Neurobiology and Treatment of Alcohol Withdrawal

ACADEMY OF PSYCHOSOMATIC MEDICINE
Psychiatrists Providing Collaborative Care for Physical and Mental Health
Neurobiology & Treatment of
Alcohol Withdrawal
Understanding the Neurocircuitry of AWS
& Principles of the BZDP Sparing Protocol
José R. Maldonado, M.D., FAPM, FACFE
Associate Professor of Psychiatry, Medicine, Surgery, Emergency Medicine & Law
Stanford University Schools of Medicine & Law
Medical Director, Psychosomatic Medicine Service
Stanford University Medical Center
Stanford, CA

Disclosure: Jose R. Maldonado, MD
• With respect to the following
presentation, there has been no
relevant (direct or indirect)
financial relationship between
Dr. Maldonado (and/or spouse)
and any for-profit company in
the past 10 years which could
be considered a conflict of
interest.
• Every drug use discussed
during the talk is considered
“off label”

Alcohol Withdrawal
Syndromes (AWS)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Tremors, irritability & insomnia
(DT’s)
Minor Withdrawal
Hallucinosis
Seizures
confusion
Days
S
y
m
p
t
o
m
I
n
t
e
n
s
i
t
y
Maldonado, J. 2010. Med Clin North Am 94(6): 1169-1205.
Complicated–AWS
3

Clinical Dilemma
• Studies have shown that in medically-ill, hospitalized subjects (i.e.,
not a specialized detoxification or substance abuse unit) most cases
of AWS are relatively mild and require only symptomatic
management (e.g., mild anxiety, insomnia, GI symptoms).
• In fact, most patients with AUD experience only mild withdrawal
symptoms.
– In most cases, the symptoms of mild alcohol withdrawal do not require medical
intervention and usually disappear within 2–7 days of the last drink.
– The incidence of AWS, among alcohol dependent subjects admitted to a general
medical hospital severe enough to require pharmacological treatment is
between 5 – 20%.
• The unnecessary prophylaxis or treatment of patients feared to be
at risk or experiencing AWS may lead to a number of unintended
consequences including sedation, falls, respiratory depression and
delirium.
Maldonado et al. Alcohol 2014, 1 – 16 .

Clinical Dilemma
• Yet, when moderate to severe AWS do occur, it is associated with:
– increased incidence of acute medical and surgical complications
– ventilator days, intensive care unit days, and hospital days
– increased in-hospital morbidity and mortality
– prolonged hospital stay
– inflated healthcare costs
– increased burden on nursing and medical staff
– further worsens cognitive functioning among withdrawing subjects.
• There is a positive correlation between the severity and duration of
delirium tremens (DT’s) symptoms and the occurrence of
pneumonia, coronary heart disease, alcohol liver disease, and
anemia.
• The mortality of untreated AWS can reach 15 – 20%
– compared with only 2% if treated.
Ungur et a; 2013. Alcohol Clin Exp Res 37(4): 675-686.

Clinical Dilemma
• Animal and human studies demonstrate that
AWS is detrimental to the CNS:
– Neuronal damage may be seen as early as 24-h after
experiencing alcohol withdrawal and death.
– AWS potentiates loss of hippocampal neurons; which is
later associated with poorer memory performance.
– Each episode of withdrawal worsens the severity and
consequences of the next one.
– An increasing number of alcohol withdrawal episodes
negatively affect emotional and cognitive functioning and
learning.

The Problem w Benzodiazepines
• BZDP represent the standard of care for the Tx of AWS and have
been shown to prevent AW-Sz and DT (Mayo-Smith, 1997).
• Potential problems with the use of BZDP:
Maldonado, Crit Care Clinic, 2008;24:657-722
1. CNS-depressant withdrawal
2. BZD have abuse liability:
• Concurrent alcohol/benzodiazepine use: 29 –
76% (Busto et al 1991; Ciraulo et al 1988)
• This is problematic in an O/P setting or when
trying to discharge home a patient on moderate
or high doses.
3. There are preclinical and clinical studies
suggesting that BZD use may increase
craving, early relapse to alcohol use, and
increased alcohol consumption (Malcolm
et al., 2002; Poulos and Zack, 2004).
4. BZD have significant interactions with alcohol, opioids, and other CNS-
depressant agents ➜ there can be additive respiratory depression and
cognitive impairment.

• Potential problems with the
use of BZDP:
5. Psychomotor retardation,
cognitive blunting, ataxia and
poor balance, ↓ mobility
6. Anxiolytic and hypnotic drugs
(benzodiazepines, Z drugs
(zaleplon, zolpidem, and
zopiclone) were associated with
significantly increased risk of
mortality over a seven year
period, after adjusting for a range
of potential confounders (Weich et
al. BMJ 2014)
7.  compensatory up-regulation of
N-methyl D-aspartate and kainite-
Rs and Ca2+ channels
8. Disrupting Thalamic gating
function

• Potential problems with the use of
BZDP:
10. Increased risk of developing BDZP-
induced delirium.
• Interfering with central cholinergic
function muscarinic transmission at
the level of the basal forebrain and
hippocampus (i.e., causing a
centrally mediated acetylcholine
deficient state)
– New evidence suggests that BZDP use may be
associated with an increased risk of dementia
(de Gage et al BMJ 2012).
• Interfering with physiologic sleep
patterns (e.g., ↓ slow wave sleep→
↑REM latency→ ↓ REM periods
duration → REM deprivation)
The probability of transitioning to delirium
increased dramatically (by 2%) for each year
of life after 65 yr.
Adjusted Odds ratio - 1.01 [(1.00, 1.02) p=0.03
Pandharipande, 2006
Repper, Stern et al, Psychosomatics, 2008

ETOH
Consumption AWS
GABA
Mg+
Inhibitors Stimulants
Associated
Clinical Sx’s
DA
NMDA/
GLU
  NA
CRF
Hallucinosis
WD SZs
Kindling
Adrenergic
Storm
DT’s
Alcohol Withdrawal Delirium as a
Pathoetiologic Model for
Acute Brain Failure
Maldonado JR. Submitted for publication. 2014
X

