BENZODIAZEPINES

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BENZODIAZEPINES MEL POHL,
MD LAS VEGAS RECOVERY CENTER
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Doctors who treat the symptom tend to give a
prescription Doctors who treat the patient are
more likely to offer guidance. J. Apley 1978
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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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Secondary Substances for Primary Benzo Admissions
Dasis report 11/21/03
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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., 1997121-5. Includ
es metabolites - in hours
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new
Beta- carboline
tetracyclic
Antagonist
Triazolo ring
Short- acting
Cyclo- pyrrolone
Imidazo- pyridine
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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

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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

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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

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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

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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

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Anxiety

• benzos good for immediate symptom relief-faster
• than SSRIs for panic.
• long-acting, low potency preferred (clonazepam or
  
• chlordiazepoxide)
• best used for exacerbations of anxiety-short term
  vs
• continuous use

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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

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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.

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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

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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

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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 gt baseline
• Also see insomnia, fatigue, headache, muscle
• twitching, tremor, sweating, dizziness,
  tinnitus
• difficulty concentrating, nausea, depression,
  
• abnormal perception of movement, irritability

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Dependence/Withdrawal, cont.

• rarely -seizures, delirium, confusion, psychosis.
• triggering of depression, mania, OCD.
• 90 of long-term users (gt8mo-1yr) experience
• significant withdrawal
• insignificant wd if used less than 2 weeks
• mild-moderate if used gt8 weeks
• Slow taper (gt30days) with /- carbamazepine,
• valproic acid, trazodone, imipramine.
• CBT effective in dc-ing benzos and controlling
• panic/anxiety.

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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

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Pharmacology

• ABSORPTION
• tablets gt 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)

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Pharmacology

• Drug Interactions
• additive with other CNS depressants
• utilizes cytochrome P450-levels increased by
• -SSRIs - (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

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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

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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 MDs
• 467 internet sites to access scheduled Rx-
• websites are short-lived -

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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.

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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.

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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)

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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

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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

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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 LFTs prior to starting
• GI upset, bone marrow supression pancreatitis

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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

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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

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Mels 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 - SSRIs, buspirone, quetiapine