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| {{Infobox medical condition (new) | | {{Infobox medical condition |
| | name = <!--{{PAGENAME}} by default--> | | | name = Kindling due to substance withdrawal |
| | synonym = | | | synonym = Withdrawal kindling |
| | image =
| | | specialty = [[Neurology]], [[Addiction medicine]] |
| | image_size =
| | | symptoms = Increasing severity of withdrawal symptoms, anxiety, tremors, seizures |
| | alt =
| | | complications = Severe seizures, delirium tremens, neurological damage, death |
| | caption =
| | | onset = During repeated withdrawal episodes |
| | pronounce =
| | | duration = Progressive worsening with repeated withdrawals |
| | specialty = neurology | | | types = Alcohol withdrawal kindling, Benzodiazepine withdrawal kindling |
| | symptoms = | | | causes = Repeated episodes of withdrawal from sedative–hypnotic substances |
| | complications = | | | risks = Chronic use of alcohol or benzodiazepines, repeated withdrawal attempts |
| | onset = | | | diagnosis = Clinical history, symptom progression |
| | duration = | | | differential = [[Alcohol withdrawal syndrome]], [[benzodiazepine withdrawal syndrome]], neurological disorders |
| | types = | | | prevention = Gradual tapering of sedative-hypnotics, medical supervision |
| | causes = | | | treatment = Medical detoxification, anticonvulsants, supportive therapy |
| | risks = | | | medication = Benzodiazepines, anticonvulsants ([[carbamazepine]], [[gabapentin]]) |
| | diagnosis = | | | prognosis = Poor if unmanaged; improved outcomes with medical intervention |
| | differential = | | | frequency = Common among chronic substance users undergoing repeated withdrawals |
| | prevention = | | | deaths = Possible without medical intervention |
| | treatment = | |
| | medication = | |
| | prognosis = | |
| | frequency = | |
| | deaths = | |
| }} | | }} |
| '''Kindling''' due to '''substance withdrawal''' refers to the neurological condition which results from repeated withdrawal episodes from [[sedative]]–[[hypnotic]] drugs such as [[alcohol]] and [[benzodiazepine]]s. | | '''Kindling due to substance withdrawal''', also known as '''withdrawal kindling''', is a neurological phenomenon resulting from repeated episodes of withdrawal from [[sedative]]–[[hypnotic]] substances, particularly [[alcohol]] and [[benzodiazepines]]. Each withdrawal episode increases the severity of subsequent withdrawal symptoms, significantly escalating risks including severe seizures and even death. |
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| Each withdrawal leads to more severe withdrawal symptoms than in previous episodes. Individuals who have had more withdrawal episodes are at an increased risk of very severe withdrawal symptoms, up to and including seizures and death. Long-term use of [[GABA]]ergic-acting sedative–hypnotic drugs causes chronic GABA [[Receptor (biochemistry)#Receptor-regulation|receptor downregulation]] as well as [[glutamate]] overactivity, which can lead to drug and neurotransmitter [[sensitization]], [[central nervous system]] hyperexcitability, and [[excitotoxicity]].