GABA GLUr DA NE VGCC
Ca+ Ch
5HT HPA
(CRF)
MEL NGF Mg+
Acute ↑ ↓ ↑ ↑ ↓ ↑ ↑ ↓ ↑ ↔
Chronic ↑ ↓ ↑ ↑ ↓ ↑ ↓ ↓ ↑↑ ↓
AWS ↓↓ ↑↑↑
(up to
300%)
↑↑↑ ↑↑ ↑ ↑↑ ↑↑ ↓↓↓ ↑↑↑ ↓
ETOH
Neuromodulation
Maldonado et al, 2014, in Press

Drug T ½ Product
Availability
Bioavailability Metabolism Protein
Binding
Mechanism Action
carbamazepine 25 h PO ∼100% Hepatic 55 % • Stabilizes neuronal membranes
• inhibits voltage-sensitive Na+ channels and/or Ca+
channels→ ↓ cortical GLU release
• Calcium Channel Blockers
• Excitatory Amino Acid Antagonists
VPA 9 -16 h PO / IV 90% Hepatic
conjugation
90 % • GABA transaminase inhibitor → ↑ GABA
• inhibits voltage-sensitive Na+ channels→ ↓
cortical GLU release
• ↓ release of the epileptogenic amino acid gamma-
hydroxybutyric acid (GHB)
gabapentin 5 – 7 h PO 60% None
Renal excretion
< 3 % • voltage-gated Ca+ channel blockade → ↓ cortical
GLU release
• NMDA antagonism
• activation of spinal alpha2-adrenergic receptors
• Attenuation of Na+ dependent action potential
vigabatrin 5 – 8 h PO 50% None sig
Renal excretion
∼0% • block the reuptake of GABA & inhibits the
catabolism of GABA→↑GABA concentrations; no
receptor agonist.
• inhibition of voltage-sensitive Na+ channels
tiagabine 7 – 9 H PO 90% Hepatic; P450
CYP3A, CYP1A2,
CYP2D6 or CYP2C19
96% • block the reuptake of GABA →↑GABA
concentrations; no receptor agonist.
• inhibition of voltage-sensitive Na+ channels
AWS Management Alternatives – Glutamate & Ca+ ch modulators
GABAPENTIN
T1/2= 5 – 7 hrs
None; renal excretion
CARBAMAZEPINE
T1/2 = 25 h
hepatic
VIGABATRIN
T1/2= 5 – 7 hrs
None; renal excretion
TIAGABINE
T1/2= 7 – 9 hrs
Ext hepatic
VPA
T1/2 = 9 – 16 h
Hepatic/conujugation

Alcohol Withdrawal Treatment – Non-Benzodiazepine Alternatives
Carbamazepine (CBZ) -1/2
Study Population Intervention AWS
Definition
Outcome
Bjorkqvist et
al. 1976
DBPCRCT
O/P ETOH Rehab
Settings-
multicenter trial,
n=105
PBO vs. CBZ:
800 mg D1-2
600 mg D3-4
400 mg D 5-6
200 mg D 7
CIWA-Ar  CBZ proved to be superior to placebo.
• The change in the total symptom score from
1st to the 2nd day of Tx was significantly
greater in the carbamazepine group than in
the placebo group.
• The patients' ability to work improved
significantly faster in the carbamazepine
group.
Ritola et al,
1981
DB-BD
Male inpatients,
n=68
CMT vs. CBZ:
400 mg D0
800 mg D1-2
600 mg D3-4
400 mg D 5-6
 70% good to excellent results, both groups
 CBZ improvement all areas, except depression
 Less dropouts in CBZ group
Agricola et al,
1982
DBRCT
University Med
Center Substance
Abuse I/P Unit,
n=60
CBZ 600 mg vs. tiapride
600 mg
CIWA-Ar  Both drugs were effective in the treatment of
AWS
• No significant difference was found between
the two treatments with respect to total
symptoms, score and visual analogue scale
assessment.
 CBZ gave faster relief of symptoms and
demonstrated a superior response on
symptoms like anxiety, fear and hallucinations.
 No case of delirium tremens was observed in
those patients who completed the trial.
Flyngering et
al, 1984
DBRCT
Male inpatients,
n=72
Barbital (BBT) vs. CBZ:
400-1200 mg D1
200-600 mg D2-6
 No overall difference between groups
 AWS duration shorter ( ∼ 9hrs) in CBZ group
 No difference in drop-out rate

Carbamazepine (CBZ) -2/2
Definition
Outcome
Malcolm et al
1989
DBRCT
VAMC, I/P unit
N=86
OXA 120mg/d vs. CBZ
800mg/d, tapering over 5
days.
CIWA-Ar  No differences between the two groups
Stuppaeck et
al 1992
DBRCT
University Med
Center
Substance Abuse
I/P Unit, n=60
OXA 120 mg (÷) vs. CBZ
800 mg (÷) tapering over
7 days.
CIWA-Ar  No clinical differences between the two groups
 Greater progression to DTs & Sz in oxazepam
group
Malcolm et al
2002
DBRCT
University Med
Center
Substance Abuse
O/P clinic, n=136
LOR 6 – 8 mg (÷) on day
1, tapering to 2 mg vs.
CBZ 600 – 800 mg on
day 1, tapering to 200
mg.
CIWA-Ar  Both drugs were equally efficacious at treating
AWS.
• But CBZ had greater efficacy than lorazepam
in preventing post-treatment relapses to
drinking over the 12 days of follow-up.
• There was a greater reduction in anxiety
symptoms, as measured by the Zung Anxiety
Scale, in the group randomized to CBZ.
Polycarpou et
al 2005
Various,
Cochrane
Review, 48
studies,
N= 3610 subjects
anticonvulsant versus
placebo comparison
CIWA-Ar  For the ACA vs. PBO comparison, therapeutic
success tended to be more common among
the ACA-treated patients (relative risk (RR)
1.32; 95% confidence interval (CI) 0.92 to 1.91)
 ACA tended to show a protective benefit
against seizures (RR 0.57; 95% CI 0.27 to 1.19).
 For the subgroup analysis of CBZ VS BZD;
• a statistically significant protective effect was
found for the anticonvulsant (p = 0.02)
• Side-effects tended to be less common in the
anticonvulsant-group (RR 0.56; 95% CI 0.31 to
1.02).

