Benzodiazepines:

1

• Unit 2
• Benzodiazepines
• use, dependence, withdrawal and
• doctor shopping
• Developed by
• Dr Adam R Winstock
• MRCP MRCPsych FAChAM

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Prevalence and common use

• Most benzodiazepines (BZD) are prescribed in
  general practice
• 2/3 of prescribing exceeds the recommended
  prescribing limit
• BZD are used as sleeping pills twice as
  frequently as they are used as tranquillizers
• They are the morphia of the new millennia - a
  treatment for every non specific agitation/
  distress
• The legitimacy of the supply does not make a drug
  safe!
• Most common drugs in Australian hospitals
  self-poisoning patients

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How they work
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Metabolism and tolerance

• BIOAVAILABLITY - excellent orally
• METABOLISM - hepatic
• Oxidation diazepam and midazolam
• Glucuronidation lorazepam, oxazepam, temazepam
• Active metabolites may accumulate with increase
  in some effects over weeks
• TOLERANCE neuroadaptive
• Tolerance occurs through uncoupling of linkage
  between GABA-A and benzodiazepine receptor site

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Active metabolites

• Medazepam Chlordiazepoxide

Diazepam
desmethyldiazepam (active)
Oxidation impaired in severe alcoholic liver
disease
Oxazepam
Temazepam
Inactive metabolites
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Therapeutic tolerance escalation of dose needed
to achieve same effect

• Tolerance to the sedative/ depressant effects of
  benzodiazepines is rapid days - few weeks
• Benzodiazepines should not be prescribed for more
  than 2 - 4 weeks
• Tolerance to the anxiolytic/ anti-convulsant
  effects develops slowly and to a limited extent
  (weeks to months)
• Tolerance to amnesic and cognitive impairing
  effects do not develop even after years of use
• Deficits in chronic users of memory, attention
  and visuospatial ability (especially in drinkers/
  elderly)

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Interactions
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Adverse effects of benzodiazepines - acute
physical

• Excessive sedation, fatigue/ psychomotor
  impairment
• Memory and other cognitive impairment
• Autonomic effects - dry mouth, blurred vision,
  urinary retention, excessive sweating
• Altered sleep physiology - reduced stage 3 4,
  beta activity)
• Ataxia with falls, especially in elderly
• Dysarthria
• Hypotonia
• Confusion
• Nausea, vomiting, constipation
• Paradoxical excitement/ release of anxiety/
  hostility is rare

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Adverse long term effects of benzodiazepines

• Increased rates of
• Accidents, falls (hip fractures etc)
• Motor vehicle accidents
• General decline in functional status
• Cognitive decline
• Self poisoning
• Dependence and withdrawal
• To minimise risk of adverse effects and
  withdrawal in most instances, benzodiazepines
  should not be prescribed for more than 4 weeks
  and scripts should be accompanied by regular
  prescriber review

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Short term indications (7 - 28 days)

• Initial management of panic and agoraphobia
• Alcohol and other drug withdrawal
• Muscle spasm disorder
• Seizure prophylaxis
• PTSD/ Grief reactions

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Long term indications

• There are no chronic conditions for which you
  could say BDZ are first line agents
• In many cases they are a chronic choice sought
  after by those who are socially excluded,
  frustrated, desperate and lacking

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Benzodiazepine dependence

• Risk of dependence increases with higher doses,
  of shorter acting medications and longer duration
  of treatment
• Rare after lt 4 weeks of treatment rising to 20 -
  40 at 6 months and as high as 60 at 12 months
• Withdrawal is neither inevitable or severe and
  best managed through a gradual, supervised
  closely monitored and supported taper over
  several weeks or months

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Patient factors increasing the risk of dependence

• Pharmacogenetics
• Personality- passive/ dependent and dissocial
• Psychiatric co morbidity
• Other substance use disorders
• Occupational hazard
• Poor level of supervision
• Access to the doctor dealer

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Dependent populations

• 1. The iatrogenic dependent patient
• Doctor initiated
• Genuine pathology
• Compliant with regime
• Lower doses of medication
• Non escalation of dose
• Long term recipient
• Not without risk of adverse effects
• Dependence on benzodiazepines can be prevented by
  using alternative interventions, psychological
  treatments or other pharmacotherapies

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Incidence of benzodiazepine withdrawal

• Some may experience a few days of rebound
  following cessation (after a few weeks of use)
• It is rare to become dependent with periods of
  use lt 3 months
• With between 3 to 12 months of use, 10 - 20 of
  patients will become dependent, rising to 20 45
  after more than a year
• Some patients are more prone to developing
  dependence than others
• More likely to be problematic in high dose
  illicit users