| | == Signs and Symptoms == |
| | | Symptoms progressively worsen with repeated withdrawal episodes and include: |
| == Symptoms == | | * Increased anxiety and agitation |
| [[Binge drinking]] is believed to increase impulsivity due to altered functioning of prefrontal–subcortical and orbitofrontal circuits. Binge drinking in alcoholics who have undergone repeated detoxification is associated with an inability to interpret [[facial expression]]s properly; this is believed to be due to kindling of the amygdala with resultant distortion of neurotransmission. Adolescents, females and young adults are most sensitive to the neuropsychological effects of binge drinking. Adolescence, particularly early adolescence, is a developmental stage which is particularly vulnerable to the neurotoxic and neurocognitive adverse effects of binge drinking due to it being a time of significant brain development.<ref name="Stephens-2008">{{Cite journal | last1 = Stephens | first1 = DN. | last2 = Duka | first2 = T. | title = Review. Cognitive and emotional consequences of binge drinking: role of amygdala and prefrontal cortex. | journal = Philos Trans R Soc Lond B Biol Sci | volume = 363 | issue = 1507 | pages = 3169–79 |date=Oct 2008 | doi = 10.1098/rstb.2008.0097 | pmid = 18640918 | pmc = 2607328 }}</ref>
| | * Tremors |
| | | * Insomnia |
| Approximately 3 percent of people who are alcohol dependent experience psychosis during acute intoxication or withdrawal. Alcohol-related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related [[psychosis]] is due to distortions to neuronal membranes, [[gene expression]], as well as [[thiamin]] deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance-induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increased risk of depression and suicide as well as psychosocial impairments.<ref name=emedicine>{{EMedicine|med|3113|Alcohol-Related Psychosis}}</ref>
| | * Severe seizures |
| | | * [[Delirium tremens]] (especially with alcohol withdrawal) |
| Repeated acute intoxication followed by acute withdrawal is associated with profound behavioural changes and neurobiological alterations in several brain regions. Much of the documented evidence of kindling caused by repeated detoxification regards increased seizure frequency. Increased fear and anxiety and cognitive impairments are also associated with alcohol withdrawal kindling due to binge drinking or alcoholics with repeated [[alcohol withdrawal]] experiences. The impairments induced by binge drinking or repeated detoxification of alcoholics cause a loss of behavioural inhibition of the prefrontal cortex; the [[prefrontal cortex]] is mediated by subcortical systems such as the amygdala. This loss of behavioral control due to brain impairment predisposes an individual to [[alcoholism]] and increases the risk of an abstaining alcoholic relapsing. This impairment may also result in long-term adverse effects on emotional behavior. Impaired associative learning may make behavioural therapies involving conditioning approaches for alcoholics less effective.<ref name="Stephens-2008" />
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| == Causes == | | == Causes == |
| Binge drinking regimes are associated with causing an imbalance between [[inhibitory]] and [[excitatory]] [[amino acids]] and changes in [[monoamine]] release in the central nervous system, which increases neurotoxicity; this may result in cognitive impairments, psychological problems, and may cause irreversible brain damage in both adolescent and adult long-term binge drinkers.<ref name="Ward-">{{Cite journal | last1 = Ward | first1 = RJ. | last2 = Lallemand | first2 = F. | last3 = de Witte | first3 = P. | title = Biochemical and neurotransmitter changes implicated in alcohol-induced brain damage in chronic or 'binge drinking' alcohol abuse. | url = http://alcalc.oxfordjournals.org/cgi/content/full/44/2/128?view=long&pmid=19155229 | journal = Alcohol Alcohol | volume = 44 | issue = 2 | pages = 128–35 |date=March–April 2009 | doi = 10.1093/alcalc/agn100 | pmid = 19155229 }}</ref><ref name="Crews-2009">{{Cite journal | last1 = Crews | first1 = FT. | last2 = Boettiger | first2 = CA. | title = Impulsivity, frontal lobes and risk for addiction. | journal = Pharmacol Biochem Behav | volume = 93 | issue = 3 | pages = 237–47 |date=Sep 2009 | doi = 10.1016/j.pbb.2009.04.018 | pmid = 19410598 | pmc = 2730661 }}</ref> Similar to binge drinkers, individuals suffering from [[alcohol dependence]] develop changes to neurotransmitter systems, which occur as a result of kindling and sensitization during withdrawal. This progressively lowers the threshold needed to cause [[alcohol-related brain damage]] and cognitive impairments, leading to altered neurological function. The changes in activity of excitatory and inhibitory neurotransmitter systems is similar to that which occurs in individuals suffering from limbic or [[temporal lobe epilepsy]].<ref name="Bob-2011">{{Cite journal | last1 = Bob | first1 = P. | last2 = Jasova | first2 = D. | last3 = Bizik | first3 = G. | last4 = Raboch | first4 = J. | title = Epileptiform activity in alcohol dependent patients and possibilities of its indirect measurement. | journal = PLoS ONE | volume = 6 | issue = 4 | pages = e18678 | month = | year = 2011 | doi = 10.1371/journal.pone.0018678 | pmid = 21541318 | pmc=3082533}}</ref>