Alcohol Withdrawal Treatment
Anticonvulsant Agents
• CBZP has been used >25 yrs to treat alcohol withdrawal in Europe
(Malcom et al, J Gen Int Med 2002;17:349-355).
• Cochrane Database Analysis of all randomized controlled trials from
1966 – 2004 comparing efficacy of carbamazepine vs. various
benzodiazepine agents.
• Main results
– 48 studies, involving 3610 subjects were included.
– For the anticonvulsant versus placebo comparison, therapeutic success tended
to be more common among the anticonvulsant-treated patients (relative risk (RR)
1.32; 95% confidence interval (CI) 0.92 to 1.91), and anticonvulsant tended to show
a protective benefit against seizures (RR 0.57; 95% CI 0.27 to 1.19).
– For the anticonvulsant versus other drug comparison, CIWA-Ar score showed
non-significant differences for the anticonvulsants compared to the other drugs at
the end of treatment (weighted mean difference (WMD) -0.73; 95% CI -1.76 to 0.31).
– For the subgroup analysis of carbamazepine versus benzodiazepine, a
statistically significant protective effect was found for the anticonvulsant (WMD -
1.04; 95% CI -1.89 to -0.20), p = 0.02), and side-effects tended to be less common
in the anticonvulsant-group (RR 0.56; 95% CI 0.31 to 1.02).
Polycarpou et al 2005

Valproic Acid (VPA) – 1/2
Definition
Outcome
Lambie et al
1980
Randomized,
single-blind trial
I/P Detox Unit
N=49
VPA 400 mg TID X7 days
vs. PBO
Severity of
Sxs scale;
occurrence of
AWS
There were 5 cases of Sz activity, all in
the control group (none in VPA)
Physical symptoms disappeared slightly
more quickly in the VPA treated group
than in the control group despite the fact
that 22 patients in the control group were
on chlormethiazole compared with only 5
patients in the sodium VPA group.
Rosenthal et al
1998
Open,
randomized trial
I/P Detox Unit
N=42
VPA vs. PHB
Day 1-500 mg PO stat
loading dose, folIowed
by 500 mg po 6 hours
later
Day 2-500 mg PO bid
Day 3-500 mg PO bid
Day 4-250 mg PO bid
Day 5-250 mg PO X1
ASQ This study offers confirmation that VPA
is as effective as PHB in the
management of AWS:
• Subjective and objective ratings of
abstinence symptoms and subjective
mood disturbance decreased
significantly in intensity in both groups
over 5 days
• There were no withdrawal-related
seizures or other acute sequelae.
Myrick et al 2000
Prospective,
randomized,
single-blind trial
I/P Detox Unit
N=11
LOR 2 mg for CIWA-Ar
scores > 6 or VPA 500 mg
TID for 4 days plus LOR
2 mg for CIWA-Ar > 6.
CIWA-Ar The Group-by-CIWA-Ar score interaction
was determined to favor VPA significantly (p
≤ 0.01).
Patients in the VPA group appeared to use
less LOR than those in the control group
over the study period.

Valproic Acid (VPA) – 2/2
Definition
Outcome
Reoux et al
2001
DBPCRCT
I/P Detox Unit
N=36
VPA 500 mg TID x7
days vs. PBO in a
double-blind manner.
Oxazepam used PRN in
both as rescue.
CIWA-Ar Use of VPA resulted in less use of OXA
(p < 0.033).
The progression in severity of withdrawal
symptoms (based on CIWA-Ar) was also
significantly greater in the placebo group
(p < 0.05).
Longo et al
2002
Randomized,
open-label study
I/P Detox Unit
N=16
BZD vs. VPA (5d detox)
vs. VPA (+6wk
maintenance).
Loading dose of 20
mg/kg/day in 2 divided
doses 6-8 hours apart on
day 1, then twice daily
thereafter
CIWA-Ar AWS reduction occurred more rapidly
and consistently in the VPA-treatment
group than the BZD-control group at 12
and 24 hour intervals (based on CIWA-
Ar scores) - not statistically significant.
Although the protocol allowed for the
availability of a “BZD rescue” in the event
of VPA non-response, none of the VPA-
treated patients required prn BZD.
Eyer et al 2011
Restrospective
Chart Review
I/P Detox Unit
N=827
CBZ (200mg TID) vs.
VPA 300mg TID)
CIWA-Ar VPA may offer some benefits compared
with CBZ in the adjunct treatment of
moderate-to-severe AWS:
 shorter need for pharmacological
treatment
 fewer ICU transfers
 a more favorable side-effect profile
Trend that VPA may be more effective
than CBZ in reducing complications
during AWS, especially WS.

