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 symptomsand diagnoses”

Rickels et al

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Dasis report11/21/03

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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 1Adapted from Giannini AJ. Drugs of abuse. 2d ed. Los Angeles: Practice

Management Information Corp., 1997:121-5.

*Includes metabolites - in hours

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new

Short-acting

Imidazo-pyridine

Triazolo ring

Antagonist

Beta-carbolinetetracyclic

Cyclo-pyrrolone

Other sedative-hypnoticsOther sedative-hypnotics Barbiturates - pentobarbital,phenobarbital,Barbiturates - pentobarbital,phenobarbital, secobarbital, butalbital (Fiorinal)secobarbital, butalbital (Fiorinal) Barb-like: glutethimide, chloral hydrate, Barb-like: glutethimide, chloral hydrate,

ethhchlorvynol (Placidyl), meprobamate ethhchlorvynol (Placidyl), meprobamate (carisoprodol/Soma)(carisoprodol/Soma)

Azapirone: buspirone (2-10 mg TID - max 60 mg/d)Azapirone: buspirone (2-10 mg TID - max 60 mg/d)-slow onset of action (1-3 wks)-slow onset of action (1-3 wks)-not abused, no withdrawal-not abused, no withdrawal-effective for anxiety disorders-not for acute-effective for anxiety disorders-not for acute-does not block benzo withdrawal -does not block benzo withdrawal -not sedating, anticonvulsant or mm relaxing-not sedating, anticonvulsant or mm relaxing-no resp dep/ cognitive/psychomotor impair-no resp dep/ cognitive/psychomotor impair

Non-Benzo HypnoticsNon-Benzo Hypnotics Zolpidem (Ambien) imadozopyridineZolpidem (Ambien) imadozopyridine Zaleplon (Sonata) pyrazolopyrimidineZaleplon (Sonata) pyrazolopyrimidine Bind to specifically to BZ-1 sitesBind to specifically to BZ-1 sites Both rapid onset (1h-2.5 h) - short action/1/2 lifeBoth rapid onset (1h-2.5 h) - short action/1/2 life Decrease sleep latency, increase REM sleepDecrease sleep latency, increase REM sleep 5-20 mg dose range5-20 mg dose range Safe in older adults, metab in liver, no active Safe in older adults, metab in liver, no active

metabolitesmetabolites Potentiate ETOH impairmentPotentiate ETOH impairment Both reinforcing, potentially abusable, and Both reinforcing, potentially abusable, and

performance-impairingperformance-impairing

GHB GHB Gamma HydroxybutyrateGamma Hydroxybutyrate

Club drug - “G” “liquid ecstasyClub drug - “G” “liquid ecstasy Aqueous solution - variable concentrationAqueous solution - variable concentration Relaxation, disinhibition, euphoriaRelaxation, disinhibition, euphoria Rapid onset, short half-life (20 minutes)Rapid onset, short half-life (20 minutes) Dependence and withdrawal occurDependence and withdrawal occur Narrow therapeutic window-side effects:Narrow therapeutic window-side effects:

Dizziness, nausea, emesis, dec resp, comaDizziness, nausea, emesis, dec resp, coma Additive with ETOH and other sed-hypnoticsAdditive with ETOH and other sed-hypnotics

Therapeutic UsesTherapeutic Uses

Sedative-hypnoticAnxiolyticPanic disorderGeneralized anxiety disorderMuscle relaxantsAnticonvulsantsAlcohol withdrawalPremenstrual syndromePsychosesAdjunct in mania of bipolar disorder

Sedative/HypnoticSedative/Hypnotic

Transient - lowest effective dose- time-limitedInsignificant 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

AnxietyAnxietybenzos 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 EffectsAdverse EffectsDiminished psychomotor performanceImpaired reaction timeLoss of coordination, decreased attentionAtaxiaFallsExcessive daytime drowsinessConfusionAmnesiaIncrease of existing depressed moodOverdose rarely lethal

Treatment of OverdoseTreatment of Overdose

Airway assessment and maintenanceVentilatory support if necessaryNG suction - activated charcoalFlumazenil - competitive antagonist

May need to repeat Q30-60 minutesCan induce withdrawal seizures in dependent pts.

REINFORCING EFFECTSREINFORCING EFFECTS

Increased with rapid drug effect - eg alprazolamSubjective effects - high - e.g. diazepam, lorazepam, triazolam, flunitrazepam, and alprazolam.Speed of onset of pleasurable effects - eg GHBIncreased reinforcement in those with history of drug abuse

ToleranceToleranceTime-dependent decrease in effect.Neurochemical basis unclearVarying 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 overuseCross-tolerance with ETOH and other sed-hyp

DependenceDependenceNegative 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 anxietyRebound - 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, Dependence/Withdrawal, cont.cont.

rarely -seizures, delirium, confusion, psychosis.triggering of depression, mania, OCD.90% of long-term users (>8mo-1yr) experience significant withdrawalinsignificant wd if used less than 2 weeksmild-moderate if used >8 weeksSlow taper (>30days) with +/- carbamazepine, valproic acid, trazodone, imipramine.CBT effective in dc-ing benzos and controlling panic/anxiety.

