Professional Documents
Culture Documents
by VANIA MODESTO-LOWE, MD, MPh; JESSICA HUARD, BS; and CYNTHIA CONRAD, MD, PhD
Dr. Modesto-Lowe is Assistant Professor and Dr. Conrad is Associate Professor from the Department of Psychiatry, University of Connecticut School of Medicine and
both are from Connecticut Valley Hospital; Ms. Huard is Master’s Physician Assistant Student, Quinnipiac University—All from Middletown, Connecticut.
Alcohol Withdrawal
Kindling: Is There a Role for
Anticonvulsants?
ABSTRACT
Animal and clinical studies
supporting the kindling hypothe-
sis of alcohol withdrawal suggest
the need to revisit current treat-
ment concepts. While traditional
approaches have emphasized
symptom reduction and preven-
tion of complications, novel
approaches include slowing
progress of clinical severity asso-
ciated with multiple withdrawals.
Currently, it is unclear if medica-
tions can halt cumulative neuro-
toxicity associated with multiple
withdrawals. However, the ability
of anticonvulsants to improve the
course of alcohol withdrawal and
their neuroprotective effects may
be of interest. The use of anti-
convulsants as probes in animal
models of kindling and controlled
trials examining the efficacy of
newer anticonvulsants in the
treatment of alcohol withdrawal
may improve understanding of
alcohol withdrawal kindling and
its treatment. ADDRESS CORRESPONDENCE TO:
Vania Modesto-Lowe, MD, MPH, Connecticut Valley Hospital, Addiction Service Division, Merrit Hall, PO Box 351,
Middletown, CT 06457; Phone: (860) 521-2604; E-mail: Vania.Modesto-Lowe@po.state.ct.us
26 Psychiatry 2005 [ M A Y ]
sensitized withdrawal seizures and (e.g. seizures) as well as the neuro- One in-vitro study has shown
neurotoxicity resulting from repeat- toxic effects of ethanol.41 that the anticonvulsants oxcarba-
ed alcohol withdrawal. Next, we will Interestingly, the anticonvulsant mazepine and lamotrigine consis-
review alcohol effects on NMDA carbamazepine has been shown to tently inhibit voltage-activated calci-
and GABA systems and speculate depress NMDA-receptor-mediated um currents.15 The anticonvulsant
how it may relate to kindling. We responses.42,43 Several other anticon- gabapentin inhibits neuronal calci-
will also discuss candidate mecha- vulsants including valproate and um influx in a concentration-
nisms of anticonvulsants putative gabapentin also attenuate gluta- dependent manner.52 If decreased
neuroprotective effects on these matergic neurotransmission.44 calcium influx indeed reduces exci-
systems. Glutamatergic-induced neurotoxici- tatory glutamate release, anticon-
ty occurring during ethanol with- vulsants may indeed exert neuro-
ETHANOL AFFECTS THE drawal is thought to be due in part protective effects during alcohol
GLUTAMATE NMDA RECEPTOR to excessive amounts of calcium withdrawal. Because current under-
SYSTEM ions entering the hyperexcitable standing of the full spectrum of the
The glutamate NMDA receptor neurons and has been implicated in biological effects of alcohol, anticon-
complex is a ligand-gated ion chan- cumulative neuronal damage associ- vulsants, and neurotransmitter sys-
nel that mediates the influx of calci- ated with repeated ethanol with- tems are incomplete, both animal
um ions when activated. The NMDA drawal.45 and human models of kindling
receptor complex and voltage-gated Evidence for involvement of the require further development.
calcium currents are both involved glutamate NMDA receptors in kin- Perhaps the use of anticonvulsants
in controlling neuronal excitability.33 dling derives from animal studies as pharmacological probes in animal
Animal studies show that acute indicating that a history of multiple kindling models may improve the
administration of ethanol disrupts withdrawal episodes correlates with understanding of kindling neurobio-
glutamatergic neurotransmission, increased sensitivity to NMDA- logical substrates as well as the
28 Psychiatry 2005 [ M A Y ]
superior to lorazepam in reducing diazepines. In a double-blind, con- reported its potential value as an
post-treatment drinking, particular- trolled, seven-day study (n=36), adjunct to chlormethiazole in treat-
ly among patients with multiple researchers evaluated the adjunc- ing four alcohol-dependent patients
withdrawal episodes. In this study, tive use of divalproex sodium to a undergoing detoxification.74
the relative risk of having a first benzodiazepine in the treatment of Gabapentin was found to be an
drink was at least three times more moderate alcohol withdrawal.62 effective treatment for insomnia
likely in lorazepam-treated patients Thirty-six patients in moderate associated with alcohol dependence
than in those receiving CBZ. alcohol withdrawal were random- in 15 detoxified patients at average
Despite these potential advantages, ized to receive either divalproex doses of 600mg/d (range
the use of carbamazepine is limited sodium (500mg TID) or placebo. All 200–1,500mg/d). In general, each
due to hematological and hepatic patients received a dose of patient showed improvements in
toxicities, in addition to multiple oxazepam (30mg) at the time they the sleep pattern questionnaire.75
drug interactions. first received the study medication Voris, et al., conducted a retro-
Oxcarbamazepine, a newly and additional oxazepam in accor- spective chart review in 49 inpa-
improved derivative of CBZ, dance with a standard, symptom tient (18) and outpatient (31) vet-
appears to have significantly less triggered detoxification protocol. erans receiving gabapentin for mild
hepatotoxicity and less drug inter- Divalproex sodium-treated patients to moderate alcohol withdrawal.76
actions.68 It may also have neuropro- required significantly less oxazepam Gabapentin dosing in general was
tective effects that need to be than placebo-treated patients. In 400mg three times a day for three
examined in the context of alcohol addition, the progression of with- days, 400mg twice a day for two
withdrawal.14 drawal severity was significantly days and 400mg once a day for one
Preliminary studies suggest that less among patients treated with day. This report indicated the
various formulations of the anticon- divalproex sodium. Although repli- potential efficacy of gabapentin for
30 Psychiatry 2005 [ M A Y ]
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