Other Anticonvulsant agents
Definition
Outcome
Stuppaeck et al
1996
ROLCT
I/P
Detoxification
unit; n = 10.
Vigabatrin 1mg BID x3
days. Individuals were
studied for a total of 7
days; OXA was allowed
PRN.
CIWA-Ar
 Overall, AWS suppression, as measured by CIWA-Ar appeared efficacious.
 One patient had a Sz on d#3 (even after having received OXA 250mg over 2
previous days).
Myrick et al 2006
Retrospective chart
review
O/P
Detoxification
unit; n = 13.
Tiagabine initiated at 2
mg to 4 mg BID vs. OXA
initiated at 30 mg BID to
QID for the first day of
treatment.
CIWA-Ar
 Both TGB and BZD-treated patients were detoxified without serious side-
effects.
 No patients experienced delirium tremens, seizures, or other complications.
Mariani et al 2006
ROLCT
University Med
Center
Substance Abuse
I/P Unit,
n = 60
Day 1. GAB 1200 mg PO loading
dose, followed in 6hrs with 600 mg
PO, followed in 6hrs with 600 mg
PO (total of 2400 mg in the first 24
hrs)
Day 2. 600 mg PO TID
Day 3. 600 mg PO BID
Day 4. 600 mg PO QD
CIWA-Ar
 There were no significant differences in the proportion of patients in each group
requiring rescue medication for breakthrough signs and symptoms of AW.
 There were no significant treatment differences in withdrawal symptoms or
psychological distress, nor were there serious adverse events.
 These findings suggest that gabapentin may be as effective as PHE in the
treatment of AWS.
Krupitsky et al 2007
placebo-controlled
randomized single-
blinded trial .
I/P Detox Unit
n = 127
Assigned X7days to either:
 Placebo
 Diazepam 10 mg TID
 lamotrigine 25 mg QID
 memantine 10 mg TID
 topiramate 25 mg QID.
Additional DZP rescue.
CIWA-Ar
 All active medications significantly reduced withdrawal severity, dysphoric
mood, and supplementary DZP administration vs. PBO
 The active medications did not differ from diazepam.
 This study provides the first systematic clinical evidence supporting the
efficacy of a number of antiglutamatergic approaches for treating alcohol
withdrawal symptoms.
Myrick et al 2009
DBRCT
I/P Detox Unit
n = 100
Randomized to double-blind
treatment with 2 doses of
GAB (Low dose: 300 mg TID
X3d, then 400mg BID on d#4;
or High Dose: 400mg TID
X3d, then 400 mg BID on
d#4); or LOR (2 mg TID X3d,
then 2 mg BID on d#4); f/u up
to 12 days.
CIWA-Ar  High-dose GAB was statistically superior but clinically similar to LOR (p =
0.009).*
 During treatment, LOR-treated participants had higher probabilities of
drinking compared to GAB-treated participants (p = 0.0002).
 Post-treatment, GAB-treated participants had less probability of drinking
during the follow-up post-treatment period (p = 0.2 for 900 mg) compared to
the LOR-treated participants (p = 0.55). *
 The GAB groups also had less craving, anxiety, and sedation compared to
LOR.

Pohorecky, J Pharm & Exp Ther, 1974
To examine the turnover in NE
neurons, 3H-tyrosine was
injected subcutaneously to rats
which had been receiving
ethanol or sucrose diets; they
were then sacrificed 10, 30, 60.
180 or 360 minutes later.
At all times the labeled NE was
higher in the ethanol group (fig.
1), suggesting that synthesis of
NE was higher in the ethanol-
treated rats. The rate of release
of 3H-NE appears to be also
higher in these animals, since
the accumulation of 3H-
metabolites was also
significantly greater (fig. 2).
Effect of Alcohol in the CNS

α2 Agonists
Centrally acting α2-adrenergic
receptors agonists:
Alpha2
agonist
GUANFACINE
T1/2 = 17 h
hepatic→ renal
CLONIDINE
T1/2=142-33 h
hepatic→renal 50%
DEXMEDETOMIDINE
T1/2=12 h
hepatic→ renal 95%
Drug α2/α1
Selectivity
dT ½ eT ½ Product
Availability
Bioavailability Protein
Binding
Guanfacine 2,640 2.5 h 17 h PO ∼100% 70%
Dexmedetomidine 1,600 6 m 2 h IV 70-80% 94%
Medetomidine 1,200
Clonidine 220 11 m 13 h PO
TDS
100%PO
60%TDS
40%
methyldopa 12 m 105 m PO/IV 50% <20%
Guanabenz 60 m 6 h PO 75% 90%
METHYLDOPA
T1/2 = 105m
GUANABENZ
T1/2 =

GUANFACINE
T1/2 = 17 h
hepatic→ renal
CLONIDINE
T1/2=142-33 h
hepatic→renal 50%
DEXMEDETOMIDINE
T1/2=12 h
METHYLDOPA
T1/2 = 105m
hepatic→ renal
GUANABENZ
T1/2 =
Clinical Effects
• Antihypertensive1,2
• Sedation1,2
• Analgesia1,2
• Decreased shivering3
• Anxiolysis4
• Patient arousability4
• Potentiate effects of opioids,
sedatives, and anesthetics1,2
• Decrease sympathetic activity1,5
Adverse Effects
• Bradycardia6
• Hypotension6
• Dry mouth2
• Vasoconstriction with rapid
infusion or at high doses2
• Nausea2
1. Kamibayashi T, et al. Anesthesiol. 2000;93:1345-1349; 2. Precedex [package insert]. Lake Forest, IL: Hospira Inc; 2004; 3. Doufas AG, et al. Stroke.
2003;34:1218-1223; 4. Riker RR, et al. Pharmacother. 2005;25(5 Pt 2):8S-18S; 5. Venn RA, et al. Brit J Anaesthesia. 2001;87:684-690; 6. Shehabi Y, et al.
Intensive Care Med. 2004;30:2188-2196.

Alpha-2 Agonists -1/3
Definition
Outcome
Bjorkqvist,
1975
DBRPCT
I/P Detox Unit
N=60
Fixed titration of PO-
clonidine (over 4d)
vs. placebo.
Nurses
eval
Self-report
Self-rated and nurse observer–rated
symptoms of alcohol withdrawal were
significantly reduced with clonidine as
compared to placebo on day 2 of treatment (p
< 0.025 and p < 0.01, respectively), with no
hypotension.*
Patients in the CLO group did better in every
index measured: the movements and tremor
improved faster; systolic blood pressure; need
for additional medication .
Walinder et
al, 1981
ROL
I/P Detox Unit
N=19
clonidine vs. fixed
carbamazepine dose
(200 mg TID) X4
days.
Comprehensive
Psychopathologi
cal
Rating Scale
(CPRS)
The results of this open study show that CLO
treatment seems to be at least as effective
as CBZP in suppression and management of
the AWS.
Wilkins et al,
1983
randomized,
cross-over
double blind
fashion
I/P Detox Unit
N=11
randomized, cross-over
double blind fashion
CLO vs. PBO
Autonomic
reactivity
Clonidine significantly suppressed
heart rate (P = 0.002), arterial blood
pressure (P = 0.006), and an
accumulated score of withdrawal
symptoms and signs (P = 0.004).