| | Kindling occurs due to repeated withdrawals from substances that modulate [[Gamma-Aminobutyric acid|GABAergic]] activity, resulting in: |
| | * Chronic downregulation of [[GABA]] receptors |
| | * Heightened [[glutamate]] activity |
| | * Increased neuronal excitability ([[excitotoxicity]]) |
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| Adaptational changes at the GABA<sub>A</sub> benzodiazepine receptor complex do not fully explain [[Drug tolerance|tolerance]], [[Drug dependence|dependence]], and [[Drug withdrawal|withdrawal]] from benzodiazepines. Other receptor complexes may be involved; in particular, the excitatory [[glutamate]] system is implicated. The involvement of glutamate in [[benzodiazepine dependence]] explains long-term potentiation as well as neuro-kindling phenomena. Use of a short-acting benzodiazepine at night as a sleeping pill causes repeated acute dependence followed by acute withdrawal. There is some evidence that a prior history of CNS depressant dependence (e.g. alcohol) increases the risk of dependence on benzodiazepines. Tolerance to drugs is commonly believed to be due to receptor [[down-regulation]]; however, there is very limited evidence to support this, and this hypothesis comes from animal studies using very high doses. Instead, other mechanisms, such as [[Uncoupling (neuropsychopharmacology)|receptor uncoupling]], may play a more important role in the development of benzodiazepine dependence; this may lead to prolonged comformational changes in the receptors or altered subunit composition of the receptors.<ref name="Allison-2003" />
| | == Risk Factors == |
| | Risk factors for withdrawal kindling include: |
| | * Long-term heavy use of alcohol or benzodiazepines |
| | * History of multiple withdrawal attempts |
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| == Pathophysiology == | | == Diagnosis == |
| === Benzodiazepines ===
| | Diagnosis is primarily based on: |
| Repeated benzodiazepine withdrawal episodes may result in similar neuronal kindling as that seen after repeated withdrawal episodes from alcohol, with resultant increased neuro-excitability. The glutamate system is believed to play an important role in this kindling phenomenon with AMPA receptors which are a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in AMPA receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal. Changes in the glutamate system and GABA system may play an important role at different time points during [[benzodiazepine withdrawal syndrome]].<ref name="Allison-2003">{{cite journal |vauthors=Allison C, Pratt JA |title=Neuroadaptive processes in GABAergic and glutamatergic systems in benzodiazepine dependence |journal=Pharmacol. Ther. |volume=98 |issue=2 |pages=171–95 |date=May 2003 |pmid=12725868 |doi=10.1016/S0163-7258(03)00029-9 }}</ref>
| | * Clinical history of repeated withdrawal episodes |
| | * Progressive worsening of symptoms |
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| === Alcohol ===
| | Differential diagnoses include: |
| {{See also|Alcohol-related brain damage}}
| | * [[Alcohol withdrawal syndrome]] |
| Binge drinking may induce brain damage due to the repeated cycle of acute intoxication followed by an acute abstinence withdrawal state.<ref name="Hunt-">{{Cite journal | last1 = Hunt | first1 = WA. | title = Are binge drinkers more at risk of developing brain damage? | journal = Alcohol | volume = 10 | issue = 6 | pages = 559–61 | month = | year = 1993| doi = 10.1016/0741-8329(93)90083-Z| pmid = 8123218 | url = }}<!--https://zenodo.org/record/1258557--></ref> Based on animal studies, regular binge drinking in the long-term is thought to be more likely to result in brain damage than chronic (daily) alcoholism. This is due to the 4- to 5-fold increase in glutamate release in nucleus accumbens during the acute withdrawal state between binges but only in dose 3 g/kg, in 2 g/kg there is no increase in glutamate release. In contrast, during withdrawal from chronic alcoholism only a 2- to 3-fold increase in glutamate release occurs. The high levels of glutamate release causes a chain reaction in other neurotransmitter systems. The reason that chronic sustained alcoholism is thought by some researchers to be less brain damaging than binge drinking is because tolerance develops to the effects of alcohol and unlike binge drinking repeated periods of acute withdrawal does not occur,<ref name="Ward-" /><ref name="Crews-2009" /> but there are also many alcoholics who typically drink in binges followed by periods of no drinking.<ref>{{cite web|url=http://www.merck.com/mmhe/sec25/ch312/ch312b.html#sec25-ch312-ch312b-560|title=Alcohol – Special Subjects – Merck Manuals Consumer Version|publisher=}}</ref> Excessive glutamate release is a known major cause of neuronal cell death. Glutamate causes neurotoxicity due to [[excitotoxicity]] and oxidative glutamate toxicity. Evidence from animal studies suggests that some people may be more genetically sensitive to the neurotoxic and brain damage associated with binge drinking regimes. Binge drinking activates microglial cells which leads to the release of inflammatory [[cytokines]] and mediators such as [[tumour necrosis factor]], and [[nitric oxide]] causing [[neuroinflammation]] leading to neuronal destruction.<ref name="Ward-" /><ref name="Crews-2009" />
