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)

Is it dangerous to use Benzodiazepines for life???

BackgroundTerminologyWithdrawal SyndromeSubjects and methodsResultsConclusionRecommendations

CONTENTS

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?

Background

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.

Terminology

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

Factors Affecting Withdrawal Severity

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.

However…

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 syndrome

Withdrawal symptoms may persist for weeks or months after 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.

Withdrawl syndrome

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.

Interdose withdrawal

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.

Physiology of Withdrawal Symptoms

GABA RECEPTORS

GABA transporter

GABA A

receptor

GABA 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.

Physiology of Withdrawal Symptoms

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.

Physiology of Withdrawal Symptoms

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.

Physiology of Withdrawal Symptoms

agonist

anxiolyticsedative hypnoticmuscle relaxantanticonvulsantamnesticdependency

partial agonist

anxiolytic only

antagonist

no clinical effect

partial inverse agonist

promnestic (memory enhancing) anxiogenic

inverse agonist

promnesticanxiogenic 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.

Withdrawal Syndrome

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

DSM-IV Diagnostic Criteria for Sedative, Hypnotic, or Anxiolytic Withdrawal

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

Diagnostic Criteria

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.

Diagnostic Criteria

BDZ Withdrawal Symptoms1. Electric shock sensations2. Muscular spasms, cramps or

fasiculations 3. Insomnia4. Blurred vision5. Dizziness6. Dry mouth7. Aches and pains8. Hearing disturbances9. Taste and smell disturbances10. Chest pain11. Flu like symptoms12. Impaired memory and concentration13. Increased sensitivity to sound14. Increased urinary frequency15. Numbness and tingling16. Hot and cold flushes 17. Headache18. Rebound REM sleep19. Stiffness20. Fatigue and weakness21. Restless legs syndrome22. Metallic taste23. Photophobia24. Paranoia

25. Hypnagogic-hallucinations 26. Nausea and vomiting27. Nightmares28. Agitation and restlessness29. Anxiety and panic attacks30. Hypochondriasis31. Impaired concentration32. Elevation in blood pressure33. Tachycardia34. Hypertension35. Postural hypotension36. Depression possible suicidal ideation 37. Tremor38. Perspiration39. Loss of appetite and weight loss40. Dysphoria41. Depersonalization42. Derealisation (Feelings of unreality)43. Obsessive compulsive disorder44. Tinnitus45. Paraesthesia46. Visual disturbances47. Mood swings48. Indecision49. 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

An abrupt or over-rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:

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 visuospatial functional 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

Hazards of prolonged BDZ use

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.

Hypothesis

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.

AIM OF THE STUDY

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.

METHODS

Gender distribution of psychiatric disorders among Chronic BDZ users

0

10

20

30

40

50

60

70

80

90

100

malesfemales

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

Gender distribution of psychiatric disorders among Chronic BDZ users

Age distribution of psychiatric disorders among Chronic BDZ users

010203040

50607080

Social

A D

Genera

lized

A D

Mix

ed A

nx Dep

Panic

DOCD

Specifi

c Phobia

PTSD

Inso

mnia

Adjust

men

t D A

nx

Adjust

men

t D D

ep

Adjust

men

t D A

nx D

ep

Maj

or Dep

D

Schizo

phrenia

Bipola

r D

Alzhe

imer

's D

Impuls

e Contro

l 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

Gender & duration of BDZ use

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

Gender & duration of BDZ use

0

20

40

60

80

100

120

140

SAD MAD OCD PTSD Imp ContD

Adj DDep

MDD BD

D/C

D/C

Total

Discontinuation & Diagnoses

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

SAD GAD MAD Panic D OCD Sp Phobia PTSD Insomnia Imp ContD

Adj D Anx Adj D Dep Adj D AnxDep

MDD Shiz BD Alz

MALES

FEMALES

Discontinuation & Withdrawal Symptoms

0

5

10

15

20

25

30

35

40

Alpra Broma Dia Clona Lorazepam

D/C

Discontinuation & Type of BDZ

0

10

20

30

40

50

60

70

80

90

100

SAD GAD MAD Panic D OCD SpPhobia PTSD MDD Schizz BD Alz Adj D Anx Adj D Dep Adj D AnxDep

Insomnia ICD

withdrawal Symp

% of Withdrawal Symptoms in Different Diagnoses

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

They were least prominent in cases suffering from Specific 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

Frequency of withdrawal Symptoms

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.

Finally…

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.

Conclusion