journal=The New Zealand Medical Journal}}</ref>
+*[[Organic brain syndrome]]<ref>{{cite journal |pmid=6107888 |url=http://www.benzo.org.uk/bwsnz.htm |year=1980 |last1=Khan |first1=A |last2=Joyce |first2=P |last3=Jones |first3=AV |title=Benzodiazepine withdrawal syndromes |volume=92 |issue=665 |pages=94–6 |journal=The New Zealand Medical Journal |access-date=7 April 2009 |archive-date=2 December 2019 |archive-url=https://web.archive.org/web/20191202195122/https://www.benzo.org.uk/bwsnz.htm |url-status=live }}</ref>
 *[[Post-traumatic stress disorder]]<ref name="pmid1675688" />
 *[[Psychosis]]<ref>{{cite journal |pmid=2595393 |year=1989 |last1=Peh |first1=LH |last2=Mahendran |first2=R |title=Psychiatric complications of Erimin abuse |volume=30 |issue=1 |pages=72–3 |journal=Singapore Medical Journal}}</ref><ref>{{cite journal |doi=10.1111/j.1600-0447.1976.tb00065.x |title=Withdrawal Psychosis: A Study of 30 Consecutive Cases |year=1976 |last1=Fruensgaard |first1=K. |journal=Acta Psychiatrica Scandinavica |volume=53 |issue=2 |pages=105–18 |pmid=3091|s2cid=1741725 }}</ref>
 *[[Suicidal ideation]]<ref name="ReferenceA">{{cite journal |pmid=11212593 |year=2001 |last1=Einarson |first1=A |last2=Selby |first2=P |last3=Koren |first3=G |title=Abrupt discontinuation of psychotropic drugs during pregnancy: Fear of teratogenic risk and impact of counselling |volume=26 |issue=1 |pages=44–8 |pmc=1408034 |journal=Journal of Psychiatry & Neuroscience}}</ref> or suicide<ref name=pdatheagtcau/><ref name="pmid28257172">{{cite journal |vauthors=Dodds TJ |title=Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature |journal=Primary Care Companion for CNS Disorders |volume=19 |issue=2 |year=2017 |pmid=28257172 |doi=10.4088/PCC.16r02037 |doi-access=free }}</ref>
-*Violence and aggression<ref name="pmid9201803" /><ref>{{cite journal |doi=10.1016/S0193-953X(05)70126-X |title=Violent Patients in the Emergency Setting |year=1999 |last1=Citrome |first1=Leslie |last2=Volavka |first2=Jan |journal=Psychiatric Clinics of North America |volume=22 |issue=4 |pages=789–801 |pmid=10623971}}</ref>
+* [[Violence]] and [[aggression]]<ref name="pmid9201803" /><ref>{{cite journal |doi=10.1016/S0193-953X(05)70126-X |title=Violent Patients in the Emergency Setting |year=1999 |last1=Citrome |first1=Leslie |last2=Volavka |first2=Jan |journal=Psychiatric Clinics of North America |volume=22 |issue=4 |pages=789–801 |pmid=10623971}}</ref>
 }}
@@ Line 105: / Line 108: @@
 {{See also|Alcohol withdrawal syndrome#Kindling|Kindling (sedative–hypnotic withdrawal)}}
-The neuroadaptive processes involved in tolerance, dependence, and withdrawal mechanisms implicate both the GABAergic and the glutamatergic systems.<ref name="Allison-2003">{{cite journal |doi=10.1016/S0163-7258(03)00029-9 |title=Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence |year=2003 |last1=Allison |first1=C |last2=Pratt |first2=J.A |journal=Pharmacology & Therapeutics |volume=98 |issue=2 |pages=171–95 |pmid=12725868}}</ref> [[Gamma-Aminobutyric acid]] ([[GABA]]) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA.<ref name="The Brain from Top to Bottom">{{cite web|last=Dubuc|first=Bruno|title=Neurotransmitters|url=http://thebrain.mcgill.ca/flash/a/a_01/a_01_m/a_01_m_ana/a_01_m_ana.html#2|publisher=The Brain from Top to Bottom|access-date=29 April 2013|url-status=live|archive-url=https://web.archive.org/web/20130629082306/http://thebrain.mcgill.ca/flash/a/a_01/a_01_m/a_01_m_ana/a_01_m_ana.html#2|archive-date=29 June 2013}}</ref> GABA mediates the influx of chloride ions through [[ligand-gated ion channel|ligand-gated chloride channel]]s called [[GABAA|GABA]]<sub>A</sub> 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.<ref name=Tallman>{{cite journal |doi=10.1146/annurev.ne.08.030185.000321 |title=The Gaba-Ergic System: A Locus of Benzodiazepine Action |year=1985 |last1=Tallman |first1=J F |last2=Gallager |first2=D W |journal=Annual Review of Neuroscience |volume=8 |pages=21–44 |pmid=2858999}}</ref> Benzodiazepines potentiate the action of GABA,<ref name=SCHOCH>{{cite journal |doi=10.1038/314168a0 |title=Co-localization of GABAA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies |year=1985 |last1=Schoch |first1=P. |last2=Richards |first2=J. G. |last3=Häring |first3=P. |last4=Takacs |first4=B. |last5=Stähli |first5=C. |last6=Staehelin |first6=T. |last7=Haefely |first7=W. |last8=Möhler |first8=H. |journal=Nature |volume=314 |issue=6007 |pages=168–71 |pmid=2983231|bibcode = 1985Natur.314..168S |s2cid=1381200 }}</ref> by binding a site between the α and γ subunits of the 5-subunit receptor<ref name = "vinkerss">{{cite journal |doi=10.1155/2012/416864 |title=Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators? |year=2012 |last1=Vinkers |first1=Christiaan H. |last2=Olivier |first2=Berend |journal=Advances in Pharmacological Sciences |volume=2012 |pmid=22536226 |pages=1–19 |pmc=3321276|doi-access=free }}</ref> thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.<ref name="pmc349220">{{cite journal |doi=10.1073/pnas.78.11.7180 |title=Diazepam and (–)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of γ-aminobutyric acid responses in cultured central neurons |year=1981 |last1=Study |first1=R. E. |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=78 |issue=11 |pages=7180–4 |bibcode=1981PNAS...78.7180S |jstor=11434 |pmid=6273918 |last2=Barker |first2=JL |pmc=349220|doi-access=free }}</ref>
+The neuroadaptive processes involved in tolerance, dependence, and withdrawal mechanisms implicate both the GABAergic and the glutamatergic systems.<ref name="Allison-2003">{{cite journal |doi=10.1016/S0163-7258(03)00029-9 |title=Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence |year=2003 |last1=Allison |first1=C |last2=Pratt |first2=J.A |journal=Pharmacology & Therapeutics |volume=98 |issue=2 |pages=171–95 |pmid=12725868}}</ref> [[Gamma-Aminobutyric acid]] (GABA) is the major inhibitory neurotransmitter of the central nervous system; roughly one-quarter to one-third of synapses use GABA.<ref name="The Brain from Top to Bottom">{{cite web|last=Dubuc|first=Bruno|title=Neurotransmitters|url=http://thebrain.mcgill.ca/flash/a/a_01/a_01_m/a_01_m_ana/a_01_m_ana.html#2|publisher=The Brain from Top to Bottom|access-date=29 April 2013|url-status=live|archive-url=https://web.archive.org/web/20130629082306/http://thebrain.mcgill.ca/flash/a/a_01/a_01_m/a_01_m_ana/a_01_m_ana.html#2|archive-date=29 June 2013}}</ref> GABA mediates the influx of [[chloride]] ions through [[ligand-gated ion channel|ligand-gated chloride channel]]s called [[GABAA receptor|GABA<sub>A</sub> receptors]]. When chloride enters the nerve cell, the cell membrane potential [[Hyperpolarization (biology)|hyperpolarizes]] thereby inhibiting [[depolarization]], or reduction in the firing rate of the post-synaptic nerve cell.<ref name=Tallman>{{cite journal |doi=10.1146/annurev.ne.08.030185.000321 |title=The Gaba-Ergic System: A Locus of Benzodiazepine Action |year=1985 |last1=Tallman |first1=J F |last2=Gallager |first2=D W |journal=Annual Review of Neuroscience |volume=8 |pages=21–44 |pmid=2858999}}</ref> Benzodiazepines potentiate the action of GABA,<ref name=SCHOCH>{{cite journal |doi=10.1038/314168a0 |title=Co-localization of GABAA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies |year=1985 |last1=Schoch |first1=P. |last2=Richards |first2=J. G. |last3=Häring |first3=P. |last4=Takacs |first4=B. |last5=Stähli |first5=C. |last6=Staehelin |first6=T. |last7=Haefely |first7=W. |last8=Möhler |first8=H. |journal=Nature |volume=314 |issue=6007 |pages=168–71 |pmid=2983231|bibcode = 1985Natur.314..168S |s2cid=1381200 }}</ref> by binding a site between the α and γ subunits of the 5-subunit receptor<ref name = "vinkerss">{{cite journal |doi=10.1155/2012/416864 |title=Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators? |year=2012 |last1=Vinkers |first1=Christiaan H. |last2=Olivier |first2=Berend |journal=Advances in Pharmacological Sciences |volume=2012 |pmid=22536226 |pages=1–19 |pmc=3321276|doi-access=free }}</ref> thereby increasing the frequency of the GABA-gated chloride channel opening in the presence of GABA.<ref name="pmc349220">{{cite journal |doi=10.1073/pnas.78.11.7180 |title=Diazepam and (–)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of γ-aminobutyric acid responses in cultured central neurons |year=1981 |last1=Study |first1=R. E. |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=78 |issue=11 |pages=7180–4 |bibcode=1981PNAS...78.7180S |jstor=11434 |pmid=6273918 |last2=Barker |first2=JL |pmc=349220|doi-access=free }}</ref>
