BENZODIAZEPINES:



Randy Brown

3/16/06

[Slide 1] BENZODIAZEPINES AND SIMILAR DRUGS

Misuse, abuse and dependence

Introduction

Overview

Benzodiazepines (BZDs) = CNS depressants; useful for many disorders

Medical disorders. Examples include:

Muscular spasm in cerebral palsy, paraplegia

Involuntary movements e.g. myoclonus (twitching or spasm of muscle or group of muscles), restless leg syndrome

Convulsive disorders (epilepsy)

Sedation prior to endoscopy/minor surgery

Psychiatric disorders. Examples include:

Anxiety disorders and Sx

E.g. panic attacks1 = discrete period of intense fear in absence of real danger + ≥ 4/13 somatic or cognitive sx. Examples:

Palpitations

Sweating

Trembling

Shortness of breath

Chest pain

Nausea/abdominal distress

Anxiety/sleep disturbance due to stresses; work shift change; jet lag

(Note to speaker: mouse click ⋄ text box “BUT. . .”

[Slide 2] Key Points However, BZDs can cause problems

Long-term BZD use (> 2 weeks) risky: adverse effects, misuse, abuse and dependence.

Certain situations ↑ risk ⋄ we can reduce risk:benefit

Prescribing practice/med characteristics

Specific BZD prescribed (pharmacology important here)

Dose

Duration

Patient characteristics. For example

Age

Co-morbid illness

Long-term use (> 2 weeks) ⋄ physiologic adaptation to BZDs ⋄ withdrawal syndrome with abrupt discontinuation or drastic dose reduction. So, taper BZDs = slow (generally 4-20 weeks).

Patient Ken = 30 yo healthy male with ~1 year c/o persistent anxious feelings, difficulty concentrating, difficulty sleeping. Prior relief with diazepam from a friend’s supply. Requests daily diazepam. At first, we may want to help and provide the diazepam. Is this really in patient’s best interests?

[Slide 3] What are BZs (and related agents)?

Benzodiazepines (BZDs) = Central nervous system depressants acting via GABA receptor. Often used as sedative/hypnotic (sleep-inducing agent) or anxiolytic (anxiety-relieving agent). 2-4 Common examples:

Sedative/hypnotics

Flurazepam (Dalmane)

Temazepam (Restoril)

Triazolam (Halcion)        

Anxiolytics

Alprazolam (Xanax)

Chlordiazepoxide (Librium)

Clonazepam (Klonopin)

Diazepam (Valium)        

Non-BZD benzodiazepine receptor agonists (BZRAs) = Also = CNS depressants acting at the GABA receptor. Used primarily for sedative/hypnotic effects. Selectivity ⋄ less anxioltic

Zaleplon (Sonata)

Zolpidem (Ambien)

Eszopiclone (Lunesta)

Though these medications are useful in certain clinical settings over the short term, there are risks with long-term prescribing to keep in mind

[Slide 4] Adverse effects

Motor impairment

Impaired motor skills (e.g. slowed response time, ↓ driving skills) 14-18

Recovers with gradual discontinuation 14, 16, 17

Studies

Barbone et al, Dundee UK. 19k + vehicle accidents over 3 years reviewed. Dose-relationship with BZD Rx and accident involvement.

Rickels K et al. Penn. 96 patients on BZD x mean 8 yrs were tapered. ↓ reaction time on test battery at 5 wks and 12 weeks after taper.

Rickels K et al. 3 years after taper, ↓ anxiety Sx

Curran et al, London. 139 subjects > 65 yo on long-term BZDs. 104 withdrawn, 35 continued. Withdrawers ↑ cognitive and psychomotor function at 24 and 52 weeks.

Gray et al, Seattle. 885 women > 65 followed for 4 years. Measures: standing balance, walking speed, and chair raises. Those on BZDs experienced greater degrees of functional decline. Dose and Rx duration-related, when baseline performance and illness indicators controlled.

Increased risk

Older (> 65)

↑ falls and hip/femur fractures 14-16, 19-22.

↓ risk if higher functional status. 17, 23

2 + BZDs 24 or concomitant alcohol use 25, 26

Motor impairment w/ BZRAs < BZDs27, 28

Cognitive impairment

Anterograde amnesia = impaired recall of new information 29-33

Useful for medical procedures (no recall for discomfort)

Same as alcoholic “blackout”

Sedation/drowsiness 13, 32, 34-40

Impairs work

Increases accidents

Respiratory depression rare unless combined with other drugs41

Studies: Rickels et al, 2000, Penn. Randomized 310 Ss to diazepam, placebo, or other med. Significant drowsiness and fatigue reported for diazepam even at 6 week f/u.

