Pentalaksanaan

penyalahgunaan
benzodiazepin
1 Shelly Iskandar
shelly@unpad.ac.id
DISCLAIMER
Cara kerja benzodiazepin
Perbandingan benzodiazepin

Peak Half-life Half-life Comparativ

Onset of
Benzodiazepine Onset parent metabolit e
Action2
(hrs) (hrs) e (hrs) Oral Dose

Long Acting
Chlordiazepoxid
Int. (po) 2-4(po) 5-30 3-100 10 mg
e (Librium®)

Diazepam1 Rapid
1(po) 20-50 3-100 5 mg
(Valium®) (po, IV)

Flurazepam
Rapid 0.5-2 inactive 47-100 30 mg
(Dalmane®)
 Half-life Half-life Comparativ
Benzodiaze Onset of Peak
parent metabolit e
pine Action2 Onset (hrs)
(hrs) e (hrs) Oral Dose
Intermediate Acting
Alprazolam1
Int. 0.7-1.6 6-20 - 0.5mg
(Xanax®)

Clonazepa
m1 Int. 1-4 18-39 - 0.25mg
(Rivotril®)
Int. (po),
Lorazepam1
Rapid (sl, 1-1.5 (po) 10-20 - 1mg
(Ativan®)
IV)
Oxazepam1
Slow 2-3 3-21 - 15mg
(Serax®)
Temazepa
m1 Slow 0.75-1.5 10-20 - 30mg
(Restoril®)
 Half-life Half-life Comparativ
Benzodiazep Onset of Peak
parent metabolit e
ine Action2 Onset (hrs)
(hrs) e (hrs) Oral Dose
Short Acting
Midazolam1 Most Ra
0.5-1 (IV 1-4 - -
(Versed®) pid IV

Triazolam
Int. 0.75-2 1.6-5.5 - 0.5mg
(Halcion®)

Rapid onset = within 15 minutes, Intermediate = 15-30 minutes, Slow = 30-60

minutes
Factors Short-Acting BZDs Long-Acting BZDs
Potency High Low
Daily dosage 4 – 6 jam b.i.d.
frequency
Interdose anxiety Frequent Rare
Accumulation Little or none Common
Hypnotic None or mild Mild to moderate
hangover effects

Rebound anxiety Frequent Infrequent

Dependency risk High Low
Onset withdrawal 1-3 days 4-7 days
symptoms
Factors Short-Acting BZDs Long-Acting BZDs
Duration 2-5 days 8-15 days
withdrawal
symptoms
Withdrawal severity Severe Mild to moderate

Paradoxical effects Frequent Infrequent

Anterograde Frequent Infrequent

amnesia
IM administration Rapid absorption Slow absorption
IV risk Low High with rapid
injection
Active metabolites None or few Many
9

Benzodiazepines are used by

approximately 4% of the
general population, with
increased prevalence in
psychiatric populations and
the elderly

Cochrane Database of Systematic Reviews 2018, Issue 3

10
Yang akan dibahas

Evidence Based Medicine terkait

indikasi penggunaan
benzodiazepine
Bagaimana peresepan
benzodiazepine yang rasional
Evidence Based Medicine untuk
terapi pada pasien dengan
gangguan penggunaan
benzodiazepine
Indikasi Penggunaan
Benzodiazepin
 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

Conditions BDZ treatment Others

Mild anxiety Not recommended Counselling

Stress reaction prophylaxis Single dose before event CBT

(dental surgery, aeroplane (alprazolam, lorazepam, Relaxati
travel) diazepam) on

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

Recommended therapy OF
GENERALIZED ANXIETY DISORDERS (2014)

Katzman MA, et al. BMC psychiatry. 2014;14(S1):S1.

 Recommended therapy OF
PANIC DISORDERS (PD) - 2014

Katzman MA, et al. BMC psychiatry. 2014;14(S1):S1.

 Systematic Review: SAFETY

 Alprazolam is the most widely prescribed for anxiety

disorders & panic disorder.
 It can be used safely and effectively when prescribed
appropriately, after thoroughly evaluating the risks and
benefits of treatment.
 Advantages of high potency benzodiazepines, include
rapid onset of anxiolytic effects and more tolerable
side effect profiles during acute treatment.

Ait-Daoud N, et al. J Addict Med. 2018 Jan;12(1):4.