 When potentiation is sustained by long-term use, neuroadaptations occur which result in decreased GABAergic response. What is certain is that surface GABA<sub>A</sub> receptor protein levels are altered in response to benzodiazepine exposure, as is receptor turnover rate.<ref name = "bateson">{{cite journal |doi=10.2174/1381612023396681 |title=Basic Pharmacologic Mechanisms Involved in Benzodiazepine Tolerance and Withdrawal |year=2002 |last1=Bateson |first1=A. |journal=Current Pharmaceutical Design |volume=8 |pages=5–21 |pmid=11812247 |issue=1}}</ref> 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|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.<ref name=Tietz>{{cite journal |pmid=3001290 |year=1986 |last1=Tietz |first1=EI |last2=Rosenberg |first2=HC |last3=Chiu |first3=TH |title=Autoradiographic localization of benzodiazepine receptor downregulation |volume=236 |issue=1 |pages=284–92 |journal=Journal of Pharmacology and Experimental Therapeutics}}</ref> 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.<ref name="Allison-2003"/><ref name = "bateson"/> 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.<ref name = "bateson"/>
@@ Line 112: / Line 115: @@
 ==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.<ref name="gabbards"/> 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.<ref name="gabbards"/>
+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, [[Epilepsy|seizure disorders]].<ref name="gabbards"/> 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.<ref name="gabbards"/>
 Symptoms may lack a psychological cause and can fluctuate in intensity with periods of good and bad days until eventual recovery.<ref name="pmid6136575">{{cite journal |doi=10.1080/02791072.1983.10472127 |title=Benzodiazepine Dependency Syndromes |year=1983 |last1=Smith |first1=David E. |last2=Wesson |first2=Donald R. |journal=Journal of Psychoactive Drugs |volume=15 |pages=85–95 |pmid=6136575 |issue=1–2}}</ref><ref>{{cite journal |pmid=1575069 |year=1992 |last1=Landry |first1=MJ |last2=Smith |first2=DE |last3=McDuff |first3=DR |last4=Baughman |first4=OL |title=Benzodiazepine dependence and withdrawal: Identification and medical management |volume=5 |issue=2 |pages=167–75 |journal=The Journal of the American Board of Family Practice}}</ref>
@@ Line 119: / Line 122: @@
 According to the [[British National Formulary]], it is better to withdraw too slowly rather than too quickly from benzodiazepines.<ref name=CSM2007/> 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]]<ref name="pmid28328330"/> 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.<ref name="pmid2864096">{{cite journal |doi=10.1136/bmj.291.6497.688 |title=Clinical management of benzodiazepine dependence |year=1985 |last1=Higgitt |first1=A C |last2=Lader |first2=M H |last3=Fonagy |first3=P |journal=British Medical Journal |volume=291 |issue=6497 |pages=688–90 |pmid=2864096 |pmc=1416639}}</ref>
+Long [[Biological half-life|half-life]] benzodiazepines like [[diazepam]]<ref name="pmid28328330"/> or [[chlordiazepoxide]] are preferred to minimize [[rebound effect]]s 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.<ref name="pmid2864096">{{cite journal |doi=10.1136/bmj.291.6497.688 |title=Clinical management of benzodiazepine dependence |year=1985 |last1=Higgitt |first1=A C |last2=Lader |first2=M H |last3=Fonagy |first3=P |journal=British Medical Journal |volume=291 |issue=6497 |pages=688–90 |pmid=2864096 |pmc=1416639}}</ref>
 ==Management==
 [[File:Chlordiazepoxidetabletsgeneric.JPG|thumb|[[Chlordiazepoxide]], 5 mg capsules, are sometimes used as an alternative to [[diazepam]] for benzodiazepine withdrawal. Like diazepam, it has a long [[elimination half-life]] and long-acting [[active metabolites]].<ref name="ashman"/><ref>{{cite book |vauthors=Lal R, Gupta S, Rao R, Kattimani S |title=Substance Use Disorder |url=http://www.whoindia.org/en/Section20/Section22_1674.htm |access-date=2009-06-06 |year=2007 |publisher=[[World Health Organization]] (WHO) |page=82 |chapter=Emergency management of substance overdose and withdrawal |chapter-url=http://www.whoindia.org/LinkFiles/Mental_Health_&_substance_Abuse_Emergency_management_of_Substance_Overdose_and_Withdrawal-Manual_For_Nursing_Personnel.pdf |quote=Generally, a longer-acting benzodiazepine such as chlordiazepoxide or diazepam is used and the initial dose titrated downward |archive-url=https://web.archive.org/web/20100613203853/http://whoindia.org/LinkFiles/Mental_Health_%26_substance_Abuse_Emergency_management_of_Substance_Overdose_and_Withdrawal-Manual_For_Nursing_Personnel.pdf |archive-date=2010-06-13 |url-status=dead }}</ref>]]
-Management of benzodiazepine dependence involves considering the person's age, comorbidity and the pharmacological pathways of benzodiazepines.<ref name="pmid28186869">{{cite journal |vauthors=Santos C, Olmedo RE |title=Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition And Treatment |journal=Emergency Medicine Practice |volume=19 |issue=3 |pages=1–20 |year=2017 |pmid=28186869 }}</ref> Psychological interventions may provide a small but significant additional benefit over gradual dose reduction alone at post-cessation and at follow-up.<ref name ="parrjm"/> 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.<ref name ="parrjm"/>
+Management of benzodiazepine dependence involves considering the person's [[Ageing|age]], [[comorbidity]] and the [[Pharmacology|pharmacological]] pathways of benzodiazepines.<ref name="pmid28186869">{{cite journal |vauthors=Santos C, Olmedo RE |title=Sedative-Hypnotic Drug Withdrawal Syndrome: Recognition And Treatment |journal=Emergency Medicine Practice |volume=19 |issue=3 |pages=1–20 |year=2017 |pmid=28186869 }}</ref> Psychological interventions may provide a small but significant additional benefit over gradual dose reduction alone at post-cessation and at follow-up.<ref name ="parrjm"/> 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]].<ref name ="parrjm"/>
 There is no standard approach to managing benzodiazepine withdrawal.<ref>{{cite journal |last1=Fluyau |first1=D |last2=Revadigar |first2=N |last3=Manobianco |first3=BE |title=Challenges of the pharmacological management of benzodiazepine withdrawal, dependence, and discontinuation. |journal=Therapeutic Advances in Psychopharmacology |date=May 2018 |volume=8 |issue=5 |pages=147–168 |doi=10.1177/2045125317753340 |pmid=29713452|pmc=5896864 }}</ref>