| | * [[Benzodiazepine withdrawal syndrome]] |
| | | * Other neurological disorders |
| Repeated acute withdrawal from alcohol which occurs in heavy binge drinkers has been shown in several studies to be associated with cognitive deficits as a result of neural kindling; neural kindling due to repeated withdrawals is believed to be the mechanism of cognitive damage in both binge drinkers and alcoholics. Neural kindling may explain the advancing pathogenesis and progressively deteriorating course of alcoholism and explain continued alcohol abuse as due to avoidance of distressing acute withdrawal symptoms which get worse with each withdrawal. Multiple withdrawals from alcohol is associated with impaired long-term nonverbal memory impairment in adolescents and to poor memory in adult alcoholics. Adult alcoholics who experienced two or more withdrawals showed more frontal lobe impairments than alcoholics who had a history of one or no prior alcohol withdrawals. The finding of kindling in alcoholism is consistent with the mechanism of brain damage due to binge drinking and subsequent withdrawal.<ref name="Courtney-2009">{{Cite journal | last1 = Courtney | first1 = KE. | last2 = Polich | first2 = J. | title = Binge drinking in young adults: Data, definitions, and determinants. | journal = Psychol Bull | volume = 135 | issue = 1 | pages = 142–56 |date=Jan 2009 | doi = 10.1037/a0014414 | pmid = 19210057 | pmc = 2748736 }}</ref>
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| ==Diagnosis==
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| === Definition ===
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| Kindling refers to the phenomenon of increasingly severe withdrawal symptoms, including an increased risk of seizures, that occurs as a result of repeated withdrawal from alcohol or other sedative–hypnotics with related modes of action. [[Ethanol]] (alcohol) has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the [[GABAA receptor|GABA<sub>A</sub>
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| receptors]], [[NMDA receptor]]s and [[AMPA receptor]]s, but the majority of research into kindling has primarily focused on alcohol.<ref name="Allison-2003" /> An intensification of anxiety and other psychological symptoms of alcohol withdrawal also occurs.<ref name="pmid20148778">{{cite journal |vauthors=Heilig M, Egli M, Crabbe JC, Becker HC |title=Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? |journal=Addict Biol |volume=15 |issue=2 |pages=169–84 |date=April 2010 |pmid=20148778 |pmc=3268458 |doi=10.1111/j.1369-1600.2009.00194.x |url=}}</ref>
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| == Treatment == | | == Treatment == |
| Failure to manage the [[alcohol withdrawal syndrome]] appropriately can lead to permanent brain damage or death.<ref name="pmid19670554">{{cite journal |vauthors=Hanwella R, de Silva V |title=Treatment of alcohol dependence |journal=Ceylon Med J |volume=54 |issue=2 |pages=63–5 |date=June 2009 |pmid=19670554 |doi=10.4038/cmj.v54i2.877}}</ref>
| | Treatment strategies focus on safely managing withdrawal symptoms and preventing complications through: |
| | | * Medically supervised detoxification |
| [[Acamprosate]], a drug used to promote abstinence from alcohol, an [[NMDA antagonist]] drug, reduces excessive glutamate activity in the central nervous system and thereby may reduce excitotoxicity and withdrawal related brain damage.<ref name="pmid15963001">{{cite journal |vauthors=De Witte P, Littleton J, Parot P, Koob G |title=Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action |journal=CNS Drugs |volume=19 |issue=6 |pages=517–37 |year=2005 |pmid=15963001 |doi=10.2165/00023210-200519060-00004}}</ref><ref>{{cite journal |vauthors=Mirijello A, D'Angelo C, Ferrulli A, Vassallo G, Antonelli M, Caputo F, Leggio L, Gasbarrini A, Addolorato G |title=Identification and management of alcohol withdrawal syndrome |journal=Drugs |volume=75 |issue=4 |pages=353–65 |date=March 2015 |pmid=25666543 |doi=10.1007/s40265-015-0358-1 |pmc=4978420}}</ref> | | * Gradual dose tapering to minimize withdrawal severity |
| | * Anticonvulsants such as [[carbamazepine]] or [[gabapentin]] |
| | * Supportive therapies addressing anxiety and insomnia |
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| == See also == | | == Prognosis == |
| * [[Kindling model]]
| | The prognosis can be poor if kindling is unmanaged. Early intervention and medical supervision significantly improve outcomes. |
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| == References == | | == Prevention == |