 D. correct DOSING OF
ALPRAZOLAM

Latest BPOM Approved Alprazolam 2020

 Systematic Review: WHEN
TO USE?
 SSRIs or SNRIs are considered 1st-line Treatment for
anxiety disorders, but it usually takes few weeks to
reach therapeutic effects  therefore…
 Benzodiazepine use may have a role in alleviating
Acute symptoms of anxiety and distress early in
treatment (Nutt, 2005).
 Psychosocial Tx might provide a more reliable
long-term strategy not only to assist withdrawal
from substances but also to promote long-term
maintenance of Tx gains and prevent relapse.

Ait-Daoud N, et al. J Addict Med. 2018 Jan;12(1):4.

 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
(CBT, 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.
Efek samping benzodiazepin
- Efek terhadap fisik secara akut

 Sedasi yang berlebihan, lelah (fatigue)/ gangguan

psikomotor
 Gangguan memori dan fungsi kognitif lainnya
 Efek otonom – mulut kering, mata kabur, retensi urin,
berkeringat berlebihan
 Mengganggu fisiologi tidur (tahap 3 & 4, gelombang beta)
 Ataksia dean jatuh, khususnya pada orang tua
 Dysarthria
 Hypotonia
 Bingung
 Nausea, muntah, konstipasi
 Paradoxical excitement/ release of anxiety/ hostility is rare
Efek jangka panjang penggunaan
benzodiazepin
Peningkatan insiden dari:
1. Kecelakaan, jatuh (patah tulang panggul, dll)
2. Kecelakaan lalu lintas
3.Penurunan fungsi secara umum
4.Penurunan fungsi kognitif
5. Keracunan
6. Ketergantungan dan gejala putus zat

Untuk meminimalkan risiko terjadinya efek samping dan gejala

putus zat, benzodiazepin tidak boleh diresepkan untuk lebih dari 4
minggu dan peresepan harus disertai dengan analisis oleh pemberi
resep
Peresepan yang
rasional
 Phases of treatment

Assessment

Stabilisation (drug and psychosocial)

Detoxification

Aftercare
FACTORS TO CONSIDER WHEN
PRESCRIBING BENZODIAZEPINE
A. Patient’s Diagnosis
B. Drug characteristics
C. Potential Drug-Drug interactions
D. Correct & required frequency of
dosing
Faktor-faktor pada pasien meningkatkan
risiko ketergantungan
Pharmacogenetics
Personality- passive/ dependent and dissocial
Psychiatric co morbidity
Menggunakan narkoba lain
Masalah pekerjaan
Tidak adanya pengawasan
Memiliki akses kepada bandar termasuk “dokter
bandar”
Terapi pada pasien
dengan gangguan
penggunaan
benzodiazepine
 Pharmacological interventions
for benzodiazepine
discontinuation in chronic
benzodiazepine users (Review)
27
Baandrup L, Ebdrup BH, Rasmussen JØ, Lindschou J,
Gluud C, Glenthøj BY
Cochrane Database of Systematic Reviews 2018,
Issue 3. Art. No.: CD011481.
28 to assess the effect and safety of
medications to facilitate
benzodiazepine discontinuation in
chronic benzodiazepine users.

 38 randomised controlled trials with 2543

participants
 treated for more than two months
 diagnosed with benzodiazepine dependence
 24 trials in Europe; 8 trials in US/ Canada;
6 trials in Asia
29 Drug can facilitate benzodiazepine
discontinuation

 Ameliorating physical withdrawal

symptoms (e.g. propranolol to reduce
tremor & tachycardia)
 Reducing psychological craving (i.e.
administering non-benzodiazepine
sedating drugs)
 Treating underlying insomnia or anxiety
symptoms (e.g. melatonin, buspirone,
imipramine).
  18 different comparisons in a total of 2295
participants
30
 Comparison on:
 discontinuing benzodiazepines
 benzodiazepine withdrawal symptoms
 Several drugs were reviewed:
 Valproate
 Tricyclic antidepressants
 Pregabalin
 Captodiame
 Paroxetine
 Flumazenil
 Carbamazepine
 Quality of the studies were low
 Tolerability and safety were poorly reported
 No conclusions
Parr et al. (2008)
32

 The empirical basis considering

the optimal pharmacological
strategy for withdrawing BZDs is
limited, but the clearest strategy is
to taper the medication