-With sufficient motivation and the proper approach, almost anyone can successfully withdraw from benzodiazepines. However, a prolonged and severe withdrawal syndrome can cause profound disability, which may lead to breakdown of relationships, loss of employment, financial difficulties, as well as more serious adverse effects such as hospitalization and suicide.<ref name=pdatheagtcau>{{Cite book | last1 = Colvin | first1 = Rod | title = Overcoming Prescription Drug Addiction: A Guide to Coping and Understanding |url=https://books.google.com/books?id=lalhQgAACAAJ |edition=3 | date = 26 August 2008 | publisher = Addicus Books | location = United States of America | isbn  = 978-1-886039-88-9 | pages = 74–76 | quote = I have treated ten thousand patients for alcohol and drug problems and have detoxed approximately 1,500 patients for benzodiazepines – the detox for the benzodiazepines is one of the hardest detoxes we do. It can take an extremely long time, about half the length of time they have been addicted – the ongoing relentless withdrawals can be so incapacitating it can cause total destruction to one's life – marriages break up, businesses are lost, bankruptcy, hospitalization, and of course suicide is probably the most single serious side effect. }}</ref> As such, long-term users should not be forced to discontinue against their will.<ref name=ashman />
+With sufficient motivation and the proper approach, almost anyone can successfully withdraw from benzodiazepines. However, a prolonged and severe withdrawal syndrome can cause profound disability, which may lead to breakdown of relationships, loss of employment, financial difficulties, as well as more serious adverse effects such as hospitalization and suicide.<ref name=pdatheagtcau>{{Cite book | last1 = Colvin | first1 = Rod | title = Overcoming Prescription Drug Addiction: A Guide to Coping and Understanding | url = https://books.google.com/books?id=lalhQgAACAAJ | edition = 3 | date = 26 August 2008 | publisher = Addicus Books | location = United States of America | isbn = 978-1-886039-88-9 | pages = 74–76 | quote = I have treated ten thousand patients for alcohol and drug problems and have detoxed approximately 1,500 patients for benzodiazepines – the detox for the benzodiazepines is one of the hardest detoxes we do. It can take an extremely long time, about half the length of time they have been addicted – the ongoing relentless withdrawals can be so incapacitating it can cause total destruction to one's life – marriages break up, businesses are lost, bankruptcy, hospitalization, and of course suicide is probably the most single serious side effect. | access-date = 28 August 2020 | archive-date = 26 July 2024 | archive-url = https://web.archive.org/web/20240726164510/https://books.google.com/books?id=lalhQgAACAAJ | url-status = live }}</ref> As such, long-term users should not be forced to discontinue against their will.<ref name=ashman />
-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.<ref name=ashman /><ref name="pwsfb" /> According to a 2015 Cochrane review, [[Cognitive behavioral therapy|cognitive behavior therapy]] plus taper was effective in achieving discontinuation in the short-term but the effect was not certain after six months.<ref>{{Cite journal|last1=Darker|first1=Catherine D.|last2=Sweeney|first2=Brion P.|last3=Barry|first3=Joe M.|last4=Farrell|first4=Michael F.|last5=Donnelly-Swift|first5=Erica|date=2015|title=Psychosocial interventions for benzodiazepine harmful use, abuse or dependence|journal=The Cochrane Database of Systematic Reviews|issue=5|pages=CD009652|doi=10.1002/14651858.CD009652.pub2|issn=1469-493X|pmid=26106751|hdl=2262/75957|hdl-access=free}}</ref>
+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.<ref name=ashman /><ref name="pwsfb" /> According to a 2015 Cochrane review, [[Cognitive behavioral therapy|cognitive behavior therapy]] plus taper was effective in achieving discontinuation in the short-term but the effect was not certain after six months.<ref>{{Cite journal|last1=Darker|first1=Catherine D.|last2=Sweeney|first2=Brion P.|last3=Barry|first3=Joe M.|last4=Farrell|first4=Michael F.|last5=Donnelly-Swift|first5=Erica|date=2015|title=Psychosocial interventions for benzodiazepine harmful use, abuse or dependence|journal=The Cochrane Database of Systematic Reviews|issue=5|pages=CD009652|doi=10.1002/14651858.CD009652.pub2|issn=1469-493X|pmid=26106751|pmc=11023022 |hdl=2262/75957|hdl-access=free}}</ref>
 ===Medications===
-While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.<ref name ="parrjm">{{cite journal |doi=10.1111/j.1360-0443.2008.02364.x |title=Effectiveness of current treatment approaches for benzodiazepine discontinuation: A meta-analysis |year=2009 |last1=Parr |first1=Jannette M. |last2=Kavanagh |first2=David J. |last3=Cahill |first3=Lareina |last4=Mitchell |first4=Geoffrey |last5=Mcd Young |first5=Ross McD. |journal=Addiction |volume=104 |pages=13–24 |pmid=18983627 |issue=1}}</ref> 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,<ref name="pmid10665894">{{cite journal |doi=10.1001/archinte.159.20.2456 |title=Facilitation of Benzodiazepine Discontinuation by Melatonin: A New Clinical Approach |year=1999 |last1=Garfinkel |first1=Doron |journal=Archives of Internal Medicine |volume=159 |issue=20 |pages=2456–60 |pmid=10665894 |last2=Zisapel |first2=N |last3=Wainstein |first3=J |last4=Laudon |first4=M|doi-access=free }}</ref> paroxetine,<ref name="pmid16958945">{{cite journal |doi=10.1111/j.1440-1819.2006.01565.x |title=Clinical application of paroxetine for tapering benzodiazepine use in non-major-depressive outpatients visiting an internal medicine clinic |year=2006 |last1=Nakao |first1=Mutsuhiro |last2=Takeuchi |first2=Takeaki |last3=Nomura |first3=Kyoko |last4=Teramoto |first4=Tamio |last5=Yano |first5=Eiji |journal=Psychiatry and Clinical Neurosciences |volume=60 |issue=5 |pages=605–10 |pmid=16958945|s2cid=44969935 |doi-access=free }}</ref> trazodone,<ref name="pmid9952057" /> or valproate<ref name="pmid9952057">{{cite journal |doi=10.1007/s002130050798 |title=Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: Effects on withdrawal symptoms and taper outcome |year=1999 |last1=Rickels |first1=K. |last2=Schweizer |first2=E. |last3=Garcia España |first3=F. |last4=Case |first4=G. |last5=Demartinis |first5=N. |last6=Greenblatt |first6=D. |journal=Psychopharmacology |volume=141 |pages=1–5 |pmid=9952057 |issue=1|s2cid=12903042 }}</ref> in conjunction with a gradual dose reduction.<ref name ="parrjm"/>
+While some substitutive pharmacotherapies may have promise, current evidence is insufficient to support their use.<ref name ="parrjm">{{cite journal |doi=10.1111/j.1360-0443.2008.02364.x |title=Effectiveness of current treatment approaches for benzodiazepine discontinuation: A meta-analysis |year=2009 |last1=Parr |first1=Jannette M. |last2=Kavanagh |first2=David J. |last3=Cahill |first3=Lareina |last4=Mitchell |first4=Geoffrey |last5=Mcd Young |first5=Ross McD. |journal=Addiction |volume=104 |pages=13–24 |pmid=18983627 |issue=1}}</ref> 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]],<ref name="pmid10665894">{{cite journal |doi=10.1001/archinte.159.20.2456 |title=Facilitation of Benzodiazepine Discontinuation by Melatonin: A New Clinical Approach |year=1999 |last1=Garfinkel |first1=Doron |journal=Archives of Internal Medicine |volume=159 |issue=20 |pages=2456–60 |pmid=10665894 |last2=Zisapel |first2=N |last3=Wainstein |first3=J |last4=Laudon |first4=M|doi-access=free }}</ref> [[paroxetine]],<ref name="pmid16958945">{{cite journal |doi=10.1111/j.1440-1819.2006.01565.x |title=Clinical application of paroxetine for tapering benzodiazepine use in non-major-depressive outpatients visiting an internal medicine clinic |year=2006 |last1=Nakao |first1=Mutsuhiro |last2=Takeuchi |first2=Takeaki |last3=Nomura |first3=Kyoko |last4=Teramoto |first4=Tamio |last5=Yano |first5=Eiji |journal=Psychiatry and Clinical Neurosciences |volume=60 |issue=5 |pages=605–10 |pmid=16958945|s2cid=44969935 |doi-access=free }}</ref> [[trazodone]],<ref name="pmid9952057" /> or [[valproate]]<ref name="pmid9952057">{{cite journal |doi=10.1007/s002130050798 |title=Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: Effects on withdrawal symptoms and taper outcome |year=1999 |last1=Rickels |first1=K. |last2=Schweizer |first2=E. |last3=Garcia España |first3=F. |last4=Case |first4=G. |last5=Demartinis |first5=N. |last6=Greenblatt |first6=D. |journal=Psychopharmacology |volume=141 |pages=1–5 |pmid=9952057 |issue=1|s2cid=12903042 }}</ref> in conjunction with a gradual dose reduction.<ref name ="parrjm"/>
