Randy Brown



Misuse, abuse and dependence


V.     Introduction

A.     Overview

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

a.      Medical disorders. Examples include:

i.                    Muscular spasm in cerebral palsy, paraplegia

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

iii.                Convulsive disorders (epilepsy)

iv.                 Sedation prior to endoscopy/minor surgery

b.      Psychiatric disorders. Examples include:

i.                    Anxiety disorders and Sx

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

i.        Palpitations

ii.      Sweating

iii.    Trembling

iv.     Shortness of breath

v.       Chest pain

vi.     Nausea/abdominal distress

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

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

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

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

b.      Certain situations ↑ risk à we can reduce risk:benefit

i.                    Prescribing practice/med characteristics

a.      Specific BZD prescribed (pharmacology important here)

b.      Dose

c.      Duration

ii.                  Patient characteristics. For example

a.      Age

b.      Co-morbid illness

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

VI.   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?

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

A.     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:

1.      Sedative/hypnotics

·        Flurazepam (Dalmane)

·        Temazepam (Restoril)

·        Triazolam (Halcion)        

2.      Anxiolytics

·        Alprazolam (Xanax)

·        Chlordiazepoxide (Librium)

·        Clonazepam (Klonopin)

·        Diazepam (Valium)        

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

V.     [Slide 4] Adverse effects

A.     Motor impairment

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

a.      Recovers with gradual discontinuation 14, 16, 17

b.      Studies

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

ii.                  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.

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

iii.                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.

iv.                 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.

c.      Increased risk

i.                    Older (> 65)

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

b.      ↓ risk if higher functional status. 17, 23

ii.                  2 + BZDs 24 or concomitant alcohol use 25, 26

d.      Motor impairment w/ BZRAs < BZDs27, 28

B.     Cognitive impairment

1.      Anterograde amnesia = impaired recall of new information 29-33

a.      Useful for medical procedures (no recall for discomfort)

b.      Same as alcoholic “blackout”

2.      Sedation/drowsiness 13, 32, 34-40

a.      Impairs work

b.      Increases accidents

c.      Respiratory depression rare unless combined with other drugs41

d.      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.

3.      Impaired visual-spatial ability 42, 43

4.      Cognitive impairment w/BZRAs

a.      Zolpidem = similar to BZDs44-46

b.      Zopiclone < BZDs27, 28 

5.      Increased risk (cognitive impairment)

a.      Patient characteristics

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

c.      Alcohol use26

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

6.      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.”

VI.   [Slide 5] Misuse, abuse, and dependence

A.     Misuse

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

2.      Long-term use = 2+ weeks

a.      Some say is not problematic 48, 49

i.                    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.

ii.                  Most patients decrease (not increase) their dose over time52

b.      Controversial due to

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

ii.                  Tolerance is likely

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

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

3.      Non-medical use (to get high)

a.      Prevalence/incidence

i.                    > 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

ii.                  Highest among age 25-4457, 62

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

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

B.     Abuse 1

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

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

b.      Recurrent use in hazardous situations

c.      Recurrent legal consequences

a.      Continued use despite recurrent/persistent interpersonal problems

b.      Not dependence

2.      Prevalence/incidence

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

b.      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.

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

C.    Dependence

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

a.      Tolerance

i.                    Larger amounts to achieve desired fx

ii.                  Lesser fx with same amount

b.      Withdrawal

i.                    Characteristic withdrawal syndrome (stay tuned)

ii.                  Use to relieve or prevent withdrawal

c.      Consumed larger amounts/longer periods than intended

d.      Persistent desire/multiple failed attempts to quit or cut back

e.      Much time obtaining, using, or recovering from effects

f.        Other important activities sacrificed

g.      Use continues despite knowledge of adverse effects

2.      (Note to speaker: Mouse click à 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

a.      Definition physical dependence

i.                    physiologic adaptation to substance;

ii.                  emergence of withdrawal during abstinence

iii.                withdrawal relieved by readministration of the substance

b.      Expected effect of chronic administration of a psychoactive medication

3.      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)

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

b.      10-15% of past-year users57

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

VII.  [Slide 6] Medication characteristics/prescribing practices

1.       Lipid solubility affects CNS penetration & onset of subjective effects.

a.      Categories:

i.                    Low. Examples: clonazepam (Klonopin), oxazepam

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

iii.                High. Examples: diazepam (Valium), clorazepate

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

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

a.      BZD/BZRA half-lives

i.                    Anxiolytics

a.      Oxazepam = 6-20 hrs

b.      Alprazolam = 6-20 hrs

c.      Diazepam = 30-100 hrs

ii.                  Sedative-hypnotics

a.      Triazolam = <6 hrs

b.      Temazepam = 6-20 hrs

iii.                 (Note to speaker: text box appears with mouse click here) ↓ half-life à ↑ abuse potential

b.      Active metabolites affect duration of action

i.                    Example (Note to speaker: arrow appears on slide to represent diazepam à oxazepam)  =  Diazepam à desmethyldiazepam à oxazepam

