Menan Abd El Maksoud Rabie, MBBCh, Msc, Arab Board, MD,

Assistant Professor of Psychiatry, Faculty of Medicine, Ain Shams University,

Member of the Egyptian Psychiatric Association (EPA),International Member of the American Psychiatric Association (APA),

Associate Member of the International Federation of Psychiatric Epidemiology

(IFPE),Managing editor at the journal of Middle East Current Psychiatry

(MECPych)

Background

Terminology

Withdrawal Syndrome

Subjects and methods

Results

Conclusion

Recommendations

The chronic use of BDZ is becoming accepted in some cultures, as it is unfortunately not as stigmatizing as chronic use of cannabis, alcohol or heroin.

When a psychiatrist advises a chronic BDZ user about the hazards of its prolonged use, what is the most subjectively annoying symptom to the patient?

Benzodiazepine withdrawal syndrome is the cluster of symptoms which appear when a person who has taken benzodiazepines long term & has developed benzodiazepine dependence stops taking benzodiazepine drug(s) or reduces the dosage too rapidly.

Chronic exposure to benzodiazepines causes physical adaptations in the brain to counteract the drug's effects. This is known as a tolerance and physical dependence.

50-80% of people who have taken benzodiazepines continually for 6 months or longer will experience withdrawal symptoms when reducing the dose.

People who have been taking benzodiazepines regularly for many years can have symptoms of withdrawal most of the time, even when they have not reduced the dose.

Often they are unaware that their poor physical and mental health is related to their long term use of the benzodiazepines

the higher the dose (DOSAGE SIZE )

the longer a benzodiazepine is used (LENGTH OF USE)

the more rapidly a benzodiazepine is discontinued (RATE OF TAPERING)

the more likely severe withdrawal symptoms will occur.

…and possibly genetic factors play a role

Severe withdrawal symptoms can still occur during gradual dose reduction or from relatively low doses

Long term use of benzodiazepines may lead to withdrawal like symptoms emerging despite a constant therapeutic dose.

Withdrawal symptoms are an adverse effect and result of drug tolerance.

In certain selected patient groups the occurrence of withdrawal symptoms are as high as 100%, whereas more than 50% of subjects are able to discontinue benzodiazepines with mild or even no withdrawal symptoms.

It is not known for sure why there is such a variation between patients but recent research in animals suggests that withdrawal may be influenced by a genetic component.

Withdrawal symptoms may persist for weeks or monthsafter cessation of benzodiazepines.

In a smaller subset of patients withdrawal symptoms may continue at a sub acute level for many months or even a year or more.

Apart from the length of time taking benzodiazepines and the dose, there are no predictors for the severity or otherwise of the withdrawal. Slowly reducing the dose of the drug minimises the severity of the withdrawal symptoms.

Patients who are physically dependent on short acting anxiolytic benzodiazepines.

Interdose withdrawal are withdrawal symptoms which occur between doses when the previous dose wears off. This can lead to symptoms such as rebound anxiety between doses and craving for the next dose.

The ability to determine the difference between relapse and rebound is very important during the withdrawal phase and can often lead to a misdiagnosis.

GABA is the second most common neurotransmitter in the CNS (after glutamate) and the most abundant inhibitory neurotransmitter; roughly 1/4 to 1/3 of synapses use GABA.

The use of benzodiazepines has an effect on almost every aspect of brain and body function, either directly or indirectly.

GABA RECEPTORS

GABA

transporter

GABA A

receptorGABA B

receptor

8-18 Stahl S M, Essential

Psychopharmacology (2000)

chloride channel

GABA A

receptor

BZ binding

site within

membrane

8-19 Stahl S M, Essential

Psychopharmacology (2000)

GABA site

BZ site

picrotoxin site

alcohol site

barbiturate

site

8-20 Stahl S M, Essential

Psychopharmacology (2000)

Benzodiazepines cause a decrease in norepinephrine, serotonin, acetylcholine and dopamine.

These neurotransmitters are needed for normal memory, mood, muscle tone and coordination, emotional responses, endocrine gland secretions, heart rate and blood pressure control.

A number of people have observed changes in their cognitive abilities following long term benzodiazepine use. Research undertaken by the School of Psychology at LaTrobe University has shown that many people who have been taking benzodiazepines long term have problems with concentration, learning and memory.

With chronic benzodiazepine use, tolerance develops rapidly to most of its effects, so that when benzodiazepines are withdrawn, various neurotransmitter systems go into overdrive due to the lack of inhibitory GABA-ergic activity.

Withdrawal symptoms then emerge as a result, and persist until the nervous system physically reverses the physical dependence which have occurred in the CNS.

