Rational Use of Benzodiazepine

in Daily Practice
Teerayuth Rungnirundorn, M.D.
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 Outline
• Overview of Benzodiazepines (BDZ) prescription

• Rationale for medical use of BDZ

• The problems of using BDZ

• Pharmacology of BDZ in relation to their use and misuse

• Rationale for assessment and treatment of high dose and

illicit BDZ users
 Overview

• There is an excessive prescribing of BDZ worldwide by

medical professionals.

• BDZ is most prescribed in old age and female patients.

• BDZ is easy to prescribed by GP compared to others

psychoactive medications.

• BDZ is regulated under the government law to prevent its

misuse but there still are illegal trade online and out of
pharmacy.
Trend of BDZ prescription in US

Bachhuber et al (2016)
BDZ prescription in different age and sex

Olfson et al (2015)
BDZ in IVDU in Indonesia

Iskandar et al (2010)
Rationale for medical use of BDZ
 Medical use of BDZ

• Anxiety disorders: anti-anxiety, anti-panic

• Insomnia: initiate sleep/ improve sleep quality (short-term)

• Seizure: rapid acting anti-epileptic

• Alcohol withdrawal: detoxification

• Sedation in surgery or using as muscle relaxant

 Rational use of BDZ for anxiety
• Advantage of BDZ is the rapid onset of action, usually apparent after a
single dose.
• BDZ can cover short term symptoms, allowing time for more specific
treatments to take effect, and can alleviate exacerbations of anxiety
which are often self-limiting.
• BDZs are indicated for the short term use (2-4 weeks only) of anxiety that
is severe, disabling or causing unacceptable distress followed by
tapering over 1 to 2 weeks, and temporary use as needed only if anxiety
symptoms occur.
• Other treatments should be offered (SSRIs, relaxation, counselling,
CBT).
 Rational use of BDZ for anxiety

Conditions BDZ treatment Others

Mild anxiety Not recommended Counselling

Stress reaction prophylaxis Single dose before event CBT

(dental surgery, aeroplane travel) (alprazolam, lorazepam, diazepam) Relaxation

Acute stress reaction, trauma Counselling

Single doses or a few days
Adjustment disorder CBT

Antidepressant
Single or intermittent courses (2-4 weeks),
Generalised anxiety disorder GABAnergic
used with other treatments e.g. antidepressant
CBT

Panic disorder Antidepressant

Single or intermittent courses (2-4 weeks),
Agoraphobia CBT (esp.
used with other treatments e.g. antidepressant
Social phobia exposure)

Adapted from Ashton (1994), RCPSYCH UK

 Rational use of BDZ for insomnia
• Insomnia must be ruled out for other treatable disorder, which might
not require BDZ.
• In the disorder that is likely to resolve soon (e.g. bereavement, time-
zone change, short-term stressor), BDZ or Z-drugs can be
prescribed for short period (3-7 days) and used as needed.
• Clinician should also offer behavioural-psychological interventions
(CBTi, sleep restriction, relaxation) for treating insomnia altogether
with BDZ.
• Regular BDZ for insomnia should be used not more than 4 weeks in
order to avoid tolerance.
 Choosing BDZ
Active
BDZ Equivalents Time to peak (hrs) Half-life
metabolite

Diazepam 5-10 0.5-1 20-50 Yes

Alprazolam 0.5 1-2 6-27 No

Lorazepam 1 2-4 10-20 No

Clonazepam 0.5 0.4-4 18-50 No

Oxazepam 40 2-4 5-20 No

Triazolam 0.5 0.7-2 2-3 No

Temazepam 20 1-2 3-19 No

Chlordiazepoxide 25 0.5-4 5-30 Yes

Flurazepam 15-30 0.5-1 2-4 Yes

Prodrug for
Chlorazepate 7.5 1-2 Yes
Nordiazepam (1-2)

Adapted from Paquin, Zimmerman and Rudolph (2014)

The problems of using BDZ
 The problems with BDZ

• Long-term (>4 weeks), regular use

1. Tolerance, dependence, abuse/diversion, overdose

2. Cognitive side effect: memory problems, chronic sedation

that can lead to fall or accident

3. Delaying recovery from emotional disorders e.g.

grief/depression by suppress normal emotion,
alexithymia, increase anxiety and low mood in longer
term

Schweizer et al.(1990), Rickels et al.(1991), BAP (2013)

BDZ Overdose Death

Park et al. (2015)

 BDZ dependence

• Prevalence is approximately 10% of people using

benzodiazepines.

• Rate of dependence depends on duration of use and dosage.

• High risk groups: anxiety, substance dependence, inpatient

with depression, older age, female.

• Benzodiazepines are primary drug of abuse in multiple drug

abusers.

• Withdrawal is similar to alcohol withdrawal.

Voyer et al.(2010), Schuckit et al. (2002) Schmidt et al.(1989), Busto et al. (1986), Holroyd and Duryee (1997)
BDZ and Cognitive impairment

de Gage et al. (2012)

 BDZ, Falls and Hip fracture
Short term use
(1-14 days), RR=2.4

Medium term use

(15-30 days), RR=1.5

Long term use

(more than 1 month), RR=1.2

Mixed term use

(medium + long), RR=1.5

Mixed term use

(insomnia only)

Overall
RR=1.5 Donnelly et al. (2017)
Pharmacology of BDZ in relation to
their use and misuse
 Plasma level of using BDZ
• Multiple dosing has no effect in healthy volunteer: No change
in plasma half-life overtime, no induction or inhibition of BDZ
metabolism

• BDZ, alcohol and methadone

- Enhance high, CNS and respiratory depression

- BDZ levels are not affected by methadone

- Methadone levels are increased by BDZ

- Chronic, not acute, alcohol use enhances BDZ metabolism

Greenblatt & Shader (1986), Law (2018)

