Download Benzodiazepine Abuse

BENZODIAZEPINES
MEL POHL, MD
LAS VEGAS RECOVERY CENTER
Doctors who treat the symptom tend to
give a prescription;
Doctors who treat the patient
are more likely to offer guidance.
J. Apley 1978
“Emerging research suggests that optimum
benzodiazepine therapy consists of judicious,
circumspect, and critically monitored use of
benzodiazepines in terms of target symptoms
and diagnoses”
Rickels et al
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Dasis report
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Dosage Conversion Table for
Benzodiazepines
Benzodiadepines
Dosages (mg)
Half-life*
Alprazolam (Xanax)
1
6-10
Chlordiazepoxide (Librium)
25
5-100+
Clonazepam (Klonopin)
.5
18-50
Clorazepate (Tranxene)
15
30-200
Diazepam (Valium)
10
30-100+
Estazolam (Prosom)
4
20-120
Flurazepam (Dalmane)
30
1-120
Midazolam (Versed)
n/a
Lorazepam (Ativan)
2
10-20
Oxazepam (Serax)
30
3-21
Quazepam (Doral)
30
20-120
Temazepam (Restoril)
30
10-12
Triazolam (Halcion)
1
2-3
Zolpidem (Ambien)
20
2.5
Zaleplon (Sonata)
20
1
Adapted from Giannini AJ. Drugs of abuse. 2d ed. Los Angeles: Practice Management
Information Corp., 1997:121-5.
*Includes metabolites - in hours
new
tetracyclic
Betacarboline
Antagonist
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Shortacting
Imidazopyridine
Triazolo
ring
Cyclopyrrolone
Other sedative-hypnotics
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Barbiturates - pentobarbital,phenobarbital,
secobarbital, butalbital (Fiorinal)
Barb-like: glutethimide, chloral hydrate,
ethhchlorvynol (Placidyl), meprobamate
(carisoprodol/Soma)
Azapirone: buspirone (2-10 mg TID - max 60 mg/d)
-slow onset of action (1-3 wks)
-not abused, no withdrawal
-effective for anxiety disorders-not for acute
-does not block benzo withdrawal
-not sedating, anticonvulsant or mm relaxing
-no resp dep/ cognitive/psychomotor impair
Non-Benzo Hypnotics
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Zolpidem (Ambien) imadozopyridine
Zaleplon (Sonata) pyrazolopyrimidine
Bind to specifically to BZ-1 sites
Both rapid onset (1h-2.5 h) - short action/1/2 life
Decrease sleep latency, increase REM sleep
5-20 mg dose range
Safe in older adults, metab in liver, no active
metabolites
Potentiate ETOH impairment
Both reinforcing, potentially abusable, and
performance-impairing
GHB
Gamma Hydroxybutyrate
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Club drug - “G” “liquid ecstasy
Aqueous solution - variable concentration
Relaxation, disinhibition, euphoria
Rapid onset, short half-life (20 minutes)
Dependence and withdrawal occur
Narrow therapeutic window-side effects:
Dizziness, nausea, emesis, dec resp, coma
 Additive with ETOH and other sed-hypnotics
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Therapeutic Uses
Sedative-hypnotic
Anxiolytic
Panic disorder
Generalized anxiety disorder
Muscle relaxants
Anticonvulsants
Alcohol withdrawal
Premenstrual syndrome
Psychoses
Adjunct in mania of bipolar disorder
Sedative/Hypnotic
Transient - lowest effective dose- time-limited
Insignificant decrease in sleep latency-1 hour
increase in sleep duration -? effect on sleep
architecture ( REM, stages 3 and 4)
Rebound insomnia - worsening of sleep - worse
than before trying benzos.
