S Tighe Benzos 2008 02 16 · Clonazepam (Rivotril) (0.5, 2 mg) Lorazepam (Ativan) (0.5, 1, 2 mg) Triazolam* (Halcion) d/c (0.125, 0.25 mg) Long Elimination half-life Diazepam (30

Using Benzodiazepinesin Primary Care

Spencer A. Tighe MD, FRCPC

Saturday, Feb. 16, 2008

OverviewHistorical context Drug informationIndicationsSide effectsAbuse vs. physical dependenceClinical practice pearlsResourcesQ & A

Historical perspective

They were great in the 60’s …but now?

Over the past 40 years … (1)

Prescribed to over 100 million people

Symptom relief (part of many Dx)Mostly for “anxiety” and insomniaInitially compared to TCAs and barbituratesMany anxiety disorders were not considered as “true” diagnoses

Over the past 40 years … (2)

Negative public attitudes in 1980s and 1990s due to …

Over prescription without clear diagnostic guidelines for anxiety disorders

Abuse potential (patients “liked” the feeling on meds)

Risk of physical dependency (tolerance to dose and withdrawal syndrome)

Drug Information

Getting to know the family …

The “chemical” slide … (1)

Classifying benzodiazepines (1)

I Potency (ability to attach to receptor)(small dose with big effect)

Low, Medium and High

II Elimination half-life(cleared fast = >> risk of withdrawal

syndrome and dependency)

Low potency benzos:

Chlordiazepoxide (Librium)(5, 10, 25 mg)

Oxazepam (Serax)(10, 15, 20 mg)

Temazepam (Restoril)(15, 30 mg)

Medium potency benzos

Chlorazepate (Tranxene)(3.5, 7.5, 15 mg)

Diazepam (Valium)(2,5, 10, 15 mg)

Flurazepam (Dalmane)(15, 30 mg)

High potency benzosAlprazolam (Xanax)(0.25, 0.5 mg)

Bromazepam (Lectopam)(1.5, 3, 6 mg)

Clonazepam (Rivotril)(0.5, 2 mg)

Lorazepam (Ativan)(0.5, 1, 2 mg)

Triazolam* (Halcion) d/c(0.125, 0.25 mg)

Long Elimination half-life

Diazepam (30 – 100h)

rapid action++ active metabolites

(incl. temazepam and oxazepam)

slow elimination

Clonazepam (20 - 80 h)

no active metabolites

Long Elimination half-life

Lower chance of withdrawal and dependency

Greater chance of accumulation and “hang over” feeling next day

Short Elimination half-life

Alprazolam (6 – 20h)

Lorazepam (10 – 20h)

(no active metabolites)

Triazolam* (ultra short – 2 – 6 hours)

Short Elimination half-life

Lower risk of accumulation and morning hangover

Greater risk of breakthrough symptoms, rebound symptoms and withdrawal syndrome

Drug Actions …

CNS action at benzo-GABA receptor siteIncreases GABA activity(inhibitory neurotransmitter action in brain)

Hypnotic: induces sleepAnxiolytic: Anticonvulsant:Myorelaxant:Amnestic:

Indications

What can I usethem for?

Approved indications

Mild to moderate anxiety, tension, excitation and agitation (not diagnosis specific)

Generalized Anxiety DisorderAcute and chronic alcohol withdrawalPanic disorder + agoraphobia (Xanax and Tranxene)InsomniaRestless leg syndromeDystonia, muscle spasmsEpilepsyTetanusPreoperative, peri-operative procedures

Plus: (not approved)

Drug induced akathisia, movementsMania (adjunct TX)PsychosisSocial PhobiaPremenstrual Dysphoric DisorderAcute agitation, aggression

Down side

May make some things worse:

Some evidence that early use post-trauma may increase incidence of PTSD

Might make depressive symptoms worse (aside from alprazolam)

Side effects

General concept …

benzo side effects are mostly related to their desired action

(too much of a good thing …)

Not a separate action, such as:carbamazepine on bone arrowTCAs on cardiac conduction

Action = Side effects

Hypnotic/sleep:

Anxiolytic/sedative:

Anticonvulsant:

Myorelaxant:

Amnestic:

Fatigue, drowsiness,

Sedation, visiospatial pbm

w/d seizures, CNS depression

Ataxia, <motor coordination

Memory, cognitive problems

What about cognitive impairment?