Definition
Outcome
Manhem et al,
1985
DBRCT
I/P Detox Unit
N=20
clonidine (0.15 – 0.3 mg
QID) vs. chlormethiazole
(500-1000mg QID) X4
days.
AWAS
Autonomic
reactivity
During treatment, BP & HR were significantly
lower following clonidine (CLO) compared
with CMT (p < 0.05 for both).
CLO treatment reduced physical AWAS
symptoms more effectively than CMT.
Plasma norepinephrine and epinephrine levels were
significantly lower in patients treated with clonidine
starting on day 1 of treatment (p < 0.01).
No specific adverse effects with clonidine, including
seizures, were reported, although 1 patient in each
group developed alcohol withdrawal delirium.
Baumgartner
& Rowen
1987
DBRPCT
I/P Detox Unit
N=61
Fixed titration of
chlordiazepoxide (50-150
mg/d, over 4d) vs.
transdermal CLO (0.2-
0.6 mg/d).
AWAS
CLO mean AWAS score was significantly
lower than CDP group (p<0.02)*.
Mean systolic BP were significantly lower in
CLO group (p<0.01).
Mean HR was significantly lower in CLO group
(p<0.001).
No patient in either group developed seizures or
progressed to delirium tremens.
Baumgartner
& Rowen
1991
DBRPCT
I/P Detox Unit
N=50
Fixed titration of
chlordiazepoxide (over 4d)
vs. transdermal CLO (0.2-
mg oral loading dose + 0.2
mg/24-hour transdermal
patches X2 on day 1).
AWAS
There was no significant difference in patient-
reported subjective symptoms of alcohol
withdrawal.
Mean systolic and diastolic blood pressure and
pulse were significantly lower for patients in the
CLO group (p < 0.001 for all).
CLO group had a better response to therapy
as assessed by the AWAS, less anxiety as
assessed by the Ham-A Rating Scale (p <
0.02), better control of heart rate and blood
pressure; better cognitive recovery.
No Sz or DTs in either group.

Definition
Outcome
Adinoff 1994
DBRPCT
I/P Detox Unit
N=25
DZP (10mg) vs. APZ
(1mg) vs. CLO (0.1 mg)
vs. PBO – all given q 1
hr until AWS ratings
dropped to <5.
CIWA-Ar
Autonomic
reactivity
APZ was significantly more efficacious than
both clonidine and placebo in decreasing
withdrawal symptoms; but did not
significantly decrease blood pressure
compared with DZP or PBO.
DZP was more effective than clonidine and
placebo on some measures of withdrawal.
CLO decreased systolic blood pressure
significantly more than the other two active
drugs and placebo, but was no more effective
than placebo in decreasing other symptoms of
withdrawal.
Dobrydnjov et al
2004
DBRCT
Surgical patients,
n=45
Diazepam vs Clonidine given
pre-op to subjects undergoing
transurethral
resection of the prostate
under spinal anesthesia
CIWA-Ar
Autonomic
reactivity
Median CIWA-Ar score: 12 vs 1 (p<0.001)
Development of AWS: 80% vs 10% (p<0.002)
• Anxiety: 67% vs 0% (p<0.001)
• Agitation: 40% vs 0% (p<0.05)
• Progression to DTs: 27% vs 7%
VS: hyperdynamic circulatory reaction
observed in D group; slightly decreased mean
arterial BP in Clo.
Khan et al 2008
Case control study
N=35 CLO Predictors associated with increased mortality by
univariate analysis: hyperthermia in the first 24
hours of DT diagnosis, persistent tachycardia, and
use of restraints
Predictors associated with decreased mortality: an
emergency department (ED) diagnosis of DT, and
use of clonidine.

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Alcohol Withdrawal Syndromes
Tremors, irritability & insomnia
Major Withdrawal (DT’s)
Minor Withdrawal
Hallucinosis
Seizures
confusion
Days
S
y
m
p
t
o
m
I
n
t
e
n
s
i
t
y
Maldonado et al, 2009

Phase I
Validation of Prediction Scale
Phase II
Head-to-Head Comparison of
Benzo vs. Non-Benzo Protocol
HIGH RISK
Perform
AWS or CIWA
Withdrawal
Prophylaxis
Protocols
Withdrawal
Treatment
Protocols
PROTOCOL A
BZDP-Sparing
Prophylaxis
Protocol
PROTOCOL B
Lorazepam Fixed
Prophylaxis
Protocol
PROTOCOL C
BZDP-Sparing
Treatment Protocol
PROTOCOL D
Lorazepam Sx- Triggered
Treatment Protocol
PAWSS
(Prediction of Alcohol Withdrawal Severity Scale)
Maldonado 2011
≥ 4
AWSS ≤ 5
CIWA ≤ 15
AWSS ≥ 6
CIWA ≥ 16
Alcohol use within the last 30 days; or
“+” Blood Alcohol Level (BAL)?
BZDP-Sparing Alcohol Withdrawal Prophylaxis & Treatment Protocol
Jose Maldonado, MD 2012
YES
Surveillance Mode
Repeat assessment scale
q 4 hrs
Either
Symptoms progression:
assessed by clinical picture &
worsening AWSS (>6)
Switch to Tx Protocol
Either
Rescue Protocol E
In case of DTs not responding to
conventional Tx consider transfer to ICU
(i.e., AWSS >10)
LOW RISK
No immediate
intervention
needed
< 4
NO
Symptom Progression- worsening AWS
(as assessed by clinical picture &
AWSS > 10; CIWA > 20)

Search terms defined
(see table 1 for
search terms)
Online Search performed on: Cochrane Central Register of
Controlled Trials, PubMed, PsychInfo, & Medline.
Articles dealing with alcohol withdrawal: N = 5753
Articles describing factors predictive of AWS
N = 2802
Unique articles describing factors predictive of AWS
N = 233
(some articles describe more than one factor)
Articles meeting inclusion criteria
N = 446
Development of
Prediction of Alcohol Withdrawal
Assessment Scale
27

PAWSS Prospective Validation Study - Results
Maldonado JR et al. Submitted Data, 2014.