Soyka, M. To Substitute Or Not Substitute—optimal

Tactics For The Management Of Benzodiazepine
Dependence. Addiction 2010 Nov;105(11):1876-7.
 Phases of treatment

Assessment

Stabilisation (drug and psychosocial)

Detoxification

Aftercare
 Assessment of BDZ users

To feel To feel
good better
To have novel: To lessen:
feelings anxiety
sensations worries
experiences fears
AND depression
to share them hopelessness
 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.
 Gejala putus zat

 Peningkatan aktivitas psikomotor

 Agitasi
 Kelemahan otot
 Hyperpyrexia
 Diaphoresis/ banyak berkeringat
 Delirium
 Kejang
 Peningkatan tekanan darah, denyut nadi, dan suhu
 Kelopak mata, lidah dan tangan mengalami tremor
Indikasi untuk rawat inap

 Keselamatan pasien berisiko (riwayat kejang,

ketergantungan alkohol, penggunaan obat multipel,
atau gangguan mental yang nyata)
 Pasien melaporkan dosis benzodiazepin yang sangat
tinggi (toleransi tidak jelas)
 Rawat jalan yang tidak sukses (ketidakmampuan
secara berkali-kali untuk melakukan penurunan dosis
di rawat jalan, penggunaan narkoba lainnya, kondisi
sosial yang tidak stabil)
 Pasien yang tidak mempertimbangkan penghentian
benzodiazepin di seting rawat jalan
 CHPD Aus.Gov. FPN Drug C.C. Benzo
Ashton 5* Giannini 5* 60* Plunkett Intel 5* Info

Alprazolam 0.5mg 1mg 1mg 1-2mg 1mg 1mg 0.5mg 1mg 0.5mg
6-
Bromazepam 5-6mg 6mg 6-12mg 6mg 6mg 12mg 6mg
Chlordiazepo 20-
xide 25mg 50mg 25mg 25mg 25mg 25mg 50mg 25mg

Clobazam 20mg 20mg

Clonazepam 0.5mg 0.5mg 4mg 1mg 4mg 2mg 0.5mg 1-2mg 0.5mg

Clorazepate 15mg 20mg 15mg 15mg 15mg 15mg 15mg

Diazepam 10mg 10mg 10mg 10mg 10mg 10mg 10mg 10mg 10mg

Estazolam 1-2mg 10mg 1-2mg 1mg

Flunitrazepa
m 1mg 2mg 2-4mg 1mg 1mg

Flurazepam 15-30mg 30mg 15mg 15mg 15-30mg 15mg 30mg 15mg

Halazepam 20mg 80mg 40mg 40mg 20mg 20mg

Ketazolam 15mg 15-30mg 15mg

 Loprazolam 1-2mg

Lorazepam 1mg 2mg 2mg 2mg 2mg 1-2mg 1mg 1-2mg 1mg

Lormetazepam 1-2mg 1-2mg

Medazepam 10mg
10-
Nitrazepam 10mg 5mg 10-20mg 10mg 10mg 20mg 10mg

Oxazepam 20mg 30mg 10mg 30-60mg 10mg 20mg 20mg 30mg 30mg
10-
Prazepam 20mg 20mg 10-20mg 10-20mg 20mg

Quazepam 20mg 15mg 20mg 20mg

20-
Temazepam 20mg 20mg 15mg 20-40mg 10mg 20mg 20mg 30mg 20mg

Triazolam 0.5mg 0.5mg 1mg 0.5mg 0.5mg 0.5mg 0.5mg 0.5mg

Z-drugs

Eszopiclone 3mg

Zaleplon 20mg

Zolpidem 20mg 20mg

42

Professor C Heather Ashton, DM, FRCP

Emeritus Professor of Psychopharmacology
Academic Psychiatry, Wolfson Research Centre, Institute of
Neuroscience, Newcastle University, Newcastle upon Tyne,
NE4 5PL, England, UK

250 papers in professional journals, books, and chapters in books

on psychotropic drugs of which over 50 concern benzodiazepines
Contoh rencana penurunan dosis

Minggu Dosis harian

1 50 mg
2 40 mg Diazepam memiliki waktu
3 35 mg paruh yang panjang dan
4 30 kadar stabil metabolit
5 25 aktif yang dapat dicapai
6 20 dengan dosis 2 kali/ hari
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
 Daily Diazepam
Morning Midday/Afternoon Evening/Night
Equivalent