Daytime drowsiness, dizziness, lightheadedness
Anxiety
benzos good for immediate symptom relief-faster
than SSRI’s for panic.
long-acting, low potency preferred (clonazepam or
chlordiazepoxide)
best used for exacerbations of anxiety-short term vs
continuous use
Adverse Effects
Diminished psychomotor performance
Impaired reaction time
Loss of coordination, decreased attention
Ataxia
Falls
Excessive daytime drowsiness
Confusion
Amnesia
Increase of existing depressed mood
Overdose rarely lethal
Treatment of Overdose
Airway assessment and maintenance
Ventilatory support if necessary
NG suction - activated charcoal
Flumazenil - competitive antagonist
May need to repeat Q30-60 minutes
Can induce withdrawal seizures in dependent
pts.
REINFORCING EFFECTS
Increased with rapid drug effect - eg alprazolam
Subjective effects - high - e.g. diazepam, lorazepam,
triazolam, flunitrazepam, and alprazolam.
Speed of onset of pleasurable effects - eg GHB
Increased reinforcement in those with history of
drug abuse
Tolerance
Time-dependent decrease in effect.
Neurochemical basis unclear
Varying rates for different behavioral effects:
sedative and psychomotor effects
diminish first (e.g. few weeks)
memory and anxiety effects persist
despite chronic use.
Varying rates with different benzos.
If no history of addiction, rarely see dose
escalation or overuse
Cross-tolerance with ETOH and other sed-hyp
Dependence
Negative reinforcement of withdrawal - major
deterrent to discontinuing use.
Difficult to distinguish between wd & rebound
anxiety upon discontinuing drug.
Withdrawal-time-limited (not part of
original anxiety state)
Relapse-reemergence of original anxiety
Rebound - increased anxiety > baseline
Also see insomnia, fatigue, headache, muscle
twitching, tremor, sweating, dizziness, tinnitus
difficulty concentrating, nausea, depression,
abnormal perception of movement, irritability
Dependence/Withdrawal,
cont.
rarely -seizures, delirium, confusion, psychosis.
triggering of depression, mania, OCD.
90% of long-term users (>8mo-1yr) experience
significant withdrawal
insignificant wd if used less than 2 weeks
mild-moderate if used >8 weeks
Slow taper (>30days) with +/- carbamazepine,
valproic acid, trazodone, imipramine.
CBT effective in dc-ing benzos and controlling
panic/anxiety.
Predictors of severe
withdrawal
High-potency-quickly eliminated
(e.g. alprazolam, lorazepam, triazolam)
higher daily dose
more rapid rate of taper (esp last 50%)
diagnosis of panic disorder (not GAD)
high pretaper levels of anxiety and depression
ETOH or other substance dependence/abuse
personality pathology -e.g. neurotic or dependent
Not motivated to discontinue use
Pharmacology
ABSORPTION
tablets > capsules
some rapidly absorbed (e.g. diazepam) -more
reinforcing than oxazepam or temazepam
lorazepam best for IM (cdp precipitates, poorly
absorbed, diazepam absorption unpredictable.
lipophilic - cross blood brain barrier easily
conjugated in liver- form water soluble metabolites
(different metabolism for different benzos)
Pharmacology
Drug Interactions:
additive with other CNS depressants
utilizes cytochrome P450-levels increased by
-SSRI’s - (less with paroxetine/Paxil,
citalopram/Celexa, and sertraline/Zoloft)
-ketoconazole, intraconazole
-antibiotics - erythromycin
-cimetidine, omeprazole
-ritonavir
-grapefruit juice
C-P450 impaired in elderly or liver failure- inc effects
Mechanisms of Action
Benzos bind to sites on GABA-A receptors
 (primary inhibitory neurotransmitter in CNS)
Opens chloride ion channel
20-30% of all synapses in mammalian brain
endogenous benzos exist in human brain/blood
chronic use - changes in gene expression on
GABA-A receptor function
Benzodiazepine Abuse
Two patterns of abuse recreational abuse (nonmedical use
to get high
quasi-therapeutic use - long-term drugtaking inconsistent with accepted medical
Practice - multiple MD’s
467 internet sites to access scheduled Rxwebsites are short-lived -
CASE 1 ERIC C.