Withdrawal symptoms typically consist of a mirror image of the drug's effects:

sedative effects and suppression of REM and SWS stages of sleep can be replaced by insomnia, nightmares, and hypnogogic hallucinations;

antianxiety effects with anxiety and panic; muscle relaxant effects are replaced with muscular

spasms or cramps; anticonvulsant effects with seizures, especially in

cold turkey or overly-rapid withdrawal.

agonist

anxiolyticsedative hypnoticmuscle relaxantanticonvulsantamnesticdependency

partial

agonist

anxiolytic

only

antagonist

no clinical

effect

partial inverse

agonist

promnestic

(memory

enhancing)

anxiogenic

inverse agonist

promnestic

anxiogenic

pro-convulsant

8-25 Stahl S M, Essential

Psychopharmacology (2000)

Studies in mice have found that discontinuation of benzodiazepines leads to decreased agonist affinity and increased inverse agonist affinity of the benzodiazepine receptors, essentially causing the receptors to reverse their natural function.

This may explain the cause of the benzodiazepine withdrawal effects, down regulation of other sub receptor types.

A. Cessation of (or reduction in) sedative, hypnotic, or anxiolytic use that has been heavy and prolonged.

B. Two (or more) of the following, developing within several hours to a few days after criterion A:

(1 ) autonomic hyperactivity (e.g., sweating or pulse rate greater than 100)

(2 ) increased hand tremor

(3 ) insomnia

(4 ) nausea or vomiting

(5 ) transient visual, tactile, or auditory hallucinations or illusions

(6 ) psychomotor agitation

(7 ) anxiety

(8 ) grand mal seizures

C. The symptoms in criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

D. The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

Specify if:

With perceptual disturbances

Withdrawal state

G1. There must be clear evidence of recent cessation or reduction of substance use after repeated, and usually prolonged and/or high-dose, use of that substance.

G2. Symptoms and signs are compatible with the known features of a withdrawal state from the particular substance or substances (see below).

G3. Symptoms and signs are not accounted for by a medical disorder unrelated to substance use, and not better accounted for by another mental or behavioral disorder.

The diagnosis of withdrawal state may be further specified by using the following:

Uncomplicated

With convulsions

Sedative or hypnotic withdrawal state

A. The general criteria for withdrawal state must be met.

B. Any three of the following signs must be present:

(1 ) tremor of the tongue, eyelids, or outstretched hands

(2 ) nausea or vomiting

(3 ) tachycardia

(4 ) postural hypotension

(5 ) psychomotor agitation

(6 ) headache

(7 ) insomnia

(8 ) malaise or weakness

(9 ) transient visual, tactile, or auditory hallucinations or illustrations

(10 ) paranoid ideation

(11 ) grand mal convulsions

Comment

If delirium is present, the diagnosis should be sedative or hypnotic withdrawal state with delirium.

1. Electric shock sensations

2. Muscular spasms, cramps or fasiculations

3. Insomnia

4. Blurred vision

5. Dizziness

6. Dry mouth

7. Aches and pains

8. Hearing disturbances

9. Taste and smell disturbances

10. Chest pain

11. Flu like symptoms

12. Impaired memory and concentration

13. Increased sensitivity to sound

14. Increased urinary frequency

15. Numbness and tingling

16. Hot and cold flushes

17. Headache

18. Rebound REM sleep

19. Stiffness

20. Fatigue and weakness

21. Restless legs syndrome

22. Metallic taste

23. Photophobia

24. Paranoia

25. Hypnagogic-hallucinations

26. Nausea and vomiting

27. Nightmares

28. Agitation and restlessness

29. Anxiety and panic attacks

30. Hypochondriasis

31. Impaired concentration

32. Elevation in blood pressure

33. Tachycardia

34. Hypertension

35. Postural hypotension

36. Depression possible suicidal ideation

37. Tremor

38. Perspiration

39. Loss of appetite and weight loss

40. Dysphoria

41. Depersonalization

42. Derealisation (Feelings of unreality)

43. Obsessive compulsive disorder

44. Tinnitus

45. Paraesthesia

46. Visual disturbances

47. Mood swings

48. Indecision

49. Irritable bowel syndrome

Convulsions, which may result in death

Catatonia, which may result in death

Coma(rare)

Hyperthermia

Organic brain syndrome

Confusion

Suicide, Attempted suicide and Suicidal ideation

Self harm

Delusions and other psychotic features

Homicidal ideation

Urges to shout, throw, break things or to harm someone

Violence

Post Traumatic Stress Disorder

Mania

Neuroleptic malignant syndrome like event (rare)

delirium tremens

Benzodiazepine withdrawal represents in part excitotoxicity to brain neurons.

Repeated benzodiazepines withdrawals may lead to sensitisation or kindling of the CNS, possibly leading to worsening cognition and symptomatology and making each subsequent withdrawal period worse.

Long term use of benzodiazepines causes cognitive, neurological and intellectual impairments, with attentional and visuospatialfunctional impairments.

After one year of abstinence ,withdrawal from benzodiazepines can lead to improved alertness and decreased forgetfulness in the elderly. There were some cognitive abilities which did not improve which are sensitive to benzodiazepines as well as age such as epsiodic memory

The main Hypothesis of this study was that chronic users of benzodiazepines experience many withdrawal symptoms, if they try to decrease the dose.