Study #2
PAWSS Prospective Validation Study - Results
Maldonado JR et al. Submitted Data, 2014.

BDZP-Sparing AWS
Management Protocol
I. Assessment:
A. Determine the patient’s risk for AWS – conduct PAWSS
a. PAWSS < 4: low risk, suggest continued monitoring and only
symptomatic management.
b. PAWSS ≥ 4: HIGH risk; prophylaxis management or active
treatment is indicated; based on CIWA score (next).
B. Determine whether the patient is actively withdrawing –
conduct CIWA/AWSS:
a. CIWA < 15 (AWSS < 6): not actively withdrawing; proceed with
prophylaxis, if indicated.
b. CIWA ≥ 15 (AWSS ≥ 6): patient already experiencing active AWS;
proceed to treatment (not prophylaxis).
C. Prophylaxis is suggested in patients who:
i. Are at risk for complicated AWS, but
ii. Are not experiencing active AWS yet.

BDZP-Sparing AWS
Management Protocol
Patient wH/O
ETOH use in the
last 30 days or
“+” BAL
PAWSS
Ptis at LOWrisk forModerate orSevere AWS;
no phophylaxis is deemed necessary may treat
MILD AWS symptomatically Proceed with BZDP-Sparring
Prophylaxis Protocol
CIWA or
AWSS
Ptalready
experiencing AWS,
proceed to Tx Protocol
CIWA≥ 15
AWSS ≥ 6
CIWA< 15
AWSS < 6
PAWSS ≥ 4PAWSS < 4

BDZP-Sparing AWS
Management Protocol
III. Non-Pharmacological Management:
A. Implement early mobilization techniques:
1. Aggressive PT & OT as soon as it is medically safe to do so
a. In bedridden patients – daily passive range of motion.
b. Get the patient up and moving as early as possible.
2. Patients out of bed as much as possible.
3. Provide patients with any required sensory aids (i.e., eyeglasses, hearing aids).
4. Promote as normal a circadian light rhythm as possible.
a. Environmental manipulations
i. light control (i.e., lights on & curtains drawn during the day; off at night)
ii. noise control (i.e., provide ear plugs, turn off TVs, minimize night staff chatter).
b. Provide as much natural light as possible during the daytime.
5. If possible, provide the patient with at least a 6-hrs period of protected
nighttime sleep (i.e., no blood draws, tests and medication administrations
unless absolutely necessary).
B. Provide adequate intellectual and environmental stimulation:
1. Encourage visitation by family and friends
2. Minimize television use.

BDZP-Sparing AWS
Management Protocol
IV. Fluid & Nutritional Replacement
A. Correct and monitor fluid balances & electrolytes.
1. Mg+ [1.7 - 2.2 mg/dl]
2. Na+ [135 - 145 mEq/L]
3. K+ [3.7 - 5.2 mEq/L]
B. Vitamin supplementation:
1. Thiamine 100 mg intravenously/intramuscularly/by mouth x 3
to 5 days
2. Folate 1 mg by mouth daily
3. Multivitamin, 1 tab by mouth daily
4. B complex vitamin 2 tabs by mouth daily
5. Vitamin K, 5 – 10 mg subcutaneously x 1 (if international
normalized ratio [INR] is >1.3)

Phase I
Validation of Prediction Scale
Phase II
Head-to-Head Comparison of
Benzo vs. Non-Benzo Protocol

Patient
(age/sex)
BAL Non-benzo regimen BZDP dose in diazepam mg equivalents per day
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6+
62 F 35 Clonidine , Gabapentin 20 5 0 0 0 0
66 F 47 Gaba 10 0 5 0 0 0
44 F 316 Gaba, Zolpidem 0 0 0 0 0 0
37 M 446 Clonidine, VPA, Gaba 35 90 10 0 0 0
46 M 382 Clonidine, Gaba 20 10 10 5 0 0
52 M 181 Clonidine, Gaba 35 25 5 0 0 0
32 M 71.4 Clonidine, VPA 5 35 95 55 10 0
51 M 360 Clonidine, Gaba 40 75 0 0 0 0
47 M 400 Clonidine, Gaba 70 25 0 0 10 0
45 M NA Clonidine, VPA, Gaba,
Haloperidol
100 275 150 10 20 0
49 M NA Clonidine, VPA, Dex,
Haloperidol
110,
Dex gtt
50,
off Dex
20 0 0 0
50 M 335 Clonidine, VPA, Dex 15,
Dex ggt
10,
off Dex
0 0 0 0
50 M 335 Clonidine, Gaba, Dex Off Dex 0 0 0 0 0

José R. Maldonado, M.D., FAPM, FACFE
Associate Professor of Psychiatry, Medicine, Surgery, Emergency Medicine & Law
Stanford University Schools of Medicine & Law
Medical Director, Psychosomatic Medicine Service
Stanford, CA
jrm@stanford.edu
Neurobiology & Treatment of
Alcohol Withdrawal:
Understanding the Neurocircuitry of AWS
& Principles of the BZDP Sparing Protocol

J.J. Rasimas, M.D., Ph.D., F.A.P.M.
Associate Professor, Psychiatry & Emergency Medicine
Penn State College of Medicine & University of Minnesota
HealthPartners / Regions Hospital St. Paul, MN
APM Annual Meeting Workshop
November 13, 2014 Fort Lauderdale, FL

Disclosure: J.J. Rasimas
With respect to the following presentation,
there has been no relevant (direct or
indirect) financial relationship between the
party listed above (and/or spouse/partner/
immediate family members) and any for-
profit company in the past 24 months which
could be considered a conflict of interest.