-*[[Antipsychotic]]s are generally ineffective for benzodiazepine withdrawal-related psychosis.<ref name="tuobicp"/><ref>{{cite journal |pmid=898354 |year=1977 |last1=Fruensgaard |first1=K |title=Withdrawal psychosis after drugs. Report of a consecutive material |volume=139 |issue=29 |pages=1719–22 |journal=Ugeskrift for Læger}}</ref> Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions.<ref name=CSM2007>{{cite web |url = http://www.bnf.org/bnf/bnf/58/3139.htm |title = Hypnotics and anxiolytics |access-date = 17 September 2007 |author = Committee on Safety of Medicines |year = 2007 |publisher = British National Formulary }}{{registration required}}</ref><ref>{{cite journal |doi=10.1254/jjp.31.689 |title=Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents |year=1981 |last1=Tagashira |first1=Eijiro |last2=Hiramori |first2=Tameo |last3=Urano |first3=Tomoko |last4=Nakao |first4=Kenzo |last5=Yanaura |first5=Saizo |journal=The Japanese Journal of Pharmacology |volume=31 |issue=5 |pages=689–99 |pmid=6118452|doi-access=free }}</ref><ref>{{cite journal |doi=10.1097/00004714-200004000-00033 |title=Neuroleptic Malignant Syndrome After Antipsychotic Drug Administration During Benzodiazepine Withdrawal |year=2000 |last1=Bobolakis |first1=Ioannis |journal=Journal of Clinical Psychopharmacology |volume=20 |issue=2 |pages=281–3 |pmid=10770479}}</ref><ref>{{cite book |last1=Randall |first1=Michael D |last2=Neil |first2=Karen E |title=Disease management |chapter-url=https://books.google.com/books?id=WhzmKPzxL3kC&q=%22Benzodiazepine+withdrawal%22+management+chlordiazepoxide&pg=PA62 |access-date=1 June 2009 |edition=1 |date=February 2004 |publisher=Pharmaceutical Press |isbn=978-0-85369-523-3 |page=62 |chapter=5}}</ref> 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.<ref>{{cite book |last1=Ebadi |first1=Manuchair |title=Desk Reference for Clinical Pharmacology |chapter-url=https://books.google.com/books?id=ihxyHbnj3qYC |edition=2nd |date=23 October 2007 |publisher=CRC Press |location=USA |isbn=978-1-4200-4743-1 |page=512 |chapter=Alphabetical presentation of drugs}}</ref>
+*[[Antipsychotic]]s are generally ineffective for benzodiazepine withdrawal-related psychosis.<ref name="tuobicp"/><ref>{{cite journal |pmid=898354 |year=1977 |last1=Fruensgaard |first1=K |title=Withdrawal psychosis after drugs. Report of a consecutive material |volume=139 |issue=29 |pages=1719–22 |journal=Ugeskrift for Læger}}</ref> Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions.<ref name=CSM2007>{{cite web |url = http://www.bnf.org/bnf/bnf/58/3139.htm |title = Hypnotics and anxiolytics |access-date = 17 September 2007 |author = Committee on Safety of Medicines |year = 2007 |publisher = British National Formulary }}{{registration required}}</ref><ref>{{cite journal |doi=10.1254/jjp.31.689 |title=Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents |year=1981 |last1=Tagashira |first1=Eijiro |last2=Hiramori |first2=Tameo |last3=Urano |first3=Tomoko |last4=Nakao |first4=Kenzo |last5=Yanaura |first5=Saizo |journal=The Japanese Journal of Pharmacology |volume=31 |issue=5 |pages=689–99 |pmid=6118452|doi-access=free }}</ref><ref>{{cite journal |doi=10.1097/00004714-200004000-00033 |title=Neuroleptic Malignant Syndrome After Antipsychotic Drug Administration During Benzodiazepine Withdrawal |year=2000 |last1=Bobolakis |first1=Ioannis |journal=Journal of Clinical Psychopharmacology |volume=20 |issue=2 |pages=281–3 |pmid=10770479}}</ref><ref>{{cite book |last1=Randall |first1=Michael D |last2=Neil |first2=Karen E |title=Disease management |chapter-url=https://books.google.com/books?id=WhzmKPzxL3kC&q=%22Benzodiazepine+withdrawal%22+management+chlordiazepoxide&pg=PA62 |access-date=1 June 2009 |edition=1 |date=February 2004 |publisher=Pharmaceutical Press |isbn=978-0-85369-523-3 |page=62 |chapter=5 |archive-date=26 July 2024 |archive-url=https://web.archive.org/web/20240726164602/https://books.google.com/books?id=WhzmKPzxL3kC&q=%22Benzodiazepine+withdrawal%22+management+chlordiazepoxide&pg=PA62 |url-status=live }}</ref> 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.<ref>{{cite book |last1=Ebadi |first1=Manuchair |title=Desk Reference for Clinical Pharmacology |chapter-url=https://books.google.com/books?id=ihxyHbnj3qYC |edition=2nd |date=23 October 2007 |publisher=CRC Press |location=USA |isbn=978-1-4200-4743-1 |page=512 |chapter=Alphabetical presentation of drugs}}</ref>
-*[[Barbiturate]]s are cross tolerant to benzodiazepines and should generally be avoided; however [[phenobarbital]] can be used, as it is relatively safe,<ref>[https://books.google.com/books?id=jyXxmyysU7gC&q=phenobarbital+dependency&pg=PA242 Clinical Guide to the Diagnosis and Treatment of Mental Disorders By Michael B. First, Allan Tasman, p. 242]</ref> see below.
+*[[Barbiturate]]s are [[Cross-tolerance|cross tolerant]] to benzodiazepines and should generally be avoided; however [[phenobarbital]] can be used, as it is relatively safe,<ref>{{Cite book |url=https://books.google.com/books?id=jyXxmyysU7gC&q=phenobarbital+dependency&pg=PA242 |title=Clinical Guide to the Diagnosis and Treatment of Mental Disorders By Michael B. First, Allan Tasman, p. 242 |isbn=978-0-470-74520-5 |access-date=14 March 2023 |archive-date=6 October 2023 |archive-url=https://web.archive.org/web/20231006082713/https://books.google.com/books?id=jyXxmyysU7gC&q=phenobarbital+dependency&pg=PA242 |url-status=live |last1=First |first1=Michael B. |last2=Tasman |first2=Allan |date=8 February 2010 |publisher=John Wiley & Sons }}</ref> see below.
-*[[Benzodiazepine]]s or cross tolerant drugs should be avoided after discontinuation, even occasionally. These include the [[nonbenzodiazepine]]s [[Z drugs|Z-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.<ref name="pmid19062773">{{cite journal |doi=10.2165/0023210-200923010-00002 |title=Withdrawing Benzodiazepines in Primary Care |year=2009 |last1=Lader |first1=Malcolm |last2=Tylee |first2=Andre |last3=Donoghue |first3=John |journal=CNS Drugs |volume=23 |pages=19–34 |pmid=19062773 |issue=1|s2cid=113206 }}</ref><ref>{{cite journal |doi=10.1017/S0264180100000412 |title=The natural history of tolerance to the benzodiazepines |year=2009 |last1=Higgitt |first1=A. |last2=Fonagy |first2=P. |last3=Lader |first3=M. |journal=Psychological Medicine. Monograph Supplement |volume=13 |pages=1–55 |pmid=2908516|s2cid=38037200 }}</ref>
+*[[Benzodiazepine]]s or [[Cross-tolerance|cross tolerant]] drugs should be avoided after discontinuation, even occasionally. These include the [[nonbenzodiazepine]]s [[Z drugs|Z-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.<ref name="pmid19062773">{{cite journal |doi=10.2165/0023210-200923010-00002 |title=Withdrawing Benzodiazepines in Primary Care |year=2009 |last1=Lader |first1=Malcolm |last2=Tylee |first2=Andre |last3=Donoghue |first3=John |journal=CNS Drugs |volume=23 |pages=19–34 |pmid=19062773 |issue=1|s2cid=113206 }}</ref><ref>{{cite journal |doi=10.1017/S0264180100000412 |title=The natural history of tolerance to the benzodiazepines |year=2009 |last1=Higgitt |first1=A. |last2=Fonagy |first2=P. |last3=Lader |first3=M. |journal=Psychological Medicine. Monograph Supplement |volume=13 |pages=1–55 |pmid=2908516|s2cid=38037200 }}</ref>