| {{Reflist}}
| | Preventive strategies include: |
| | * Medical supervision during withdrawal |
| | * Gradual tapering rather than abrupt cessation |
| | * Avoidance of repeated withdrawal episodes |
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| {{DEFAULTSORT:Kindling (sedative-hypnotic withdrawal)}} | | {{DEFAULTSORT:Kindling (sedative-hypnotic withdrawal)}} |
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| [[Category:Sedatives]] | | [[Category:Sedatives]] |
| [[Category:Withdrawal syndromes]] | | [[Category:Withdrawal syndromes]] |
| {{dictionary-stub1}}
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| Kindling due to substance withdrawal
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| Synonyms
|
N/A
|
| Pronounce
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N/A
|
| Specialty
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Neurology, Addiction medicine
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| Symptoms
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Increasing severity of withdrawal symptoms, anxiety, tremors, seizures
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| Complications
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Severe seizures, delirium tremens, neurological damage, death
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| Onset
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During repeated withdrawal episodes
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| Duration
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Progressive worsening with repeated withdrawals
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| Types
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Alcohol withdrawal kindling, Benzodiazepine withdrawal kindling
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| Causes
|
Repeated episodes of withdrawal from sedative–hypnotic substances
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| Risks
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Chronic use of alcohol or benzodiazepines, repeated withdrawal attempts
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| Diagnosis
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Clinical history, symptom progression
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| Differential diagnosis
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Alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, neurological disorders
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| Prevention
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Gradual tapering of sedative-hypnotics, medical supervision
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| Treatment
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Medical detoxification, anticonvulsants, supportive therapy
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| Medication
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Benzodiazepines, anticonvulsants (carbamazepine, gabapentin)
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| Prognosis
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Poor if unmanaged; improved outcomes with medical intervention
|
| Frequency
|
Common among chronic substance users undergoing repeated withdrawals
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| Deaths
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Possible without medical intervention
|
Kindling due to substance withdrawal, also known as withdrawal kindling, is a neurological phenomenon resulting from repeated episodes of withdrawal from sedative–hypnotic substances, particularly alcohol and benzodiazepines. Each withdrawal episode increases the severity of subsequent withdrawal symptoms, significantly escalating risks including severe seizures and even death.
Signs and Symptoms[edit]
Symptoms progressively worsen with repeated withdrawal episodes and include:
- Increased anxiety and agitation
- Tremors
- Insomnia
- Severe seizures
- Delirium tremens (especially with alcohol withdrawal)
Kindling occurs due to repeated withdrawals from substances that modulate GABAergic activity, resulting in:
Risk Factors[edit]
Risk factors for withdrawal kindling include:
- Long-term heavy use of alcohol or benzodiazepines
- History of multiple withdrawal attempts
Diagnosis[edit]
Diagnosis is primarily based on:
- Clinical history of repeated withdrawal episodes
- Progressive worsening of symptoms
Differential diagnoses include:
Treatment[edit]
Treatment strategies focus on safely managing withdrawal symptoms and preventing complications through:
- Medically supervised detoxification
- Gradual dose tapering to minimize withdrawal severity
- Anticonvulsants such as carbamazepine or gabapentin
- Supportive therapies addressing anxiety and insomnia
Prognosis[edit]
The prognosis can be poor if kindling is unmanaged. Early intervention and medical supervision significantly improve outcomes.
Prevention[edit]
Preventive strategies include:
- Medical supervision during withdrawal
- Gradual tapering rather than abrupt cessation
- Avoidance of repeated withdrawal episodes