 Old as time
 Moving target
 We lead and we follow
 Responsibility
◦ Suspicion
◦ Acumen
◦ Formulation
◦ Care
◦ Education

 29 y/o man—substance use history
 Delivered by police after neighbors called
◦ Loud disturbance, pounding on walls
◦ Found shirtless, violent with police
◦ Restrained…H 10 + L 2 + D 25…H 10 again
 T 37.8, P 127, R 18, BP 148/92, O2 sat 96% on RA
◦ Admission vital signs, sedate and hypertonic
◦ Remains restrained, in ICU
 Labs are drawn and pending…
 You’re called 4 hours later when he’s tearing up
the place at midnight

15.7
16 292 14.6 27.3
47.4 1.1
144 106 31 8.6
18 106 2.0
5.1 20 1.8
7.25 44 92 19

 CK 664 U/L
◦ MB 3.1
 Trop 0.11 ng/mL
 AST 39
 ALT 79
 Albumin 3.6
 EKG Sinus tach, normal intervals
 UDAS + THC, BZDs
 Wide eyed, angry
Bolt-up in bed
 No more vitals
HR 156 before leads off
 Will not calm
 Seems oriented to place
But odd thoughts…
Paranoid
Whatcha gonna do???...
What did he take?...

Ecstasy = MDMA
Failed hemostatic and appetite suppressant
Like a highly serotonergic amphetamine
Actually reverses reuptake pumps
Releases NE and DA
Monoamine Syndrome
Particularly dangerous to combine with
antidepressants

 Bath Salts or Plant Food
Slang term for a variety (mixture) of synthetic stimulants
NRG-1, Mephedrone, 2C-E, MDPV, et al.
As a class, the compounds are referred to as cathinones

Cathinones are a group of related
compounds with stimulant properties
Natural cathinone is from the Khat
(Qat, Miraa) plant, indigenous to the
Horn of Africa—Somalia, Ethiopia,
Eritrea, and Djibouti
Bath salts are synthetic cathinones
Most common synthetic cathinone
is 2,4 Methylenedioxypyrovalerone,
then mephedrone and methylone
Catha edulis (Khat)

Artic blasting station Cotton cloud NRG-1
Atomic Dream Q concentrated
Bayou revitalisant Dynamite Red dove
Blaze Euphoria Resin
Blitz Hurricane charlie Scar face
Blue moon Ivory wave Serenity
Blue silk Ivory wave ultra Super stain remover
Bohemian bath salts Kush blitz White cloud
Bolivian bath salts Lady bubbles White diamonds
Dr booga shooga Legal White dove
Cloud 9 Love potion 69 White girls bath salts
Cloud 10 Moon dust White lightening
Columbian odorizer Night cap Zoom
Spiller et al. Clin Tox 2011

2005 - first mentioned in online drug forums
2007 - first seizure of Bath salts in Germany
◦ shipped from China
2008 - first seizure of Bath salts in the US
2010 - widespread use of Bath Salts reported in the US
2011 - sale and possession are banned in many US states
Times News - April 2, 2011

Lipophilic substitution of the side chains of this core
ephedrine structure is associated with varying
degrees of hallucinogenic and stimulatory effect.

 Endogenous phenethylamines are derivatives of
tyrosine
◦ Dopamine
◦ Norepinephrine
 Exogenous phenethylamines
◦ Stimulate DA and noradrenergic receptors
◦ Stimulate catecholamine release
◦ Stimulate serotonin receptors
Psychostimulants Cocaine Ecstasy
Methamphetamine Ephedra
Bath Salts Mescaline

Dopamine NorepinephrinePhenethylamine
Amphetamine Methamphetamine Mephedrone
Ecstasy
MDPV
…and more…

Substituted phenethylamine
Increases concentration of neurotransmitters
5-HT > DA > NE
(4-methylmethcathinone, 4-MMC, or 4 methylephedrone)
Slang - meph, drone, M-Cat, and many others

Kehr et al. British J of Pharm 2011

 Swallowed, snorted, or injected by 20-30 year olds
 Slower acting than coke or meth, but with similar
monoaminergic effects…that last (~4-12 hours).
Tachycardia
Hypertension
Anxiety/Agitation
Psychosis
Clin Tox 2010 and EAPCCT 2010 and NACCT 2010.
Diaphoresis
Mydriasis
Sz/Rhabdo (rare)

 Similar to MDMA, but less enjoyable
Anxiety, panic, palpitations
Preferred mostly for its legality and low cost
 Produce profound dysphoria and paranoia, sometimes with
hallucinosis in susceptible patients
Psychiatric symptoms outlast physiologic toxicity
Carhart-Harris. Drug Alcohol Depend. 2011.
Wood, et al. J Med Toxicol. 2010 and Brandt, et al. Drug Test Anal. 2010

 Intoxication
 Substance induced psychosis
 Delirium
 .
 .
 .
 Substance use disorder
◦ Substance related (unspecified?) depressive disorder
◦ Other Specified Bipolar disorder

 Hypocholinergia
◦ Arousal
◦ Attention
◦ Memory
◦ Language
◦ Task switching
◦ Executive function
 Hyperdopaminergia
◦ Aggression
◦ Desire
◦ Movement
◦ Vigilance
◦ Rapid appraisal
◦ Goal direction

 Higher lipophilicity  longer CNS persistence
◦ Prolonged catecholamine surge
 Cholinergic compensation
◦ Environmental context
◦ Reserve capacity overwhelmed  delirial imbalance
 Added receptor effects
◦ NMDA antagonism mood and
◦ Glutamatergic disruption  cognitive changes
Cortico – Limbic Dis-Synchrony

38 Cases from March 2011 to January 2012
14 transferred from other hospitals
18 with co-ingestants
6 cocaine
5 opioid
4 alcohol
4 cannabis
3 synthetic cannabinoids (unconfirmed)