Research questions were about age, gender & diagnoses of the users & the effects on type of drug, duration of use, withdrawal symptoms and discontinuation rate.

To describe the characteristics of chronic benzodiazepine (BDZ) users and to identify the Most Annoying Withdrawal Symptom (MAWS) which may play a key role in hindering the discontinuation of the drug, and delaying abstinence.

547 BDZ chronic users were subjected to Psychiatric history and examination,

They were diagnosed according to DSM-IV diagnostic criteria and they were advised to decrease the doses of BDZ gradually (1/4 dose every 4 weeks)

In subsequent visits they were asked to check in a list of withdrawal symptoms & they were asked to specify the most annoying symptom from their subjective point of view.

Males with SAD, GAD, MAD, Panic D, MDD, Adjustment D with depressive symptoms, PTSD, Insomnia, BD & Schizophrenia were more prone than females with the same diagnoses to use BDZ.

Females with OCD, Adjustment D with anxiety symptoms, Alzheimer’s D, were more commonly using BDZ

0

10

20

30

40

50

60

70

80

Soci

al A

D

Gen

eraliz

ed A

D

Mix

ed A

nx Dep

Pan

ic D

OCD

Spec

ific

Phobia

PTSD

Inso

mnia

Adju

stm

ent D

Anx

Adju

stm

ent D

Dep

Adju

stm

ent D

Anx

Dep

Maj

or Dep

D

Sch

izophre

nia

Bip

olar D

Alz

heim

er's

D

Impuls

e Contr

ol D

Mean Age

0 20 40 60 80 100 120

SAD

GAD

MAD

Panic

OCD

Sp Phobia

PTSD

MDD

Schiz

BD

Alz

Adj D Anx

Adj D Dep

Adj D Anx Dep

Insomnia

ICD

FEMALE

MALE

Males suffering from Impulse Control Disorder were using BDZ for the longest Duration (M100 ms)

Females suffering from Panic D, Adjustment D with depressive symptoms & Alzheimer’s D 80-100 ms

Males suffering from Schizophrenia, BD, Panic D & MDD 60-80 ms

Females suffering from MAD, OCD, GAD, SAD 60-80 ms

0

20

40

60

80

100

120

140

SAD MAD OCD PTSD Imp Cont

D

Adj D

Dep

MDD BD

D/C

D/C

Total

Despite withdrawal symptoms,

42.1% of OCD pts,

36.8% of schizophrenia pts,

34.2% of MDD pts,

28.6 % of BD pts,

28.6% of Adj D dep pts,

18.8% of Adj D anx dep pts,

16.7% of Adj D anx pts

were able to D/C BDZ doses within 3 months, with the aid of non BDZ psychiatric ttt and supportive psychotherapy

0

50

100

150

200

250

300

350

400

450

Withdrawal Symp No Withdrawal Symp

D/C

Cont

0

20

40

60

80

100

120

SA D GA D M A D Panic D OC D Sp Phob ia PTSD Insomnia Imp C ont

D

A dj D A nx A dj D D ep A dj D A nx

D ep

M D D Shiz B D A lz

MALES

FEMALES

0

5

10

15

20

25

30

35

40

Alpra Broma Dia Clona Lorazepam

D/C

0

10

20

30

40

50

60

70

80

90

100

SAD GAD M AD Panic D OCD SpPhobia PTSD M DD Schizz BD Alz Adj D Anx Adj D Dep Adj D Anx

Dep

Insomnia ICD

withdrawal Symp

Withdrawal Symptoms were most prevalent (100%) with Alzheimer’s D and Imp Cont D.

They were least prominent in cases suffering fromSpecific phobia (60%), PTSD (75%) & Adj D anx s (75%)

Insomnia

Irritability

Dysphoria

Apprehension to stop39

Impulsivity

Palpitation

Psychomotor Agitation

Body Pains

Headache

Exessive Thinking

IBS

Tremors

Ms Twitches

Obsessions

GM Fits

Dyspnea

Malaise

Nightmares

Hallucinations

Paranoid Ideas

Nausea

Sweating

Postural Hypotension

Sedative, hypnotic, or anxiolytic dependence is influenced by several factors: the most important is the pharmacology of drugs.

Dependence is also affected by the beliefs and values of physicians, who must be aware of their attitudes toward dispensing drugs of this class.

Finally, patients, and society at large, are influenced by the moral, economic, and political views of the time.

Taken together these factors influence medical care, sometimes to the detriment of patients, who may be denied appropriate medication because of such biases.

The gender, age and diagnosis, the type of BDZ and the duration of its use significantly affect the perception of the patient about the withdrawal symptoms.

Insomnia is the most subjectively annoying withdrawal symptom, followed by irritability and dysphoria.

It is not impossible to D/C BDZ for your patient as soon as they are willing to start living their lives without dependence.