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Withdrawal symptoms
More severe but rare symptoms include seizures,
euphoria, incoherent thoughts, hostility,
grandiosity, disorientation, tactile,
auditory/visual hallucinations, suicidal thoughts
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Signs

• Increased psychomotor activity
• Agitation
• Muscular weakness
• Tremulousness
• Hyperpyrexia
• Diaphoresis
• Delirium
• Convulsions
• Elevated blood pressure, pulse and temperature
• Tremor of eyelids, tongue and hands

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Rate of taper v intensity of withdrawal

• Generally there is a trade off between rapid
  withdrawal (intense, relatively short-duration
  symptoms) and slower withdrawal (protracted and
  less intense symptoms)
• For example, in one study 7 of patients reported
  mild withdrawal and there were no cases of
  rebound using a 2 4 month taper of
  benzodiazepine dose, in contrast to a 2 4 week
  taper, in which 35 reported mild withdrawal and
  35 rebound anxiety

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Example of a dose reduction schedule
Week Daily dose 1 50 mg 2 40
mg 3 35 mg 4 30 5 25 6 20 7 15 8 15 9
10 10 10 11 7.5 mg 12 7.5 mg 13 5
mg 14 5 mg 15 2.5 mg
Given long half life of diazepam and active
metabolites steady level of active drugs are
achieved with b.d dosing
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Distinguishing withdrawal from anxiety

• Tinnitus
• Involuntary movements
• Perceptual changes
• Increase in stages 3 and 4 of sleep and REM
• Time course come on quicker with shorter acting
  than longer acting
• Time limited withdrawal- 4 weeks

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Rebound phenomena

• Abrupt withdrawal after benzodiazepine treatment
  for as little as a few days, or up to 4 weeks,
  may result in 2 or 3 days of rebound anxiety
  and insomnia
• Onset time is related to the half-life of the
  drug
• Symptoms may be the same as those for which
  benzodiazepines were originally prescribed
• Severity may exceed that of the original of the
  symptoms that were being treated
• Time limited

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Community based BZD withdrawal

• Estimate the average daily BZD intake
• Calculate an equivalent dose of Diazepam and
  substitute
• Give Diazepam in divided doses b.d/ tds/ qid,
• lt daily pick up, 1 - 2 weekly scripts
• Reduce dose by between 10 - 20 / 1 - 2 weeks
• Slower reduction may be necessary when the dose
  is down to 15mg daily
• Regularly review and titrate dose to the severity
  of symptoms
• If symptoms re-emerge, the dose may be held at
  the plateau for 1 - 2 weeks or even increased for
  a few days before reduction is resumed

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Encourage your patients to reduce their use of
benzodiazepinessend a letter

• Dear Patient,
• I am concerned
• Problems and risks associated
• Benefits of reducing use
• Ways of reducing use
• I can help
• Come in and talk about it,
• Consider a tapered monitored supported reduction
• Note study 18 quit by themselves after request
  by GP (Cormack et al 1994m BJ GP)

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Indication for inpatient treatment

• The safety of the patient is at risk (history of
  seizures, alcohol dependence, poly drug use, or
  significant mental illness)
• The patient reports very high doses of
  benzodiazepine use (uncertain tolerance)
• Ambulatory setting unlikely to succeed (repeated
  inability to complete outpatient reductions,
  other drug use, unstable social environment)
• The patient will not consider withdrawal in an
  ambulatory setting

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Sleep during withdrawal

• Sleep latency prolonged
• Stage 2 decreases in duration
• REM- increase in duration and intensity
• Vivid dreams/ nightmares
• Gradual return to normal sleep architecture over
  weeks and months
• Address obvious issues- noise/ light/ caffeine
• Sleep diary and follow up

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Problems with outpatient daily dose taper

• Monitoring compliance
• Doctor shopping
• Daily supervised dispensing ideal (but may be
  time consuming and cost intensive)
• High drop out rate or return to alternate
  supplies

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After the taper

• Follow up, reassurance, urine tests (optional)
• Insomnia and sleep difficulties may continue for
  several months- provide alternative strategies eg
  PMR, VR, CBT, sleep hygiene, yoga, acupuncture,
  hypnosis, ear plugs, eye mask etc
• Utility of CBT uncertain, probably best reserved
  for those with co morbid anxiety disorder
• For identified panic disorder, CBT can
  significantly improve the proportion that
  complete BZD discontinuation (Otto et al 1993,
  Spiegal et al 1999)

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Co morbid psychiatric disease

• Need to reassess at fortnightly intervals
  minimum of 3 - 4 weeks off BDZ before making
  diagnosis
• Panic disorder up to 1/3
• Anxiety disorders in 1/3 - 2/3
• Co morbid substance use disorder in 1/3
• Personality disorders
• PTSD