Impaired visual-spatial ability 42, 43

Cognitive impairment w/BZRAs

Zolpidem = similar to BZDs44-46

Zopiclone < BZDs27, 28 

Increased risk (cognitive impairment)

Patient characteristics

> age 65 generally at  increased risk20, 47, but higher function/ better physical health decrease risk23

Alcohol use26

Prescribing patterns: Faster-acting, more highly lipid soluble agents ⋄ greater risk of sedation35-39

Treatment = discontinue BZDs/BZRAs slowly (more later)

Transition: “Another set of problems to keep in mind are use disorders, since BZDs and BZRAs are potentially habit-forming.”

[Slide 5] Misuse, abuse, and dependence

Misuse

“Misuse” ≠ formal diagnostic category; used to describe use outside recommended practice (not abuse/dependence)

Long-term use = 2+ weeks

Some say is not problematic 48, 49

Most patients take less than prescribed 50, 51

Romach et al. Toronto. Conducted 3 surveys 1 year apart of 312 regular alprazolam users. No reported dose escalation. 75% reported ongoing symptom relief. BUT most had attempted to DC on their own & experienced withdrawal Sx. Most physicians had not discussed discontinuation.

Most patients decrease (not increase) their dose over time52

Controversial due to

Risks of side effects (e.g. cognitive/motor impairment)

Tolerance is likely

Loss of effects (sedative/hypnotic) +/- dose escalation

Prevalence/incidence (long-term use) = 2% of individuals who have ever used (APA Task Force)53-56

Non-medical use (to get high)

Prevalence/incidence

> age 12: 2-12% ever, 0.3% in last year, 0.1-0.2% used in last month (National Survey on Drug Use and Health, Monitoring the Future)56-61

Highest among age 25-4457, 62

25-50% of alcoholics have used BZDs non-medically63-65

Includes individuals not prescribed BZDs, but borrowed from friends/family 66

Abuse 1

Diagnostic criteria: >= one of the following in 12 month period

Failure to fulfill major obligations (work, school, home)

Recurrent use in hazardous situations

Recurrent legal consequences

Continued use despite recurrent/persistent interpersonal problems

Not dependence

Prevalence/incidence

Unknown, mixed with dependence in most large surveys57, 58, 67

Estimated lifetime prevalence of 0.4%66: Schuckit et al. San Diego. 2002. Part of Collaborative Study on the Genetics of Alcoholism. 9330 subjects in overall sample. 34 had sed-hyp abuse (mainly BZDs). ↑ risk with younger age, unemployed, separated/divorced, cannabis, cocaine, alcohol use disorder.

Risk factors similar to those for misuse (non-medical use) or dependence 66, 68

Dependence

Diagnostic criteria:1 3+ in 12 month period, repetetively:

Tolerance

Larger amounts to achieve desired fx

Lesser fx with same amount

Withdrawal

Characteristic withdrawal syndrome (stay tuned)

Use to relieve or prevent withdrawal

Consumed larger amounts/longer periods than intended

Persistent desire/multiple failed attempts to quit or cut back

Much time obtaining, using, or recovering from effects

Other important activities sacrificed

Use continues despite knowledge of adverse effects

(Note to speaker: Mouse click ⋄ highlighting of “tolerance” and “withdrawal”, emphasizing that physical dependence is only part of substance dependence.) Distinction from physical dependence: Physical dependence only part of substance dependence 5

Definition physical dependence

physiologic adaptation to substance;

emergence of withdrawal during abstinence

withdrawal relieved by readministration of the substance

Expected effect of chronic administration of a psychoactive medication

Prevalence/incidence of BZD dependence (National Survey on Drug Use and Health,57 National Comorbidity Survey,58, 59, Epidemiologic Catchment Area Study,67 Drug Abuse Warning Network)

0.3-5% lifetime risk general population (sedative/hypnotic dependence, mainly BZDs) 57-59, 66, 67

10-15% of past-year users57

What can we as care providers do to minimize the risk of these agents for our patients?

[Slide 6] Medication characteristics/prescribing practices

 Lipid solubility affects CNS penetration & onset of subjective effects.

Categories:

Low. Examples: clonazepam (Klonopin), oxazepam

Intermediate. Examples: lorazepam (Ativan), alprazolam (Xanax)

High. Examples: diazepam (Valium), clorazepate

(Note to speaker: mouse click ⋄ following text:) ↑ lipid solubility ⋄ ↑ abuse/dependence

[Slide 12] Metabolism affects duration of action (half-life)2, 3, 5, 13

BZD/BZRA half-lives

Anxiolytics

Oxazepam = 6-20 hrs

Alprazolam = 6-20 hrs

Diazepam = 30-100 hrs

Sedative-hypnotics

Triazolam = 2 week duration

Dose outside accepted range

Highly lipid soluble & short half-life agents

Patients

> 65 yo

Substance use (especially BZDs & EtOH) & psychiatric history

Social stressors (unemployment, marital status)

If taken daily for >2 weeks, taper slowly & ↓ rate during last ½ of taper

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