Anterograde amnesia might occur (90 minutes after dosing)Cognitive problems might be associated with sedation / decreased attentionChronic use associated with cognitive problems beyond those of the underlying illnessPET / MRI scan research does not show any brain changes due to chronic use

POINT: inform patients of this side effect risk

Abuse vs. dependence

Need to clarify terms …

Benzo abuse…

Benzo abuse is like abuse of any chemical

Remember to take a history of alcohol and other substance abuse(patient and their family)

Substance Abuse

Maladaptive pattern of any substance useClinically significant impairment / distressUse causing 1 + within 12 month period:

Failure to fulfill obligations (work, school, home …)Physically hazardous situation (DUI ..)Recurrent legal problemsContinued used despite psychosocial problems

Not substance dependence

vs Physical dependence

Seen with many medications:(read: SSRIs, SNRIs)

Tolerance (< effect and > amount needed)i.e. need to titrate the dose upward over time

Withdrawal (substance-specific syndrome)Need to slowly decrease / discontinue medication

Does not imply:Lack of efficacy – may still be helpfulPhysical dangerNegative impact on psychosocial functioning

vs Substance Dependence disorder

Maladaptive pattern of substance useClinically significant impairment / distressUse causing 3+ within 12 month period:

Tolerance (< effect and > amount needed)Withdrawal (substance-specific syndrome)> amounts and > time usingContinued desire to use and out of control> time obtaining substanceActivities given up to useStill using while knowing it’s a problem

Withdrawal syndrome

AnxietyIrritabilityInsomniaHyperacusisNauseaPoor concentration

TremourDepersonalizationHyperesthesiaMyoclonisDeliriumSeizures

Clinical Practice Pearls

take home messages …

Think “acute illness” model

Benzos work their best if the symptoms are transient, episodic, and have clear environmental precipitants …

If symptoms are part of a chronic, persistent disorder, first line TXs are usually not benzodiazepines …

Think “like Rx’ing opiates”

Generally well toleratedQuick acting, good symptom control Good for acute symptoms - chronic symptoms need med reviewNot for everyone – abuse potentialSide effects related to excess drug activityWithdrawal syndrome similar to indication

Regular TX monitoring needed

(similar regulation by government)

Think “Is there a better alternative?”

Insomnia:Brief, occasional (e.g. Travel) – 7 – 10 days,Chronic insomnia? – sleep study, consider newer agents first (Imovane, etc. Desyrel)

Generalized Anxiety Disorder:may be an option, even long term

Panic disorder:acute TX with benzo – add SSRI – taper as

Social phobia:Can be effective if used on irregular, context-specific

Simple phobia:Can be helpful for flying, performance, etc.

Think “Red Flags” (1)

The elderlymore metabolites, slower clearance = accumulation = >> side effects>> sedation = fallsMemory / confusion = review meds

Sleep apneaBenzos contraindicated - make this worse

More “Red Flags” (2)

PregnancyAll freely cross placentaT1 teratogenicity possible (>> cleft palate)T3 Fetal Benzodiazepine Syndrome

(floppy, temp. problems and withdrawal syndrome)

Breast feeding7 – 13 % into milkCan cause lethargy and temperature regulation problems

Physical dependencyRegular review of doses – watch for increases (only < 2% do if abuse is not an issue)

Resources

WWWs …

www.benzo.org.uk

www.racgp.org.au/guidelines/benzodiazepines

www.psychiatrist.com

If in doubt …

s.tighe@pqhcs.com

Questions ?