I.Randy Brown
3/16/06
II.[Slide 1] BENZODIAZEPINES AND SIMILAR DRUGS
III.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 = <6 hrs
Temazepam = 6-20 hrs
(Note to speaker: text box appears with mouse click here) ↓ half-life ↑ abuse potential
Active metabolites affect duration of action
Example (Note to speaker: arrow appears on slide to represent diazepam oxazepam)=Diazepam desmethyldiazepam oxazepam
No active metabolites: lorazepam, oxazepam, temazepam
t1/2 varies widely between individuals. Duration and elimination half-life varies with
Older than ~65 slowed metabolism
Presence of liver disease slowed
Medication interactions
Genetics
BZRAs
Zolpidem (Ambien) = 0.5-3 hrs
Zaleplon (Sonata) = 1 hr
Eszopiclone (Lunesta) = 3.5-6 hrs
[Slide 7] Patient factors also affect risk
Substance dependence history
Sedative/hypnotics47, 69, 70
Alcoholism 47, 64-66, 71-73
Opioids66, 73-76
Stimulants66, 75
Specific psychiatric diagnoses
Anxiety disorders
Panic 66, 73
Any anxiety disorder = 17-27% lifetime BZD abuse or dependence (vs. 0.3-5% in general population)77-79
Major depression 62, 66, 73, 80
Antisocial personality disorder 1, 66 = pervasive pattern of disregard for/violation of rights of others beginning in childhood or early adolescence
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.
Social/demographic factors
Unemployment 82, 83
Poor social support: separated, divorced or widowed marital status 62, 66, 84
Low socioeconomic status 62, 66, 82
Female58, 62, 66, 82, 83
Detection of misuse, abuse, dependence49, 92-94
Considerations during follow-up visit
Did the patient ↑ dose on own?
Did the patient take the medication for additional reason (e.g. euphoria)?
Remember risk factors for misuse, abuse, dependence
Consider speaking with close family (with patient’s permission)
Behavioral indicators
Dose escalation not discussed with doc and no evidence of acutely worsening condition
Early refills
Repeated prescription loss/theft
Functional decline rather than improvement.
Conflict in relationships
Occupational dysfunction
Neglect of usual daily activities
Focus on obtaining medication rather than managing illness/symptoms
Attends visits for med refills, but fails appointments for consultation/ancillary care
Adverse effects associated with use
History: falls, motor-vehicle accidents, memory deficits
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.””
[Slide 8] Discontinuing BZDs
Withdrawal
Chronic BZD (or alcohol use) 95, 96
Downregulation of GABAergic inhibitory function
↑ glutamate/NMDA receptor function
Abrupt discontinuation unopposed excitatory CNS activity
Classic signs and symptoms of sedative withdrawal
Less severe/more common: anxiety, agitation, diaphoresis, tachycardia, hypertension
Severe/uncommon: hallucinosis, seizures
BZRAs also may physical dependence/withdrawal
Much more rare than for BZDs97-99
Less dependence/withdrawal than BZDs due to ↑ side effects (nausea, anxiety) with ↑ dose for BZRAs99
Risk even lower for zopiclone.100-103
BZRA withdrawal severity can = BZD (rare seizures)104
Tapering BZDs is way to avoid withdrawal49, 105, 106
Don’t abruptly stop BZDs/BZRAs if taken daily for 2+ weeks
Slow taper
Divide daily dose into BID-QID
Taper 25% every 3-7 days initially
Last half of taper often more difficult
↑↑ rebound anxiety and withdrawal symptoms (especially with short-acting agents47, 82, 87)
↓ rate of taper during last half of taper. (e.g. Initial daily dose = 100 mg, ↓ rate of taper when reach 50mg daily.) 105
Appropriate support may improve outcome49, 107
Cognitive behavioral therapy 108
Higher self-rating of social support 84
Weekly physician follow-up
[Slide 9] Summary
Long-term use of BZDs and similar drugs ↑ risk for:
Side effects
Misuse, abuse, dependence
Withdrawal
Prescribing practices and patient characteristics increase risk
Prescribing
> 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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