Transcript Kindling in Alcohol Withdrawl

Kindling in Alcohol
Withdrawal
Derek S. Mongold MD
Resident in Family Medicine and Psychiatry
08-11-08
Source: Alcohol Health and Research World
Vol. 22, No. 1, 1998
By Howard C. Beckner Ph. D.
Case 1
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L.B., 52 yo. male, 30 year history of alcohol
dependence.
Never through detox in the past.
Drinks 24 beers per day.
Presents for help to “stop drinking.”
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Case 2
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R.J., 52 yo. male, 30 year history of alcohol
dependence.
Multiple episodes of detox and subsequent
relapses after a short period of time.
Drinks 24 beers per day.
Presents for help to “stop drinking.”
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Case Studies
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Who has the best prognosis for sustained
abstinence?
Does prior short episodes of sobriety help with
abstinence?
Who is at higher risk for complicated
withdrawal?
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Kindling
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Term first introduced by Goddard and
colleagues (1969).
Phenomenon where repeated weak electrical
stimulation of discrete brain regions eventually
produced overt behavioral effects
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Kindling
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Electrodes implanted into brain and produced
repeated weak stimulation.
Initially produced no overt behavioral effects.
Over time the same stimuli produced full motor
seizures
Suggests the brain had become sensitized to the
stimulation.
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Kindling
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Additional studies found sensitization could
occur with electrical or chemical stimuli (Gelbert
1992; Post et al. 1988).
However, it is critical that subconvulsive
stimulus be administered in a repeated,
intermittent fashion.
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Kindling
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Kindling is a durable phenomenon and, once the
enhanced excitability is established it can last for
at least several months
Most likely reflects long-term changes in
neuronal circuitry and function (McNamara and
Wada 1997).
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Kindling
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When applied to alcohol withdrawal, each
withdrawal-induced episode may serve as a
subconvulsive stimulus that supports a kindling
process (Ballenger and Post 1978).
Repeated episodes in a short period (as seen in
repeated episodes of binge drinking) may speed up the
kindling process.
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Kindling in Alcohol withdrawal
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Hospitalized alcoholics who suffered a seizure
during detox were more likely to have a history
of numerous withdrawal episodes than were
hospitalized alcoholics who did not suffer
seizures.
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Kindling in Alcohol withdrawal
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Brown and colleagues (1998) found 48% of
inpatients who had seizures had experienced five
or more previous withdrawal episodes.
Only 12% of patents who had no seizures had
experienced five or more previous withdrawal
episodes.
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Kindling in Alcohol withdrawal
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Clinically significant, because patients
experiencing Alcohol related withdrawal seizures
have a poorer prognosis and higher mortality
rate than people with seizures from an unknown
cause (Pienin-keroinen et al. 1992).
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Kindling in Alcohol withdrawal
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Therefore, after multiple withdrawal episodes,
patients become sensitized and subsequently
experience more severe withdrawal symptoms.
However, all these studies have severe
limitations. None are blinded, prospective,
placebo controlled trials. All seem to be
retrospective analysis.
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Kindling in Alcohol withdrawal
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Other concurrent and intervening variables
associated with alcoholism may affect kindling
and are not controlled for (e.g. malnutrition and
variable periods of alcohol exposure and abstinence)
These variables may confound results
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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Several studies found that withdrawal symptoms
were more severe in animals with previous
withdrawal experience than in animals that
experienced first-time withdrawal.
Seizures seem to be particularly susceptible to
kindling and have been a focus of research.
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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Mice exposed to alcohol vapors for 16 hours
resulted in a mild withdrawal response during
first withdrawal.
Repeated intoxication-withdrawal cycles induced
progressively more severe withdrawal-related
convulsions (Becker 1994).
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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Of course it produced more intense withdrawal.
The rats were exposed to more alcohol, but does
the withdrawal worsen because of episodic
exposures or because of the total amount of
alcohol exposure.
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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Becker and Hale 1993; Becker et al. 1997
Exposed two groups of mice to the same
amount of alcohol but to different schedules of
exposures.
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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One group was continuously exposed to alcohol
vapors for 48 hours
The other group was exposed for a total of 48
hours but the exposure time was divided into
three cycles of 16 hours of intoxication
separated by 8 hours of abstinence.
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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Mice exposed to interrupted alcohol exposure
exhibited more severe withdrawal seizures
compared to the mice who received
uninterrupted alcohol exposure.