ii.                  No active metabolites: lorazepam, oxazepam, temazepam

c.       t1/2 varies widely between individuals.  Duration and elimination half-life varies with

i.                    Older than ~65 à slowed metabolism

ii.                  Presence of liver disease à slowed

iii.                Medication interactions

iv.                 Genetics

d.      BZRAs

i.                    Zolpidem (Ambien) = 0.5-3 hrs

ii.                  Zaleplon (Sonata) = 1 hr

iii.                Eszopiclone (Lunesta) = 3.5-6 hrs

VIII.[Slide 7] Patient factors also affect risk

A.     Substance dependence history

1.      Sedative/hypnotics47, 69, 70

2.      Alcoholism 47, 64-66, 71-73

3.      Opioids66, 73-76

4.      Stimulants66, 75

B.     Specific psychiatric diagnoses

1.      Anxiety disorders

a.      Panic 66, 73

b.      Any anxiety disorder = 17-27% lifetime BZD abuse or dependence (vs. 0.3-5% in general population)77-79

2.      Major depression 62, 66, 73, 80

3.      Antisocial personality disorder 1, 66 = pervasive pattern of disregard for/violation of rights of others beginning in childhood or early adolescence

4.      Borderline personality disorder 1, 81 = pervasive pattern of instability of relationships, self-image, and affect. Marked impulsivity. Frantic efforts to avoid real or imagined abandonment.

C.    Social/demographic factors

1.      Unemployment 82, 83

2.      Poor social support: separated, divorced or widowed marital status 62, 66, 84

3.      Low socioeconomic status 62, 66, 82

4.      Female58, 62, 66, 82, 83

IX.    Detection of misuse, abuse, dependence49, 92-94

A.     Considerations during follow-up visit

1.      Did the patient ↑ dose on own?

2.      Did the patient take the medication for additional reason (e.g. euphoria)?

3.      Remember risk factors for misuse, abuse, dependence

4.      Consider speaking with close family (with patient’s permission)

B.     Behavioral indicators

a.      Dose escalation not discussed with doc and no evidence of acutely worsening condition

i.                    Early refills

ii.                  Repeated prescription loss/theft

b.      Functional decline rather than improvement.

i.                    Conflict in relationships

ii.                  Occupational dysfunction

iii.                Neglect of usual daily activities

c.      Focus on obtaining medication rather than managing illness/symptoms

d.      Attends visits for med refills, but fails appointments for consultation/ancillary care

e.      Adverse effects associated with use

i.                    History: falls, motor-vehicle accidents, memory deficits

ii.                  Exam/observation: slurred speech, drowsiness

Transition: “If a patient develops adverse effects, abuse or dependence, how can we take them off of BZDs safely? First I’ll review pathophysiology of withdrawal then discuss particulars of a safe taper.””

X.     [Slide 8] Discontinuing BZDs

A.     Withdrawal

1.      Chronic BZD (or alcohol use) 95, 96

a.      Downregulation of GABAergic inhibitory function

b.      ↑ glutamate/NMDA receptor function

c.      Abrupt discontinuation à unopposed excitatory CNS activity

d.      Classic signs and symptoms of sedative withdrawal

i.                    Less severe/more common: anxiety, agitation, diaphoresis, tachycardia, hypertension

ii.                  Severe/uncommon: hallucinosis, seizures

2.      BZRAs also may à physical dependence/withdrawal

a.      Much more rare than for BZDs97-99

b.      Less dependence/withdrawal than BZDs due to ↑ side effects (nausea, anxiety) with ↑ dose for BZRAs99

c.      Risk even lower for zopiclone.100-103

d.      BZRA withdrawal severity can = BZD (rare seizures)104

B.     Tapering BZDs is way to avoid withdrawal49, 105, 106

1.      Don’t abruptly stop BZDs/BZRAs if taken daily for 2+ weeks

2.      Slow taper

a.      Divide daily dose into BID-QID

b.      Taper 25% every 3-7 days initially

c.      Last half of taper often more difficult

i.                    ↑↑ rebound anxiety and withdrawal symptoms (especially with short-acting agents47, 82, 87)

ii.                  ↓ rate of taper during last half of taper. (e.g. Initial daily dose = 100 mg, ↓ rate of taper when reach 50mg daily.) 105

3.      Appropriate support may improve outcome49, 107

a.      Cognitive behavioral therapy 108

b.      Higher self-rating of social support 84

c.      Weekly physician follow-up

XI.   [Slide 9] Summary

A.     Long-term use of BZDs and similar drugs ↑ risk for:

1.      Side effects

2.      Misuse, abuse, dependence

3.      Withdrawal

B.     Prescribing practices and patient characteristics increase risk

1.      Prescribing

a.      > 2 week duration

b.      Dose outside accepted range

c.      Highly lipid soluble & short half-life agents

2.      Patients

a.      > 65 yo

b.      Substance use (especially BZDs & EtOH) & psychiatric history

c.      Social stressors (unemployment, marital status)

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







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