Sign / Symptom Bath Salts, et al. (38) Bath Salts Only (20)
Delirium/confusion 28 (73%) 12 (60%)
Hypertension 10 (26%) 5 (25%)
Tachycardia 10 (26%) 7 (35%)
Hyperreflexia 8 (21%) 5 (25%)
Paranoia 8 (21%) 3 (15%)
Agitation 7 (18%) 5 (25%)
Hallucinations 6 (15%) 5 (25%)
Akathisia 5 (13%) 1 (5%)
Tremor 3 (8%) 2 (10%)
11/38 patients restrained

Bath Salts, et al. (38) Bath Salts Only (20)
Rhabdomyolysis 18 (47%) 5 (25%)
Renal Injury 11 (29%) 6 (30%)
Metabolic
Acidosis
10 (26%) 2 (10%)
Leukocytosis 7 (18%) 4 (20%)
Increased LFTs 5 (13%) 1 (5%)

Bath Salts, et al. (38) Bath Salt Only (20)
Benzodiazepines 21 (55%) 11 (55%)
Antipsychotics 5 (13%) 2 (10%)
Intravenous Fluids 9 (24%) 5 (25%)
4 to inpatient psychiatry

None at Harrisburg Hospital
Risks
Mixed with opioids: heroin or methadone
Mixed with stimulants cocaine, MDMA, other cathinones via
serotonin syndrome / agitated delirium
Deaths – in addition to co-ingestion
With coronary disease
With anemia
With MVA and multiple blunt force injuries
Dickson J. Anal. Tox. 2010
Lusthof For. Sci. Int. 2011
Murray J. Med. Toxicol. 2012
Maskell J. Anal. Tox. 2011

Substituted phenylethylamine
Monoamine releaser
Serotonin receptor agonist
Triple reuptake inhibitor
NET > DAT > SERT
Naphyrone
(RS)-1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one
(napthylpyrovalerone, O-2482, NRG-1)

 Hallucinations and stimulation almost always involve
enhanced serotonin neurotransmission
 Based on this serotonergic mechanism of designer drugs,
serotonin syndrome could theoretically occur after the
use of any of them
◦ More severe monoaminergic effects from phenethylamines
 Attend to ABCs, vital signs, and mental status
 Diagnosis often established by history and physical
examination alone
 Drug screens, even if positive, confirm use, not toxicity
◦ And don’t come back in time to impact care

 Diazepam 20 mg IV q5minutes
◦ 3 doses
◦ One dose of 40 mg IV  Riker score of 3
 Vital signs stabilized with treatment
◦ First set after initial BZD doses: HR 146 bpm, BP 174/99
◦ Tense UEs, Rigid LEs with Sustained clonus
◦ Lorazepam 6 mg IV q1h PRN x 30 hours
 NSS 4L IV, then 200 ml/hr continuous
 Non-delirious at 40 hours, but “on edge”
◦ Paranoid ideation—robot rats in the walls at home
◦ Took “White Lightening” to “Get sh** done”
 Haloperidol given when neuro exam normalized
Discharged (with much effort) to dual diagnosis facility
Mephedrone + Tox Sendout Assay

 Hallucinogenic / psychostimulant effect alone
◦ Fully alert, oriented, and aware under the influence
◦ Euphoria, dysphoria, and emotional lability
◦ Supportive care, perhaps Rx BZDs …or Antipsychotic
 Psychosis / agitation
◦ Hallmark of more robust central effect
◦ BZDs first and early (targeting the mechanism), then antipsychotic
◦ More antipsychotic if only psychobehavioral symptoms persist
But if there’s more…

 Hyperautonomia / Abnormal Neurologic Exam
◦ Mydriasis, diaphoresis
◦ Ataxia
◦ Hypertension
◦ Tachycardia
◦ Hyper-reflexia / Clonus
◦ Delirium
 BZDs the core of Rx, Adjunctive antipsychotic PRN once
autonomic indices begin to respond
◦ If they do not, phenobarbital…propofol…dexmedetomidine…

Centrally acting α2-adrenergic receptor agonists:
Alpha2
agonist
GUANFACINE
T1/2 = 17 h
hepatic→ renal
CLONIDINE
T1/2=142-33 h
hepatic→renal 50%
DEXMEDETOMIDINE
T1/2=12 h
Drug α2/α1
Selectivity
dT ½ eT ½ Product
Availability
Bioavailability Protein
Binding
Guanfacine 2,640 2.5 h 17 h PO ∼100% 70%
Dexmedetomidine 1,600 6 m 2 h IV 70-80% 94%
Medetomidine 1,200
Clonidine 220 11 m 13 h PO
TDS
100%PO
60%TDS
40%
methyldopa 12 m 105 m PO/IV 50% <20%
Guanabenz 60 m 6 h PO 75% 90%
METHYLDOPA
T1/2 = 105m
GUANABENZ
T1/2 = 6 h

 Addiction treatment models do not yet differ from standard
◦ Psychosocial programs central
◦ Perhaps even greater emphasis on abstinence is required
◦ Similar pharmacologic adjuncts to cocaine Tx ? … and/or antipsychotic
 Persistent Psychosis
◦ Unlike “organic” syndromes, antipsychotic appears effective
◦ Noting the drug mechanisms, atypical antipsychotics have been
recommended – serotonergic as well as dopaminergic
 May help to minimize necessary dose / potency equivalents
 May reduce incidence of treatment emergent side effects
 May be physically protective in case of relapse
◦ Role for antimanic / mood stabilizer therapy ?
Case reports, series,
and clinical wisdom…

 Preserving consciousness while altering mood
and perception is what drugs are all about
◦ Most of the fun stuff has been illegal
◦ So…make your own!...or shop the web!!
 It might not go well if you do
 Clinical suspicion
 Demographics, Time course, Vital signs, Mental status
 Be a student and keep up with trends (always behind…)
 Serotonin and the Monoamines
◦ For this…Benzos are GOOD
◦ Alpha 2 Agonists may be helpful…better?
 Prepare for a complex psychosomatic course
 Collaborate, educate, and expect resistance

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