Suggests that REPEATED alcohol withdrawal
may be critical for kindling effect to take place.
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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Animals with repeated withdrawal episodes had
greater changes in brain activity on EEG
(Poldrugo and Snead 1984; Veatch and Gonzalez
1996; Walker and Zornetzer 1974)
Changes appear as spikes and sharp waves in
specific brain regions.
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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These EEG changes to withdrawal episodes
affect certain regions of the brain, but total
amount of alcohol exposure effects other areas
(Veatch and Gonzalez 1996).
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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History of withdrawal decreases the duration
and extent of intoxication necessary to provoke
subsequent withdrawal response (Anton and
Becker 1995)
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Experimental Evidence of Kindling
in Alcohol Withdrawal
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Therefore, although alcohol dose and duration
of alcohol exposure are important factors for an
H&P, number of withdrawal episodes may be
just as important when predicting severity of
withdrawal episodes.
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Treatment Implications of Kindling
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Debate still exists over whether all patients
experiencing alcohol withdrawal should be
treated aggressively
e.g. benzodiazepine taper verses symptom
triggered benzodiazepine administration.
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Treatment Implications of Kindling
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Growing body of evidence suggests that if left
untreated, repeated withdrawal episodes (even
relatively mild ones), may progress to a more
severe, life threatening syndrome in the future.
Treatment of early withdrawal episodes may
delay the development of later kindled
withdrawal seizures (Ulrichsen et al. 1992; 1995)
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Treatment Implications of Kindling
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However, repeated administration of sedative
hypnotics may be associated with serious
drawbacks (Becker and Littleton 1996; Mayo-Smith
and bernard 1995).
In particular, enhanced withdrawal seizures can
occur as a result of withdrawal from sedative
hypnotics (Worse, more dangerous seizures from
benzodiazepine withdrawal than from alcohol
withdrawal).
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Clinical Significance of kindling
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Most studies have focused on withdrawal
seizures.
Could other withdrawal symptoms be
exacerbated by repeated withdrawal cycles?
Progressive intensification of dysphoria from
abstinence and enhanced positive subjective
feelings of alcohol’s intoxicating effects could
increase a patient’s motivation to resume
drinking.
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Clinical Significance of kindling
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Several studies have suggested that changes in
brain mechanisms involved in mediating
alcohol’s rewarding effects may become more
pronounced following successive intoxication
and withdrawal experiences.
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Clinical Significance of kindling
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Roberts et al. 1996
Rats undergoing withdrawal were given the
opportunity to self-administer alcohol.
Their consumption increased and became
progressively more stable over successive
withdrawal episodes.
Treatment with GABA agents modified the
withdrawal-related consumption.
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Clinical Significance of kindling
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Weiss et al. 1996
Possible most interesting study of all.
Rats undergoing withdrawal restored deficits in
brain levels of dopamine by drinking.
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Clinical Significance of kindling
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Dopamine-mediated neurotransmission in
various brain regions has been shown to play a
key role in mediating both alcohol’s rewarding
effects and dysphoria associated with withdrawal
from chronic alcohol exposure (Koob et al. 1998)
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Could a medication that acts to increase
dopamine levels (e.g. Wellbutrin) decrease the
rewarding effects and dysphoria associated with
alcohol?
Is that the mechanism it works on to decrease
nicotine cravings?
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Clinical Significance of kindling
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Also, repeated withdrawal episodes, particularly
if they occur in similar settings, may contribute
to relapse through a conditioned withdrawal
response.
e.g. neutral stimuli such as a physician or
hospital room may become cues to trigger
withdrawal symptoms much like a familiar bar
may trigger the urge to drink.
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Role of Kindling in Brain Damage
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Multiple withdrawal experiences may render a
person more vulnerable to brain damage.
There may be enhanced excitotoxicity with
progressive increases in excitatory
neurotransmission.
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Role of Kindling in Brain Damage
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Alcohol withdrawal activates the hypothalamicpituitary-adrenocortical (HPA) axis.
Levels of hormones secreted by the adrenal
cortex (corticosteroids) increase.
In animals with more episodes of withdrawal,
the corticosteroid level is higher and remains
high longer (Becker and Littleton 1996).
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Role of Kindling in Brain Damage
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Corticosteroids make some neurons more
excitable.
Prolonged excitation secondary to steroids alter
seizure susceptibility and may produce neural
damage, particularly in the hippocampus.