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2. Non-prescribed/ illicit dependence
Dependent populations (cont)

• Use may commence without a medical prescription
• Usually younger, poly drug user
• Associated with escalating doses, high dose,
  binge use and other risky patterns of use
• Access through doctor shopping/ black market
• Other substance use disorders
• Significant other psychosocial problems- doctor
  initiated, doctor maintained?
• short T ½ with rapid absorption and brain
  penetration, such as flunitrazepam

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Sought after effects in non medical settings

• Similar to alcohol with initial disinhibition
  followed by sedation
• Euphoria/ relaxation especially when combined
  with other CNS depressants
• Emotional blockade/ amnesia
• Disinhibition- shoplifting/ violence etc
• Poly drug use function- termination of stimulant
  drug effect/ self management of withdrawal

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Signs of intoxication

• Sedation from which the individual may be roused
  in response to stimulation, but with rapid
  relapse when not stimulated
• Slurred speech and drooling
• Inattention, apathy, memory impairments
• Loss of balance and coordination (ataxia) often
  associated with stumbling (gait disturbance)
• Disinhibition, frequently presenting as
  loquaciousness/ aggression /disinhibition in some

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Warning signs

• High dose users may exhibit drug-seeking
  behaviour
• Turn up on Fridays at 4.55pm
• Request an escalation of the dose
• Lose the script (feed the script to the dog)
• Forge scripts
• Be charming/ be not charming
• Be smart/ be not smart
• Obtain prescriptions from several doctors
• Use several types of benzodiazepines
• Use these drugs intravenously

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Assessing the non medical users consumption

• The validity of self-report is often compromised
  by the cognitive effects of the drugs as well as
  recall bias
• Overestimation is common
• Binge patterns need to be identified
• In assessing tolerance, many users will report
  levels of use associated with intoxication and
  sedation- far in excess of what is required to
  avoid withdrawal
• In cases of uncertain tolerance, prescribing
  replacement or withdrawal doses in an outpatient
  setting can be difficult
• Within hospital, a common problem will be the
  difficulty in determining a suitable replacement
  dose of diazepam that will reduce the risk of
  seizures

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Benzodiazepine use among those with opioid
dependence (including those receiving
methadone/buprenorphine)

• Benzodiazepine use is common (1/3 - 2/3)
• High rates of high risk behaviours and
  psychiatric illness
• Commonly taken for self-medication of withdrawal
  or enhancing the opioid depressant effect
• High overdose risk
• High rates of other psychiatric conditions

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Anxiety, benzodiazepines and CBT

• The majority of anxiety disorders are optimally
  treated with cognitive behavioral therapies (CBT)
• There is a considerable overlap in the symptoms
  of the major anxiety disorders
• Depression and anxiety often co-exist
• Effective treatments for one often address the
  other

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Anxiety disorders, panic and agoraphobia The
gap between guidelines and practice

• Despite recommendations on first line management
  of these conditions, there has been little change
  in prescribing practice for them over last decade
• Guidelines support use of CBT and SSRIs
• Delay to effect, resource intensive, access
  limited, rely on motivation instead of a
  prescription
• (Bruce S et al. 2003 Am J Psych)

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Prevalence of anxiety disorders

• 2 F 1 M
• 20 lifetime
• 15 last year
• Least common is OCD (0.7), most common specific
  phobia (7)
• 50 significantly improve at 6 16 months
• Complete recovery rare

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Diagnosis in primary care

• 10 - 45 of anxiety disorders are missed in
  primary care
• Improved detection when co morbid with depression
• Severity, duration and intensity of anxiety
  associated with prognosis
• Overall worse long term prognosis than depression
• 60 have co morbid psychiatric diagnosis
• (1/3 have depression)

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Main treatment options

• Pharmacological
• Psychological, cognitive and behavioral
  (exposure) therapies (8 - 20 hour sessions with
  half as homework)
• Self help
• For recent, mild anxiety states monitor,
  support, reassure
• Stepped approach/ combination of approaches

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SSRIs - the beginning and the end

• SSRIs are effective across the range of anxiety
  disorders and suitable for first line treatment
  Note side effects are early and short lived
  insomnia, nervousness, nausea, sexual
  dysfunction
• Start low (half dose for the first 4-7 days)
• Abrupt cessation- discontinuation syndrome
  dizziness, insomnia, flu like symptoms
• Discuss with patient- inform and advise
• Some evidence to support dose-response
  relationship
• Potential for increased suicide attempts in
  children and adolescents
• TCAs- potential cardiac and CNS toxicity after
  overdose

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Other short term effective agents in the
management of anxiety disorders