 Pharmacological factors associated
with BDZ abuse

• Speed of onset of effects

- Rapid onset > slow onset whether long or short acting

• Dose of benzodiazepine

- Higher dose > lower dose

• For drug abusers, they can use slow-onset BDZ as a base

on which to use rapid-onset BDZ to get a buzz

Darke et al.(1994) Griffiths & Wolf (1990), Law (2018)

 Onset and half-life of BDZ

Intermediate
Rapid onset Slow onset
onset

Ultra-short half- Early onset of withdrawal

life (<8 hrs)

More abused
Short half-life (8-
24 hrs)
Less abused

Long half-life
(>24 hrs) Late onset of withdrawal

Law (2018)
 Onset and half-life of BDZ
a=anxiolytic, e=anti-epileptic, s=hypnotic for sleep

Intermediate
Rapid onset Slow onset
onset

Ultra-short half-
Midazolam
life (<8 hrs)

Alprazolama
Flunitrazepams
Short half-life (8- Lorazepama,s Oxazepama
Temazepams
24 hrs) Temazepams Loprazolams
(cap, solution)
(tab)

Diazepams Chlordiazepoxidea
Long half-life
Nitrazepams Clonazepame
(>24 hrs)
Flurazepams Clobazama,e

Law (2018)
 Elimination

• All BDZ are metabolised by liver and excreted in urine.

• Metabolism includes oxidation mostly via CYP3A4 and

glucuronide conjugation. Most are oxidised to
nordiazepam (desmethyldiazepam) and oxazepam.

• Lorazepam, oxazepam and temazepam are metabolised

by conjugation alone.

• Urine immunoassay screening most often detect

metabolites e.g. desmethyldiazepam or oxazepam.

Wyatt (2016)
 BDZ and tolerance

Rapid tolerance
Partial tolerance Little tolerance
(not usually complete)

Positive mood Antiepileptic Anxiolytic

Sedation Anti-panic

Cognitive-motor effect

Argyropoulos and Nutt (1999), Lucki and Rickels (1986)

 Rationale for assessment and
treatment of high dose and illicit BDZ
users
 Phases of treatment

Assessment

Stabilisation (drug and psychosocial)

Detoxification

Aftercare
 Assessment of BDZ users
• What are they using?

- Type of BDZ, dose, frequency, duration, route

• Why are they using it?

- For self-medication: anxiety, insomnia, intrusive thought in trauma,

depression —> within therapeutic dose or excessive?

- For fun: only BDZ or with other drugs e.g. depressants (more high and cope
with tolerance) or stimulants (for calming down the effect)

• What are the consequences of using it?

- Benefits (self-medications or high) and risks/harms (physical and mental

disorders, injuries, overdose, law, finance, relationship, occupation)
 Stabilisation
• Educate about possible harms of misuse

• Further assessing and treating physical and mental

disorders (IVDU-related diseases, anxiety, depression,
insomnia, psychological trauma, other drugs dependence)

• Motivate to reduce or stop using BDZ in maladaptive

pattern using motivational interviewing

• Choose setting for detoxification: OPD or IPD

• Plan for detoxification with or without prescription of BDZ

 Detoxification
• Detox success rates are 35-55% in general population, and are 15-30% in
substance users.

• Treatment of choice is gradual BDZ reduction not more than 20% reduction
of dose per visit (every 1-2 weeks or longer, may be for 3 months to a year)

• For substance users, a partial detox may be useful and feasible, then remain
stable at therapeutic dose

• In case of short-acting BDZ users, no need to switch to long-acting BDZ

before detox, except for wanting to de-condition users from BDZ or having
problematic withdrawal.

• Rarely should dose of more than 30 mg diazepam equivalent per day be

prescribed.

Voshaar et al (2006), Parr et al(2008), NICE, DH (2017)

 Detoxification
• In case of multi-BDZ use, convert all BDZ to single BDZ is a
treatment of choice. Never prescribe > 1 BDZ by the same route.

• Work collaboratively with patient, it will make more success than

authoritative approach.

• Set boundary of treatment e.g. prescribe only if clear diagnosis,

treatment resistance, or if likely to improve outcome of other
treatment with benefits outweighing risks.

• Calculate the number of prescribed BDZ fitted with number of days

• Adjunctive medications may help: carbamazepine, valproate,

melatonin, trazodone, paroxetine.
Parr et al. (2008)
 Aftercare
• All dependency syndromes need aftercare as all have high risk for relapse.

• Protracted BDZ withdrawal may occur e.g., insomnia, anxiety, depression,

tinnitus, abnormal skin sensation, pain, irritable bowel, and it can last 6
months to 1 year.

• Aftercare help BDZ ex-users to adapt to a drug-free lifestyle and build up

relapse prevention strategies.

• Monitor for development of psychiatric disorders e.g. anxiety and

depression, and development of other drugs of abuse.

• Clinician should not restart BDZ once detoxed, or increase their dose if not
detoxed, even after 3-5 years follow-up. There are alternative anxiolytics or
treatments.

Holton and Tyrer (1990), Rickels et al (1991), Law (2018)

 Conclusion
• BDZ is underrated in medical practice in terms of harms.

• One should use BDZ as indicated and as needed.

• Clinician should be aware of BDZ misuse in patients esp.

substance users, anxiety or mood disorder patients.

• Educate, gradual tapering off BDZ is important with or without

adjunctive medications as well as assessing and treating co-
morbidities.

• Aftercare is necessary to prevent relapse and rebuild drug-

free lifestyle.
“It is more difficult to withdraw people from
benzodiazepines than it is from heroin”

–Professor Malcolm H Lader

Teerayuth.R@chula.ac.th