Recreational Use
34 yo caucasian male, single-lives in 1/2 way house
Alprazolam 2mg - chews up to 5-10 tabs per dayTolerance developed 4 months ago
Oxycodone 10 mg - up to 20 per day
Clonazepam 1mg - 6-8 per day for 2 weeks
History of ETOH - 1pint/day - DC 3 months ago
Withdrawal - tremors, nausea, vomiting, severe
anxiety, sleeplessness, backaches, anorexia, sweats
Supervised release from prison in ‘02-on probation.
Minimal depression, no SI, no psych Rx.
CASE 2 - Sharon Z.
Quasi-therapeutic Use
68 yo caucasian female, married, working as a
home health aide, husband is verbally abusive
Lorazepam 2mg - 9-10 per day - cut back to 5mg
per day because of confrontation with daughter
Ran out 2 days prior to admit - tried to get from
another MD who encouraged admission
WD - sever anxiety, tremor, diarrhea, neck pain,
sleep disturbance, decreased energy, depression.
No other substances - gambles $100/day if using pills
Attempted inpatient Rx 2 yrs ago, but left AMA
SI but no plan - tried venlafaxine, caused GI distress.
Detoxification
Traditional Taper Method - using benzo
Substitution and taper
Anticonvulsants (possibly decrease electrical
excitation in the limbic system)
Carbamazepine (Tegretol)
Gabapentin (Neurontin)
Valproic acid (Depakote)
Substitution and Tapersimple and uncomplicated
Phenobarbital, chlordiazepoxide or clonazepam
Calculate equivalent dose - provide in divided dose
Add prn doses of benzos during 1st week
After dose stabilized, gradually reduce dose - 10%
of starting dose.
Slow last 25% of dose - hold to stabilize
Frequent visits - withdrawal agreement
Tolerance Testing
High or erratic dose, illicit source, polysubstance
or alcohol plus benzo use.
In 24-hour medically monitored setting
200 mg pentobarbital PO Q 2h - hold for
intoxication, slurred speech, ataxia, somnolence.
After 24-48 hrs, calculate 24 hr stabilizing dose
Give stabilizing dose for 24 hrs divided
Switch to phenobarbital (30mg = 100mg
pentobarbital)
Initiate gradual taper
Additional Measures
Carbamazepine - decreased subjective symptoms
200 mg TID
In conjunction with phenobarbital or cdp taper
GI upset, neutropenia, thrombocytopenia, low Na.
Valproic acid - attenuates withdrawal - GABA-ergic
250 mg TID
In conjunction with phenobarbital or cdp taper
Continue for 2-3 wks or more after taper
Need to check LFT’s prior to starting
GI upset, bone marrow supression pancreatitis
Additional Measures, cont
Gabapentin - 200-300 mg TID - edema, fatigue
Tiagapine (Gabitril) - gaba-ergic Propranolol - diminish adrenergic s/s (60-120 mg/d)
Clonidine - not effective
Buspirone - not effective
Trazadone - decreases anxiety-improve sleep - helpful
CBT - improves rate of successful discontinuation
and rate of abstinence from benzos
Taper Method
Slow, gradual decrease in dosage (e.g. .5 mg
Alprazolam every 3-5 days or as slow as .25mg
Every 7-14 days (or 10% of starting dose per wk)
Last doses are hardest to eliminate - (?5% per wk)
Varies from patient to patient
Ambulatory setting - reliable followup
Best with therapeutic-dose benzo dependence
Only benzo dependence (no other drugs/ETOH)
Supportive therapy
Limited Rx - withdrawal agreement
Mel’s Method
Phenobarbital protocol - uses modified CIWA
VS and score Q 2 hrs for first 24-48 hrs.
-Score 4-7 - 15 mg
-Score 8-15 - 30 mg
-Score 16-24 - 45 mg
-Score 25-30 - 60 mg
-Adjust dose upward based on symptom relief
-Anticonvulsant - gabapentin, valproic acid,tiagabine
-Psych eval - SSRI’s, buspirone, quetiapine