-*[[Bupropion]], which is used primarily as an antidepressant and smoking cessation aid, is contraindicated in people experiencing abrupt withdrawal from benzodiazepines or other sedative-hypnotics (e.g. alcohol), due to an increased risk of seizures.<ref name="WellbutrinPI">{{cite web |title = Wellbutrin XL Prescribing Information |date=December 2008 |publisher = [[GlaxoSmithKline]] |url = http://us.gsk.com/products/assets/us_wellbutrinXL.pdf |access-date=2010-01-16 |archive-url=https://web.archive.org/web/20090326063052/http://us.gsk.com/products/assets/us_wellbutrinXL.pdf |archive-date=2009-03-26 }}</ref>
+*[[Bupropion]], which is used primarily as an [[antidepressant]] and smoking cessation aid, is contraindicated in people experiencing abrupt withdrawal from benzodiazepines or other [[sedative]]-hypnotics (e.g. alcohol), due to an increased risk of seizures.<ref name="WellbutrinPI">{{cite web |title = Wellbutrin XL Prescribing Information |date=December 2008 |publisher = [[GlaxoSmithKline]] |url = http://us.gsk.com/products/assets/us_wellbutrinXL.pdf |access-date=2010-01-16 |archive-url=https://web.archive.org/web/20090326063052/http://us.gsk.com/products/assets/us_wellbutrinXL.pdf |archive-date=2009-03-26 }}</ref>
 *[[Buspirone]] augmentation was not found to increase the discontinuation success rate.<ref name = "Voshaar">{{cite journal |doi=10.1192/bjp.189.3.213 |title=Strategies for discontinuing long-term benzodiazepine use: Meta-analysis |year=2006 |last1=Voshaar |first1=R. C. O. |journal=British Journal of Psychiatry |volume=189 |issue=3 |pages=213–20 |pmid=16946355 |last2=Couvée |first2=JE |last3=Van Balkom |first3=AJ |last4=Mulder |first4=PG |last5=Zitman |first5=FG|doi-access=free }}</ref>
 *[[Caffeine]] may worsen withdrawal symptoms because of its stimulatory properties.<ref name=ashman /> At least one animal study has shown some [[Receptor modulator|modulation of the benzodiazepine site]] by caffeine, which produces a lowering of seizure threshold.<ref>{{cite journal |doi=10.1016/0091-3057(87)90133-X |title=Coincidence of seizure susceptibility to caffeine and to the benzodiazepine inverse agonist, DMCM, in SWR and CBA inbred mice |year=1987 |last1=Seale |first1=Thomas W. |last2=Carney |first2=John M. |last3=Rennert |first3=Owen M. |last4=Flux |first4=Marinus |last5=Skolnick |first5=Phil |journal=Pharmacology Biochemistry and Behavior |volume=26 |issue=2 |pages=381–7 |pmid=3575358|s2cid=30168114 }}</ref>
 *[[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.<ref name="pmid19062773"/>
 *[[Ethanol]], the primary [[alcohol (drug)|alcohol]] in [[alcoholic beverage]]s, even mild to moderate use, has been found to be a significant predictor of withdrawal failure, probably because of its [[cross tolerance]] with benzodiazepines.<ref name=ashman /><ref name="pmid19062773"/><ref name="pmid2222130">{{cite journal |doi=10.1001/archpsyc.1990.01810220024003 |title=Long-term Therapeutic Use of Benzodiazepines: II. Effects of Gradual Taper |year=1990 |last1=Schweizer |first1=Edward |journal=Archives of General Psychiatry |volume=47 |issue=10 |pages=908–15 |pmid=2222130 |last2=Rickels |first2=K |last3=Case |first3=WG |last4=Greenblatt |first4=DJ}}</ref><!-- See full text -->
-*[[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.<ref name="Denis-2006">{{cite journal |doi=10.1002/14651858.CD005194.pub2 |title=Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings |year=2006 |last1=Denis |first1=Cecile |last2=Fatseas |first2=Melina |last3=Lavie |first3=Estelle |last4=Auriacombe |first4=Marc |editor1-last=Denis |editor1-first=Cecile |pmid=16856084 |issue=3 |pages=CD005194 |journal=Cochrane Database of Systematic Reviews}} {{Retracted|doi=10.1002/14651858.CD005194.pub3|pmid=23780681|http://retractionwatch.com/2010/09/20/progressive-how-the-cochrane-library-handles-updates-in-progress/ ''Retraction Watch''}}</ref> Flumazenil stimulates the up-regulation and reverses the [[Uncoupling (neuropsychopharmacology)|uncoupling]] of [[benzodiazepine receptors]] to the [[GABAA receptor|GABA<sub>A</sub> receptor]], thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.<ref>{{cite journal |doi=10.1080/1355621021000005973 |title=Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: A randomized, placebo-controlled study |year=2002 |last1=Gerra |first1=G. |last2=Zaimovic |first2=A. |last3=Giusti |first3=F. |last4=Moi |first4=G. |last5=Brewer |first5=C. |journal=Addiction Biology |volume=7 |issue=4 |pages=385–95 |pmid=14578014|s2cid=21255719 }}</ref><ref>{{cite journal |doi=10.1016/0143-4179(91)90077-V |title=The benzodiazepines: Anxiolytic and withdrawal effects |year=1991 |last1=Little |first1=H.J. |journal=Neuropeptides |volume=19 |pages=11–4 |pmid=1679209|s2cid=13734753 }}</ref> 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]] 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.<ref name="Denis-2006">{{cite journal |doi=10.1002/14651858.CD005194.pub2 |title=Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings |year=2006 |last1=Denis |first1=Cecile |last2=Fatseas |first2=Melina |last3=Lavie |first3=Estelle |last4=Auriacombe |first4=Marc |editor1-last=Denis |editor1-first=Cecile |pmid=16856084 |issue=3 |pages=CD005194 |journal=Cochrane Database of Systematic Reviews}} {{Retracted|doi=10.1002/14651858.CD005194.pub3|pmid=23780681|http://retractionwatch.com/2010/09/20/progressive-how-the-cochrane-library-handles-updates-in-progress/ ''Retraction Watch''|intentional=yes}}</ref>{{needs update|date=October 2024}} Flumazenil stimulates the up-regulation and reverses the [[Uncoupling (neuropsychopharmacology)|uncoupling]] of [[benzodiazepine receptors]] to the [[GABAA receptor|GABA<sub>A</sub> receptor]], thereby reversing tolerance and reducing withdrawal symptoms and relapse rates.<ref>{{cite journal |doi=10.1080/1355621021000005973 |title=Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: A randomized, placebo-controlled study |year=2002 |last1=Gerra |first1=G. |last2=Zaimovic |first2=A. |last3=Giusti |first3=F. |last4=Moi |first4=G. |last5=Brewer |first5=C. |journal=Addiction Biology |volume=7 |issue=4 |pages=385–95 |pmid=14578014|s2cid=21255719 }}</ref><ref>{{cite journal |doi=10.1016/0143-4179(91)90077-V |title=The benzodiazepines: Anxiolytic and withdrawal effects |year=1991 |last1=Little |first1=H.J. |journal=Neuropeptides |volume=19 |pages=11–4 |pmid=1679209|s2cid=13734753 }}</ref> 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.<ref name="L. Saxon, S. Borg & A. J. Hiltunen 148–151">{{Cite journal
@@ Line 156: / Line 159: @@
  }}</ref> 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 [[Tremor|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&nbsp;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.<ref>{{cite journal |doi=10.1177/026988119200600303 |title=A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal |year=1992 |last1=Lader |first1=M. H. |last2=Morton |first2=S. V. |journal=Journal of Psychopharmacology |volume=6 |issue=3 |pages=357–63 |pmid=22291380|s2cid=23530701 }}</ref> A study by Professor Borg in Sweden produced similar results in patients in protracted withdrawal.<ref name="pmid9201803">{{cite journal |doi=10.1007/s002130050278 |title=Effects of flumazenil in the treatment of benzodiazepine withdrawal - a double-blind pilot study |year=1997 |last1=Saxon |first1=L. |last2=Hjemdahl |first2=P. |last3=Hiltunen |first3=A. J. |last4=Borg |first4=S. |journal=Psychopharmacology |volume=131 |issue=2 |pages=153–60 |pmid=9201803|s2cid=19374966 }}</ref> 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.<ref>{{cite web |url= http://www.rocheusa.com/products/romazicon/pi.pdf |title= Romazicon |author= Roche USA |date= October 2007 |publisher= Roche Pharmaceuticals USA |url-status= dead |archive-url= https://web.archive.org/web/20080625161218/http://www.rocheusa.com/products/romazicon/pi.pdf |archive-date= 25 June 2008}}</ref>