May underlie cognitive deficits related to chronic
binge drinking (Hunt 1993).
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Role of Kindling in Brain Damage
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Becker and Littleton, 1996
Showed that repeated alcohol withdrawal is in
fact associated with increased cognitive
dysfunction.
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Conclusion
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Repeated alcohol withdrawal may exacerbate
severity of future withdrawal episodes (e.g.
seizures).
This progressive intensification may be the
manifestation of a kindling mechanism.
Kindling may cause changes in the HPA axis
that make the brain more vulnerable to neuronal
damage.
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Conclusion
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Finally, Kindling may contribute to an
exacerbation of psychological components of
withdrawal (e.g. dysphoria when not drinking and
increased subjective positive feelings when drinking) that
increase relapse risk.
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Conclusion
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Therefore, each withdrawal episode may be
viewed as part of a potentially long-term process
that can lead to dangerous exacerbation of
withdrawal symptoms with each subsequent
episode.
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Conclusion
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New treatment strategies for alcohol detox
should try to quantify their impact on the
kindling process and should try to minimize it as
much as possible.
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Case Studies
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Who has the best prognosis for sustained
abstinence?
Does prior short episodes of sobriety help with
abstinence?
Who is at higher risk for complicated
withdrawal?
www.DerekMongold.com
Questions
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Should patients who are not ready to quit
drinking be forced (e.g. detained and
committed) to be detoxed?
How much future withdrawal and relapse risk
are we causing patients by giving them multiple
detoxifications?
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Questions
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Should patients with minimal withdrawal
symptoms be treated with a benzo taper versus
symptom triggered benzo administration to
prevent future problems?
Does the multiple withdrawal cycles that some
patients experience cause more harm or does
exposure to AA/NA meetings and therapy that
patients receive during detoxification cause more
beneficial results for future relapse rates?
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Questions
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If patients are told of the kindling effect, will it
become an excuse continue to drink and not try
to quit?
Is there a kindling effect to other substances of
abuse such as benzodiazepines?
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Mechanisms
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Primary inhibitory neurotransmitter in mammals
is GABA.
Blocking the GABA receptor can cause seizures.
Activating GABA reduces CNS excitability
Alcohol works on GABA. This is probably
what contributes to alcohol’s sedative effects
(Mihic and Harris 1997).
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Mechanisms
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After chronic alcohol exposure, the CNS adapts
to the alcohol-induced GABA activation by
reducing GABA-mediated transmission.
Studies have shown that multiple withdrawal
episodes caused enhanced sensitivity to GABA
antagonists (Becker and Littleton 1996; Kokka et al.
1993; McCown and Breese 1993)
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Mechanisms
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Activation of GABA receptors cause chloride
ions to enter the neuron and dampens neuronal
activity
This flow of chloride into the cell was decreased
in the hippocampus of rats exposed to chronic
intermittent alcohol treatment (Kang et al. 1996).
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Mechanisms
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Rats with a history of multiple withdrawal
episodes exhibited reduced GABA-mediated
neuronal inhibition.
The subunit composition of the GABA receptor
(GABA receptor consists of five subunits) was altered
in the hippocampus of these animals.
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Mechanisms
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Changes also occur in excitatory neurons when
exposed to repeated withdrawal cycles.
Glutamate in the primary excitatory
neurotransmitter.
Has two types of receptors.
One can be excited with NMDA and the other
can be activated with kainate (but not NMDA).
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Mechanisms
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Excitation of either glutamate receptor subtype
is associated with seizures.
Animals with a history of multiple alcohol
withdrawal episodes are more sensitive to
seizures caused by NMDA exposure than
animals that have only undergone a single
withdrawal episode.
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Mechanisms
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Repeated alcohol exposure and withdrawal
increases the number of NMDA receptors on
cells.
This causes a rise in NMDA-induced flow
calcium ions through receptor channels and into
neurons (Hu and Ticku 1997).
This increase in calcium entry can cause
excessive cellular activity and cell death.
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Mechanisms
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Could an NMDA antagonist such as Namenda
help limit cell death?
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Mechanisms
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Kainate receptors are located on different
neurons than NMDA receptors. Multiple
withdrawal experiences in mice did not increase
the animals’ sensitivity to the convulsant
properties of kainate.
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Mechanisms
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Therefore the kindling process do not involve all
glutamate receptors and may be associated with
selective neurochemical changes in specific
brain regions.
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