1. LAS VEGAS RECOVERY CENTER
BENZODIAZEPINES
MEL POHL, MD
LAS VEGAS RECOVERY CENTER

2. Doctors who treat the symptom tend to
give a prescription;
Doctors who treat the patient
are more likely to offer guidance.
J. Apley 1978

3. “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

7. Secondary Substances for Primary Benzo Admissions
Dasis report
11/21/03

9. Dosage Conversion Table for Benzodiazepines
Benzodiadepines Dosages (mg) Half-life*
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Clorazepate (Tranxene)
Diazepam (Valium)
Estazolam (Prosom)
Flurazepam (Dalmane)
Midazolam (Versed) n/a
Lorazepam (Ativan)
Oxazepam (Serax)
Quazepam (Doral)
Temazepam (Restoril)
Triazolam (Halcion)
Zolpidem (Ambien)
Zaleplon (Sonata)
Adapted from Giannini AJ. Drugs of abuse. 2d ed. Los Angeles: Practice Management Information Corp., 1997:121-5.
*Includes metabolites - in hours

10. new
Beta-
carboline
tetracyclic
Antagonist
Triazolo
ring
Short-
acting
Cyclo-
pyrrolone
Imidazo-
pyridine

11. Other sedative-hypnotics
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

12. Non-Benzo Hypnotics 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

13. GHB Gamma Hydroxybutyrate
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

14. Therapeutic Uses Sedative-hypnotic Anxiolytic Panic disorder
Generalized anxiety disorder
Muscle relaxants
Anticonvulsants
Alcohol withdrawal
Premenstrual syndrome
Psychoses
Adjunct in mania of bipolar disorder

15. 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

16. 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

17. 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

18. 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.

19. 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

20. 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

21. 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

22. 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.

23. 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

24. 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)

25. 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

26. 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

27. Benzodiazepine Abuse Two patterns of abuse -
recreational abuse (nonmedical use
to get high
quasi-therapeutic use - long-term drug-
taking inconsistent with accepted medical
Practice - multiple MD’s
467 internet sites to access scheduled Rx-
websites are short-lived -

28. 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 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.

29. CASE 2 - Sharon Z. Quasi-therapeutic Use
68 yo caucasian female, married, working as a
home health aide, husband is verbally abusive
Lorazepam 2mg 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.

30. 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)

31. Substitution and Taper- simple 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

32. 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 hrs, calculate 24 hr stabilizing dose
Give stabilizing dose for 24 hrs divided
Switch to phenobarbital (30mg = 100mg
pentobarbital)
Initiate gradual taper

33. 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
Continue for 2-3 wks or more after taper
Need to check LFT’s prior to starting
GI upset, bone marrow supression pancreatitis

34. Additional Measures, cont
Gabapentin mg TID - edema, fatigue
Tiagapine (Gabitril) - gaba-ergic -
Propranolol - diminish adrenergic s/s ( 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

35. 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

36. Mel’s Method Phenobarbital protocol - uses modified CIWA
VS and score Q 2 hrs for first hrs.
-Score mg
-Score mg
-Score mg
-Score mg
-Adjust dose upward based on symptom relief
-Anticonvulsant - gabapentin, valproic acid,tiagabine
-Psych eval - SSRI’s, buspirone, quetiapine