+: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, [[Depersonalization|depersonalisation]], [[cramps]] and [[Tremor|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&nbsp;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.<ref>{{cite journal |doi=10.1177/026988119200600303 |title=A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal |year=1992 |last1=Lader |first1=M. H. |last2=Morton |first2=S. V. |journal=Journal of Psychopharmacology |volume=6 |issue=3 |pages=357–63 |pmid=22291380|s2cid=23530701 }}</ref> A study by Professor Borg in Sweden produced similar results in patients in protracted withdrawal.<ref name="pmid9201803">{{cite journal |doi=10.1007/s002130050278 |title=Effects of flumazenil in the treatment of benzodiazepine withdrawal - a double-blind pilot study |year=1997 |last1=Saxon |first1=L. |last2=Hjemdahl |first2=P. |last3=Hiltunen |first3=A. J. |last4=Borg |first4=S. |journal=Psychopharmacology |volume=131 |issue=2 |pages=153–60 |pmid=9201803|s2cid=19374966 }}</ref> 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.<ref>{{cite web |url= http://www.rocheusa.com/products/romazicon/pi.pdf |title= Romazicon |author= Roche USA |date= October 2007 |publisher= Roche Pharmaceuticals USA |url-status= dead |archive-url= https://web.archive.org/web/20080625161218/http://www.rocheusa.com/products/romazicon/pi.pdf |archive-date= 25 June 2008}}</ref>
-*[[Fluoroquinolone]] antibiotics<ref name="PMC1368276">{{cite journal|last = Unseld|first = E|author2 = G Ziegler |author3= A Gemeinhardt |author4=U Janssen |author5=U Klotz| title = Possible interaction of fluoroquinolones with the benzodiazepine-GABAA-receptor complex (summary)| journal = British Journal of Clinical Pharmacology|volume=30|issue=1|pages= 63–70|date = July 1990| doi =10.1111/j.1365-2125.1990.tb03744.x| pmid=2167717 | pmc=1368276}}</ref><ref name="Ashton1">{{cite web| last = Ashton| first = Heather| title = The Ashton Manual Supplement| work = Benzodiazepines: How They Work & How to Withdraw| publisher = benzo.org.uk| date = April 2011| url =https://benzo.org.uk/ashsupp11.htm}}</ref><ref name="Kamath1">{{cite journal| last = Kamath| first = Ashwin| title = Fluoroquinolone Induced Neurotoxicity: A Review| journal = Journal of Advanced Pharmacy Education & Research| volume = 3| issue = 1| pages = 16–19| date = 2013| url = http://www.japer.in/doc/jan-march%202013/93.pdf| archive-url = https://web.archive.org/web/20140211060608/http://www.japer.in/doc/jan-march%202013/93.pdf| url-status = dead| archive-date = 2014-02-11| access-date = 17 October 2015}}</ref> 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, [[tremor]]s, status epilepticus, suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal.<ref name="ashman" /><ref>{{cite journal |doi=10.3399/bjgp08X280317 |title=Benzodiazepine tolerance, dependency, and withdrawal syndromes and interactions with fluoroquinolone antimicrobials |year=2008 |last1=McConnell |first1=John Girvan |journal=British Journal of General Practice |volume=58 |issue=550 |pages=365–6 |pmid=18482496 |pmc=2435654}}</ref><ref name="pmid2167717">{{cite journal |doi=10.1111/j.1365-2125.1990.tb03744.x |title=Possible interaction of fluoroquinolones with the benzodiazepine-GABAA- receptor complex |year=1990 |last1=Unseld |first1=E |last2=Ziegler |first2=G |last3=Gemeinhardt |first3=A |last4=Janssen |first4=U |last5=Klotz |first5=U |journal=British Journal of Clinical Pharmacology |volume=30 |pages=63–70 |pmid=2167717 |issue=1 |pmc=1368276}}</ref><ref>{{cite journal |doi=10.3109/10673229709000304 |title=Antibiotics: Neuropsychiatric Effects and Psychotropic Interactions |year=1997 |last1=Sternbach |first1=Harvey |last2=State |first2=Rosanne |journal=Harvard Review of Psychiatry |volume=5 |issue=4 |pages=214–26 |pmid=9427014|s2cid=21259675 }}</ref><ref>{{cite web |url=http://bnf.org/bnf/bnf/57/3944.htm |archive-url=https://archive.today/20120630132605/http://bnf.org/bnf/bnf/57/3944.htm |url-status=dead |archive-date=30 June 2012 |title=Quinolones |access-date=16 February 2009 |author=Committee on Safety of Medicines |author-link=Committee on Safety of Medicines |author2=Medicines and Healthcare products Regulatory Agency |year=2008 |publisher=[[British National Formulary]] |location=United Kingdom |url-access=registration }}</ref> [[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.<ref>{{cite journal |pmid=8297186 |year=1993 |last1=Wong |first1=PT |title=Interactions of indomethacin with central GABA systems |volume=324 |pages=5–16 |journal=Archives Internationales de Pharmacodynamie et de Thérapie}}</ref><ref>{{cite book |last1=Delanty |first1=Norman |title=Seizures: Medical Causes and Management |url=https://books.google.com/books?id=u2B3SdfE8-gC&q=fluoroquinolones+gabaa+nsaids&pg=PA152 |date=November 2001 |publisher=Humana Press |isbn=978-0-89603-827-1 |pages=152–153 |chapter=Medication associated seizures |chapter-url=https://books.google.com/books?id=u2B3SdfE8-gC&pg=PA147 }}{{Dead link|date=October 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref>{{cite journal |doi=10.1038/sj.bjp.0701411 |title=Selective antagonism of the GABAAreceptor by ciprofloxacin and biphenylacetic acid |year=1997 |last1=Green |first1=M. A. |last2=Halliwell |first2=R. F. |journal=British Journal of Pharmacology |volume=122 |issue=3 |pages=584–90 |pmid=9351519 |pmc=1564969}}</ref>
+*[[Fluoroquinolone]] antibiotics<ref name="PMC1368276">{{cite journal|last = Unseld|first = E|author2 = G Ziegler |author3= A Gemeinhardt |author4=U Janssen |author5=U Klotz| title = Possible interaction of fluoroquinolones with the benzodiazepine-GABAA-receptor complex (summary)| journal = British Journal of Clinical Pharmacology|volume=30|issue=1|pages= 63–70|date = July 1990| doi =10.1111/j.1365-2125.1990.tb03744.x| pmid=2167717 | pmc=1368276}}</ref><ref name="Ashton1">{{cite web| last = Ashton| first = Heather| title = The Ashton Manual Supplement| work = Benzodiazepines: How They Work & How to Withdraw| publisher = benzo.org.uk| date = April 2011| url = https://benzo.org.uk/ashsupp11.htm| access-date = 20 December 2019| archive-date = 19 September 2020| archive-url = https://web.archive.org/web/20200919043719/https://benzo.org.uk/ashsupp11.htm| url-status = live}}</ref><ref name="Kamath1">{{cite journal| last = Kamath| first = Ashwin| title = Fluoroquinolone Induced Neurotoxicity: A Review| journal = Journal of Advanced Pharmacy Education & Research| volume = 3| issue = 1| pages = 16–19| date = 2013| url = http://www.japer.in/doc/jan-march%202013/93.pdf| archive-url = https://web.archive.org/web/20140211060608/http://www.japer.in/doc/jan-march%202013/93.pdf| url-status = dead| archive-date = 2014-02-11| access-date = 17 October 2015}}</ref> 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 ([[photophobia]]) and sound ([[hyperacusis]]), [[tremor]]s, [[status epilepticus]], suicidal thoughts and suicide attempt. Fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal.<ref name="ashman" /><ref>{{cite journal |doi=10.3399/bjgp08X280317 |title=Benzodiazepine tolerance, dependency, and withdrawal syndromes and interactions with fluoroquinolone antimicrobials |year=2008 |last1=McConnell |first1=John Girvan |journal=British Journal of General Practice |volume=58 |issue=550 |pages=365–6 |pmid=18482496 |pmc=2435654}}</ref><ref name="pmid2167717">{{cite journal |doi=10.1111/j.1365-2125.1990.tb03744.x |title=Possible interaction of fluoroquinolones with the benzodiazepine-GABAA- receptor complex |year=1990 |last1=Unseld |first1=E |last2=Ziegler |first2=G |last3=Gemeinhardt |first3=A |last4=Janssen |first4=U |last5=Klotz |first5=U |journal=British Journal of Clinical Pharmacology |volume=30 |pages=63–70 |pmid=2167717 |issue=1 |pmc=1368276}}</ref><ref>{{cite journal |doi=10.3109/10673229709000304 |title=Antibiotics: Neuropsychiatric Effects and Psychotropic Interactions |year=1997 |last1=Sternbach |first1=Harvey |last2=State |first2=Rosanne |journal=Harvard Review of Psychiatry |volume=5 |issue=4 |pages=214–26 |pmid=9427014|s2cid=21259675 }}</ref><ref>{{cite web |url=http://bnf.org/bnf/bnf/57/3944.htm |archive-url=https://archive.today/20120630132605/http://bnf.org/bnf/bnf/57/3944.htm |url-status=dead |archive-date=30 June 2012 |title=Quinolones |access-date=16 February 2009 |author=Committee on Safety of Medicines |author-link=Committee on Safety of Medicines |author2=Medicines and Healthcare products Regulatory Agency |year=2008 |publisher=[[British National Formulary]] |location=United Kingdom |url-access=registration }}</ref> [[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.<ref>{{cite journal |pmid=8297186 |year=1993 |last1=Wong |first1=PT |title=Interactions of indomethacin with central GABA systems |volume=324 |pages=5–16 |journal=Archives Internationales de Pharmacodynamie et de Thérapie}}</ref><ref>{{cite book |last1=Delanty |first1=Norman |title=Seizures: Medical Causes and Management |url=https://books.google.com/books?id=u2B3SdfE8-gC&q=fluoroquinolones+gabaa+nsaids&pg=PA152 |date=November 2001 |publisher=Humana Press |isbn=978-0-89603-827-1 |pages=152–153 |chapter=Medication associated seizures |chapter-url=https://books.google.com/books?id=u2B3SdfE8-gC&pg=PA147 }}{{Dead link|date=October 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref>{{cite journal |doi=10.1038/sj.bjp.0701411 |title=Selective antagonism of the GABAAreceptor by ciprofloxacin and biphenylacetic acid |year=1997 |last1=Green |first1=M. A. |last2=Halliwell |first2=R. F. |journal=British Journal of Pharmacology |volume=122 |issue=3 |pages=584–90 |pmid=9351519 |pmc=1564969}}</ref>
 *[[Imidazenil]] has received some research for management of benzodiazepine withdrawal, but is not currently used in withdrawal.<ref>{{cite journal |doi=10.1016/j.neuropharm.2005.04.005 |title=Imidazenil: An antagonist of the sedative but not the anticonvulsant action of diazepam |year=2005 |last1=Auta |first1=J |last2=Costa |first2=E |last3=Davis |first3=J |last4=Guidotti |first4=A |journal=Neuropharmacology |volume=49 |issue=3 |pages=425–9 |pmid=15964602|s2cid=44619421 }}</ref>
 *[[Imipramine]] was found to statistically increase the discontinuation success rate.<ref name = "Voshaar"/>
 *[[Melatonin]] augmentation was found to statistically increase the discontinuation success rate for people with insomnia.<ref name = "Voshaar"/>
-*[[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.<ref name="gabbards"/> In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.<ref>{{cite journal |doi=10.3109/10401239309148974 |title=Phenobarbital Versus Clonazepam for Sedative-Hypnotic Taper in Chronic Pain Patients: A Pilot Study |year=1993 |last1=Sullivan |first1=Mark |last2=Toshima |first2=Michelle |last3=Lynn |first3=Pamela |last4=Roy-Byrne |first4=Peter |journal=Annals of Clinical Psychiatry |volume=5 |issue=2 |pages=123–8 |pmid=8348204}}</ref><ref>{{cite web |url=http://www.benzo.org.uk/can-drb.htm |title=Dr Ray Baker's Article on Addiction: Benzodiazepines in Particular |access-date=14 February 2009 |author= Ray Baker}}</ref>
+*[[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.<ref name="gabbards"/> In a comparison study, a rapid taper using benzodiazepines was found to be superior to a phenobarbital rapid taper.<ref>{{cite journal |doi=10.3109/10401239309148974 |title=Phenobarbital Versus Clonazepam for Sedative-Hypnotic Taper in Chronic Pain Patients: A Pilot Study |year=1993 |last1=Sullivan |first1=Mark |last2=Toshima |first2=Michelle |last3=Lynn |first3=Pamela |last4=Roy-Byrne |first4=Peter |journal=Annals of Clinical Psychiatry |volume=5 |issue=2 |pages=123–8 |pmid=8348204}}</ref><ref>{{cite web |url=http://www.benzo.org.uk/can-drb.htm |title=Dr Ray Baker's Article on Addiction: Benzodiazepines in Particular |access-date=14 February 2009 |author=Ray Baker |archive-date=29 July 2020 |archive-url=https://web.archive.org/web/20200729082230/https://www.benzo.org.uk/can-drb.htm |url-status=live }}</ref>
 *[[Pregabalin]] may help reduce the severity of benzodiazepine withdrawal symptoms,<ref name="Oulis-2010">{{Cite journal  | last1 = Oulis | first1 = P. | last2 = Konstantakopoulos | first2 = G. | title = Pregabalin in the treatment of alcohol and benzodiazepines dependence. | journal = CNS Neuroscience & Therapeutics | volume = 16 | issue = 1 | pages = 45–50 | year = 2010 | doi = 10.1111/j.1755-5949.2009.00120.x | pmid = 20070788 | pmc = 6493856 }}</ref> and reduce the risk of relapse.<ref name="Oulis-2012">{{Cite journal  | last1 = Oulis | first1 = P. | last2 = Konstantakopoulos | first2 = G. | title = Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence. | journal = Expert Opinion on Investigational Drugs | volume = 21 | issue = 7 | pages = 1019–29 |date=Jul 2012 | doi = 10.1517/13543784.2012.685651 | pmid = 22568872 | s2cid = 24354141 }}</ref>
 *[[Propranolol]] was not found to increase the discontinuation success rate.<ref name = "Voshaar"/>
@@ Line 183: / Line 186: @@
 {{cite web | year = 2017 | title = Drug misuse and dependence: UK guidelines on clinical management | url = http://www.nta.nhs.uk/uploads/clinical_guidelines_2007.pdf | location = London | publisher = Department of Health (England), Scottish Government, Welsh Assembly Government, Northern Ireland Executive | access-date = 29 September 2020 | archive-date = 19 September 2010 | archive-url = https://web.archive.org/web/20100919022743/http://www.nta.nhs.uk/uploads/clinical_guidelines_2007.pdf | url-status = dead }}</ref>
 The recommended reduction rates range from 50% of the initial dose every week or so,<ref>{{harvp | Soyka | 2017 | loc = Treatment of Withdrawal Symptoms, p. 1151 }} cited  {{cite book | last1 = Soyka | first1 = M | year = 2015 | title = Medikamentenabhängigkeit | location = Stuttgart, Germany | publisher = Schattauer }}</ref>
-to 10-25% of the daily dose every 2 weeks.<ref name=UKGuidelines2017 />
+to 10–25% of the daily dose every 2 weeks.<ref name=UKGuidelines2017 />
 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&nbsp;mg dose of diazepam or 2.5&nbsp;mg dose of chlordiazepoxide.<ref name="ashman" />
 For most people, discontinuation over 4–6 weeks or 4–8 weeks is suitable.<ref>{{harvp | Soyka | 2017 | loc = Treatment of Withdrawal Symptoms, p. 1151 }}</ref>
@@ Line 194: / Line 197: @@
 ===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,<ref name=tinnitus/><ref>{{cite journal |doi=10.1097/00004714-198810000-00010 |title=Protracted Tinnitus after Discontinuation of Long-Term Therapeutic Use of Benzodiazepines |year=1988 |last1=Busto |first1=Usoa |last2=Fornazzari |first2=Luis |last3=Naranjo |first3=Claudio A. |journal=Journal of Clinical Psychopharmacology |volume=8 |issue=5 |pages=359–362 |pmid=2903182}}</ref> psychosis, cognitive deficits, [[gastrointestinal complaint]]s, insomnia, paraesthesia (tingling and numbness), pain (usually in limbs and extremities), muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, dizziness and [[blepharospasm]]<ref name="pwsfb"/> 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.