• Citalopram
• Paroxetine
• Sertraline
• Venlafaxine
• Buspirone
• Imipramine
• Hydroxyzine
• Benzodiazepines
• Psychological treatments have broadly similar
  outcomes

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Generalised anxiety disorder (GAD)

• Incidence
• Excessive, inappropriate, persistent anxiety and
  worry, most days for 6 months, with symptoms of
  autonomic hyperactivity, restlessness, muscular
  tension, apprehensive expectation and raised
  vigilance
• The optimal treatment is psychological support
  First Line supportive counselling, relaxation
  techniques, complementary therapies, exercise,
  CBT, stress management
• Medication options - buspirone, SSRIs, TCAs,
  benzodiazepines, propranolol

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Panic disorder

• Unpredictable, unexpected, unexplainable,
  debilitating episodes/ surges of
• Intense anxiety
• Fear and sense of impending doom
• Significant hyper arousal symptoms
  palpitations, nausea, tremor, hyperventilation,
  sweating, chest pain
• First line of treatment
• Psychological therapies CBT, group therapy
• Adjunct medication options SSRIs, TCAs,
  benzodiazepines
• More common in women

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Agoraphobia

• Situational specific
• Unwarranted fear of certain places usually
  associated with crowds. Not being able to easily
  remove oneself from the situation.
• Associated with anticipatory avoidance, anxiety
  and sometimes panic
• First line of treatment
• Psychological therapies graded exposure and
  response prevention, CBT
• Medication options SSRIs, TCAs and
  benzodiazepines

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Post Traumatic Stress Disorder (PTSD)

• Incidence 5 - 8
• Characterised by hypervigilance, avoidance,
  flashbacks, depression, anxiety on re-exposure or
  expectation of such
• Associated with increase risk of alcohol and
  other sedative use disorders
• Psychological therapies supportive counseling,
  debriefing in some circumstances, CBT, group
  therapy, rapid eye movement desensitisation,
  psychodynamic psychotherapy,
• Medication SSRIs, TCAs, benzodiazepines

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Differentiating between anxiety and
benzodiazepine/ alcohol use disorders

• Anxiety disorders and drug use typically commence
  in adolescent
• Very early substance use often marker for other
  problems
• There may be history of childhood shyness/
  nervousness
• Identify onset of substance use and function with
  respect to mood alteration or positive peer
  influences

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What medication?

• Little to choose between them in terms of
  effectiveness
• Shorter acting drugs useful as sedatives- less
  chance of a hangover
• Short acting medications with rapid onset- more
  for panic disorders
• Diazepam is effective in most conditions- comes
  in tablet sizes that support later graded
  reduction
• NOTE Short acting potent drugs such as
  flunitrazepam, alprazolam and oxazepam are most
  easily abused

When do I use benzodiazepines in the management
of anxiety? After at least 2 other therapeutic
approaches have not worked
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When not to use benzodiazepines

• Respiratory insufficiency
• Myasthenia gravis
• Depression- they can make it worse
• Prior substance use disorders
• Severe hepatic dysfunction, encephalopathy,
  endogenous BDZ ligands implicated in pathogenesis
  
• Children
• Pregnancy

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When to refer to specialist services?

• If you feel inexperienced or unfamiliar with the
  presentation
• If you have tried two treatment options with no
  response
• If there is co morbid substance use/ psychiatric
  illness
• If the desired intervention is unavailable within
  the primary care setting
• If there are physical/ medication complications

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Referring to specialist services

• Encourage patient to consider psychological
  therapies
• Provide an explanation of the basic processes
  with a rationale for their efficacy
• Consider engaging family and support services
• Consider patient preferences
• Remember outcomes are less effective in those
  who continue to use benzodiazepines
• A preliminary assessment prior to commencing a
  withdrawal regime is advisable

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Summary

• Structured, time limited, interventions are
  effective in assisting many chronic users of
  benzodiazepines to reduce or stop use
• Medication taper reducing by 5 - 10 every 1 - 2
  weeks or more slowly especially towards end (lt
  15mg / day)
• Weekly visits for assessment and support (and to
  provide script)
• Additional psychological therapies may be of use
  in those with co morbid anxiety disorders
• Anti depressants can be appropriately commenced
  before withdrawal if there is evidence of a pre
  existing affective disorder
• Coordinated follow up, reassurance, interest and
  reassessment are essential.
• Write letters asking for a medication review

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End of Slide Show
The Can Do Initiative Managing Mental Health
and Substance Use in General Practice
Overview Session A Definitions prevalence
Session B Assessment history taking Session
C Common explanations Unit 1 Alcohol Unit
2 Benzodiazepines Unit 3 Cannabis Unit 4
Amphetamines Unit 5 Opioids and pain Unit 6
Pregnancy