Predictors of severe Predictors of severe withdrawalwithdrawal

High-potency-quickly eliminated (e.g. alprazolam, lorazepam, triazolam)higher daily dosemore rapid rate of taper (esp last 50%)diagnosis of panic disorder (not GAD)high pretaper levels of anxiety and depressionETOH or other substance dependence/abusepersonality pathology -e.g. neurotic or dependentNot motivated to discontinue use

PharmacologyPharmacology

ABSORPTION tablets > capsulessome rapidly absorbed (e.g. diazepam) -more reinforcing than oxazepam or temazepamlorazepam best for IM (cdp precipitates, poorly absorbed, diazepam absorption unpredictable.lipophilic - cross blood brain barrier easilyconjugated in liver- form water soluble metabolites (different metabolism for different benzos)

PharmacologyPharmacologyDrug Interactions:

additive with other CNS depressantsutilizes 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 ActionMechanisms of ActionBenzos bind to sites on GABA-A receptors (primary inhibitory neurotransmitter in CNS)Opens chloride ion channel20-30% of all synapses in mammalian brainendogenous benzos exist in human brain/bloodchronic use - changes in gene expression on GABA-A receptor function

Benzodiazepine AbuseBenzodiazepine AbuseTwo patterns of abuse -

recreational abuse (nonmedical use to get highquasi-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 -

CASE 1 ERIC C. CASE 1 ERIC C. Recreational Use Recreational Use

34 yo caucasian male, single-lives in 1/2 way houseAlprazolam 2mg - chews up to 5-10 tabs per day-Tolerance developed 4 months agoOxycodone 10 mg - up to 20 per dayClonazepam 1mg - 6-8 per day for 2 weeksHistory of ETOH - 1pint/day - DC 3 months agoWithdrawal - tremors, nausea, vomiting, severe anxiety, sleeplessness, backaches, anorexia, sweatsSupervised release from prison in ‘02-on probation.Minimal depression, no SI, no psych Rx.

CASE 2 - Sharon Z.CASE 2 - Sharon Z.Quasi-therapeutic UseQuasi-therapeutic Use

68 yo caucasian female, married, working as a home health aide, husband is verbally abusiveLorazepam 2mg - 9-10 per day - cut back to 5mg per day because of confrontation with daughterRan out 2 days prior to admit - tried to get from another MD who encouraged admissionWD - sever anxiety, tremor, diarrhea, neck pain, sleep disturbance, decreased energy, depression.No other substances - gambles $100/day if using pillsAttempted inpatient Rx 2 yrs ago, but left AMASI but no plan - tried venlafaxine, caused GI distress.

DetoxificationDetoxification

Traditional Taper Method - using benzoSubstitution and taperAnticonvulsants (possibly decrease electrical excitation in the limbic system)

Carbamazepine (Tegretol)Gabapentin (Neurontin)Valproic acid (Depakote)

Substitution and Taper-Substitution and Taper-simple and simple and

uncomplicateduncomplicated

Phenobarbital, chlordiazepoxide or clonazepamCalculate equivalent dose - provide in divided doseAdd prn doses of benzos during 1st weekAfter dose stabilized, gradually reduce dose - 10%of starting dose.Slow last 25% of dose - hold to stabilizeFrequent visits - withdrawal agreement

Tolerance TestingTolerance Testing

High or erratic dose, illicit source, polysubstance or alcohol plus benzo use.In 24-hour medically monitored setting200 mg pentobarbital PO Q 2h - hold for intoxication, slurred speech, ataxia, somnolence.After 24-48 hrs, calculate 24 hr stabilizing doseGive stabilizing dose for 24 hrs dividedSwitch to phenobarbital (30mg = 100mg pentobarbital)Initiate gradual taper

Additional MeasuresAdditional Measures Carbamazepine - decreased subjective symptoms200 mg TIDIn conjunction with phenobarbital or cdp taperGI upset, neutropenia, thrombocytopenia, low Na.Valproic acid - attenuates withdrawal - GABA-ergic250 mg TIDIn conjunction with phenobarbital or cdp taperContinue for 2-3 wks or more after taperNeed to check LFT’s prior to startingGI upset, bone marrow supression pancreatitis

Additional Measures, Additional Measures, contcont

Gabapentin - 200-300 mg TID - edema, fatigueTiagapine (Gabitril) - gaba-ergic - Propranolol - diminish adrenergic s/s (60-120 mg/d)Clonidine - not effectiveBuspirone - not effectiveTrazadone - decreases anxiety-improve sleep - helpfulCBT - improves rate of successful discontinuation and rate of abstinence from benzos

Taper MethodTaper MethodSlow, 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 patientAmbulatory setting - reliable followupBest with therapeutic-dose benzo dependenceOnly benzo dependence (no other drugs/ETOH)Supportive therapyLimited Rx - withdrawal agreement

Mel’s MethodMel’s Method

Phenobarbital protocol - uses modified CIWAVS 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