+Protracted withdrawal syndrome refers to symptoms persisting for months or even years. A significant minority of people withdrawing from benzodiazepines, perhaps 10–15%, experience a [[protracted withdrawal syndrome]] which can sometimes be severe. Symptoms may include tinnitus,<ref name=tinnitus/><ref>{{cite journal |doi=10.1097/00004714-198810000-00010 |title=Protracted Tinnitus after Discontinuation of Long-Term Therapeutic Use of Benzodiazepines |year=1988 |last1=Busto |first1=Usoa |last2=Fornazzari |first2=Luis |last3=Naranjo |first3=Claudio A. |journal=Journal of Clinical Psychopharmacology |volume=8 |issue=5 |pages=359–362 |pmid=2903182}}</ref> psychosis, cognitive deficits, [[gastrointestinal complaint]]s, insomnia, [[Paresthesia|paraesthesia]] (tingling and numbness), [[pain]] (usually in limbs and extremities), [[Myalgia|muscle pain]], [[weakness]], tension, painful tremor, shaking attacks, jerks, [[dizziness]] and [[blepharospasm]]<ref name="pwsfb"/> 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.<ref>{{cite journal |doi=10.1111/j.1600-0447.1990.tb01375.x |title=The prolonged benzodiazepine withdrawal syndrome: Anxiety or hysteria? |year=1990 |last1=Higgitt |first1=A. |last2=Fonagy |first2=P. |last3=Toone |first3=B. |last4=Shine |first4=P. |journal=Acta Psychiatrica Scandinavica |volume=82 |issue=2 |pages=165–8 |pmid=1978465|s2cid=41458371 }}</ref> 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.<ref name=pwsfb /><ref>{{cite journal | journal = Psychiatric Annals |date=March 1995 | volume = 25 | issue = 3 | pages = 174–179 | title = Protracted Withdrawal From Benzodiazepines: The Post-Withdrawal Syndrome | author = Ashton CH | publisher = benzo.org.uk | url = http://www.benzo.org.uk/pha-1.htm |doi=10.3928/0048-5713-19950301-11 }}</ref> Symptoms continue to improve over time, often to the point where people eventually resume their normal lives, even after years of incapacity.<ref name="ashman"/>
+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.<ref>{{cite journal |doi=10.1111/j.1600-0447.1990.tb01375.x |title=The prolonged benzodiazepine withdrawal syndrome: Anxiety or hysteria? |year=1990 |last1=Higgitt |first1=A. |last2=Fonagy |first2=P. |last3=Toone |first3=B. |last4=Shine |first4=P. |journal=Acta Psychiatrica Scandinavica |volume=82 |issue=2 |pages=165–8 |pmid=1978465|s2cid=41458371 }}</ref> 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.<ref name=pwsfb /><ref>{{cite journal | journal = Psychiatric Annals | date = March 1995 | volume = 25 | issue = 3 | pages = 174–179 | title = Protracted Withdrawal From Benzodiazepines: The Post-Withdrawal Syndrome | author = Ashton CH | publisher = benzo.org.uk | url = http://www.benzo.org.uk/pha-1.htm | doi = 10.3928/0048-5713-19950301-11 | access-date = 16 April 2008 | archive-date = 20 September 2020 | archive-url = https://web.archive.org/web/20200920105333/https://www.benzo.org.uk/pha-1.htm | url-status = live }}</ref> Symptoms continue to improve over time, often to the point where people eventually resume their normal lives, even after years of incapacity.<ref name="ashman"/>
-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.<ref name="gabbards">{{Cite book | last1 = Gabbard | first1 = Glen O. | title = Gabbard's Treatments of Psychiatric Disorders, Fourth Edition (Treatments of Psychiatric Disorders) | date = 15 May 2007 | publisher = American Psychiatric Publishing | url=https://books.google.com/books?id=-T2aEqfwLW4C&pg=PA209 | isbn  = 978-1-58562-216-0 | pages = 209–211 }}</ref> The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal.<ref name="ashman"/> 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.<ref>{{cite journal |doi=10.1016/S0887-6177(03)00096-9 |title=Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: A meta-analysis |year=2004 |last1=Barker |first1=M |journal=Archives of Clinical Neuropsychology |volume=19 |issue=3 |pages=437–54 |pmid=15033227 |last2=Greenwood |first2=KM |last3=Jackson |first3=M |last4=Crowe |first4=SF|doi-access=free }}</ref>
+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.<ref name="gabbards">{{Cite book | last1 = Gabbard | first1 = Glen O. | title = Gabbard's Treatments of Psychiatric Disorders, Fourth Edition (Treatments of Psychiatric Disorders) | date = 15 May 2007 | publisher = American Psychiatric Publishing | url = https://books.google.com/books?id=-T2aEqfwLW4C&pg=PA209 | isbn = 978-1-58562-216-0 | pages = 209–211 | access-date = 28 August 2020 | archive-date = 26 July 2024 | archive-url = https://web.archive.org/web/20240726164531/https://books.google.com/books?id=-T2aEqfwLW4C&pg=PA209#v=onepage&q&f=false | url-status = live }}</ref> The change in symptoms has been proposed to be due to changes in receptor sensitivity for GABA during the process of tolerance reversal.<ref name="ashman"/> 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.<ref>{{cite journal |doi=10.1016/S0887-6177(03)00096-9 |title=Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: A meta-analysis |year=2004 |last1=Barker |first1=M |journal=Archives of Clinical Neuropsychology |volume=19 |issue=3 |pages=437–54 |pmid=15033227 |last2=Greenwood |first2=KM |last3=Jackson |first3=M |last4=Crowe |first4=SF|doi-access=free }}</ref>
 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,<ref name=pwsfb/> 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.<ref name="L. Saxon, S. Borg & A. J. Hiltunen 148–151"/> This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
@@ Line 219: / Line 222: @@
 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 follow-up, 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.<ref name="Curran2003"/> 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.<ref name="Curran2003"/> At the 24-week follow-up, 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 [[Substance dependence|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.<ref name="Curran2003"/>
-The authors also warned of the similarities in pharmacology and mechanism of action of the newer [[nonbenzodiazepine]] [[Z drugs]].<ref name="Curran2003">{{cite journal |pmid=14580077 |year=2003 |last1=Curran |first1=HV |last2=Collins |first2=R |last3=Fletcher |first3=S |last4=Kee |first4=SC |last5=Woods |first5=B |last6=Iliffe |first6=S |title=Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life |volume=33 |issue=7 |pages=1223–37 |journal=Psychological Medicine|doi=10.1017/S0033291703008213 |s2cid=20586160 |url=http://discovery.ucl.ac.uk/14113/1/14113.pdf }}</ref>
+The authors also warned of the similarities in pharmacology and mechanism of action of the newer [[nonbenzodiazepine]] [[Z drugs]].<ref name="Curran2003">{{cite journal |pmid=14580077 |year=2003 |last1=Curran |first1=HV |last2=Collins |first2=R |last3=Fletcher |first3=S |last4=Kee |first4=SC |last5=Woods |first5=B |last6=Iliffe |first6=S |title=Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life |volume=33 |issue=7 |pages=1223–37 |journal=Psychological Medicine |doi=10.1017/S0033291703008213 |s2cid=20586160 |url=http://discovery.ucl.ac.uk/14113/1/14113.pdf |access-date=29 June 2019 |archive-date=22 September 2017 |archive-url=https://web.archive.org/web/20170922202231/http://discovery.ucl.ac.uk/14113/1/14113.pdf |url-status=live }}</ref>
-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.<ref>{{cite book |last1=Salzman |first1=Carl |title=Clinical geriatric psychopharmacology |url=https://books.google.com/books?id=RXvpjJ1Un2gC&pg=PA450 |edition=4th |date=15 May 2004 |publisher=Lippincott Williams & Wilkins |location=USA |isbn=978-0-7817-4380-8 |pages=450–3}}</ref>
+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.<ref>{{cite book |last1=Salzman |first1=Carl |title=Clinical geriatric psychopharmacology |url=https://books.google.com/books?id=RXvpjJ1Un2gC&pg=PA450 |edition=4th |date=15 May 2004 |publisher=Lippincott Williams & Wilkins |location=USA |isbn=978-0-7817-4380-8 |pages=450–3}}</ref>
 ==See also==
@@ Line 228: / Line 231: @@
 *[[Alcohol withdrawal syndrome]]
 *[[Benzodiazepine dependence]]
+*[[List of benzodiazepines]]
-*[[Benzodiazepine equivalence]]
-*[[Opioid withdrawal syndrome]]
+*[[Opioid withdrawal]]
 *[[Physical dependence]]
 *[[Post-acute-withdrawal syndrome]]
 *[[Rebound effect]]
-*[[SSRI discontinuation syndrome]]
+*[[Antidepressant discontinuation syndrome]]
 *[[Neuroleptic discontinuation syndrome]]
 {{div col end}}
@@ Line 254: / Line 257: @@
 *[http://www.benzo.org.uk/manual/ Benzodiazepines: How they work and how to withdraw by Professor Heather Ashton]
 *[http://www.mindincamden.org.uk/mtproject.htm The Minor Tranquilliser Project, For support, Camden, UK] {{Webarchive|url=https://web.archive.org/web/20130325092749/http://www.mindincamden.org.uk/mtproject.htm |date=25 March 2013 }}
-*{{Curlie|Health/Mental_Health/Disorders/Substance_Related/Support_Groups/}}
 {{Psychoactive substance use}}

v t e Unnecessary health care
Causes	Direct-to-consumer advertising Overscreening Overdiagnosis Fee-for-service Defensive medicine Unwarranted variation Overmedication Overmedicalization Prescription cascade Quaternary prevention Disease mongering Political abuse of psychiatry
Overused health care	Caesarean delivery on maternal request Antibiotic misuse Benzodiazepine use disorder Opioid use disorder Psychoactive drug Proton-pump inhibitor Polypharmacy treatment of incidentaloma
Tools and situations	Deprescribing Choosing Wisely Medication discontinuation Withdrawal syndrome
Works about unnecessary health care	Overtreated The Treatment Trap Selling Sickness Overdosed America