Starting dosage alprazolam 2mg alprazolam 2mg alprazolam 2mg 120mg

alprazolam
Stage 1
alprazolam 2mg alprazolam 2mg 1.5mg 120mg
(one week)
diazepam 10mg

Stage 2 alprazolam 1mg

alprazolam 2mg alprazolam 2mg 120mg
(one week) diazepam 20mg

alprazolam
Stage 3 alprazolam 1mg
1.5mg alprazolam 2mg 120mg
(one week) diazepam 20mg
diazepam 10mg

Stage 4 alprazolam 1mg alprazolam 1mg

alprazolam 2mg 120mg
(one week) diazepam 20mg diazepam 20mg

Stage 5 alprazolam 1mg alprazolam 1mg alprazolam 1mg

110mg
(1-2 weeks) diazepam 20mg diazepam 10mg diazepam 20mg

alprazolam
Stage 6 alprazolam 1mg alprazolam 1mg
0.5mg 100mg
Stage 7 alprazolam 1mg alprazolam 1mg Stop alprazolam
90mg
(1-2 weeks) diazepam 20mg diazepam 10mg diazepam 20mg

Stage 8 alprazolam 0.5mg alprazolam 1mg

diazepam 20mg 80mg
(1-2 weeks) diazepam 20mg diazepam 10mg

Stage 9 alprazolam 0.5mg alprazolam 0.5mg

diazepam 20mg 80mg
(1-2 weeks) diazepam 20mg diazepam 10mg

Stage 10 alprazolam 0.5mg Stop alprazolam

diazepam 20mg 60mg
(1-2 weeks) diazepam 20mg diazepam 10mg

Stage 11 Stop alprazolam

diazepam 10mg diazepam 20mg 50mg
(1-2 weeks) diazepam 20mg
Stop midday dose;
Stage 12 divert 5mg each
diazepam 25mg diazepam 25mg 50mg
(1-2 weeks) to morning and
night doses
Stage 13
diazepam 20mg -- diazepam 25mg 45mg
(1-2 weeks)

Stage 14
diazepam 20mg -- diazepam 20mg 40mg
(1-2 weeks)
  No standard tapering regimens
46
 Rate of tapering depends on:
 the starting dose
 duration of therapy
 risk of relapse
 how well tapering is tolerated by the
patient.
 Higher doses (> 10 mg diazepam
equivalents/day)  tapered more
rapidly
 <10 mg tapered more slowly (e.g. 5 mg
2x1for 2 weeks  1x1 for 2 weeks  2 mg
2x1 for 2 weeks  berhenti).
47
Stabilisation and maintenance
therapy

 Some patients are reluctant to consider ceasing

their benzodiazepine
 Harm reduction  using a long half-life substitute to
prevent intoxication and withdrawal phenomena,
and allowing the patient to engage in holistic
treatment of their dependence, before slowly
reducing the dose.

Brett,J., Murnion,B. Management of benzodiazepine misuse

and dependence. Aust Prescr 2015;38:152–5
48
Stabilisation and maintenance
therapy

 Characteristics:
 On a high diazepam equivalent dose
 Have a range of aberrant drug-related behaviours
(especially doctor shopping)
 Chaotic social setting
 Unstable psychiatric diagnoses
 Patients who are alcohol or drug dependent
 should be referred to a specialist addiction service.

Brett,J., Murnion,B. Management of benzodiazepine misuse

and dependence. Aust Prescr 2015;38:152–5
 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)

50
Discontinuation with the aim
of abstinence
 Long-term abstinence:
 25% at 12 months for complicated
dependence
 15 to 80% for older adults in general practice
 Lower risk of relapse:
 a daily dose of 10 mg diazepam or less
 have made a substantial dose reduction
 high life satisfaction
 No use of other drugs
 without unstable psychiatric/ medical comorbidity
Traditional Service Approach
Severity
Symptoms

Acute symptoms,
Discontinuous treatment
Crisis management
Remission
Time
 A Recovery-Oriented Approach
(ongoing care, typical for chronic conditions)

Severity
Symptoms

Continuous Treatment Response

Remission
Time
 Conclusion
54
 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.