Benzodiazepines: Toxicity, Cognitive Impairment, Long-Term Damage & The Post Wit

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The Benzodiazepines

 

Toxicity, Cognitive Impairment, Long-Term

Damage & The Post Withdrawal Syndrome

 

Dr R F Peart BSc, PhD

December 2000

 

Swedish Translation by Ove Carlsson · Danish Translation by Steen Jarbøel

 

Abstract

 

There is a great deal of misinformation, mythology and ignorance

surrounding the benzodiazepines, their uses and problems. The attitude

of denial by many has a severe impact on patients trying to get help

from doctors, treatment for dependency, DLA and other benefits, and

help for legal actions.

 

This paper is an attempt to bring together apparently diverse aspects

in a format that hopefully will be informative and a source of further

information for those seeking help and compensation for the

destruction of their lives.

 

Contents

 

1.

 

Introduction

2.

 

Elimination Half Lives and Accumulation

3.

 

Individual Variability and Dependence

4.

 

Toxicity

5.

 

Adverse Reactions and Events

6.

 

Toxic Poisoning

7.

 

Medical Literature

 

Section A - Cognitive Impairment/Long Term Damage - Reference List and

Extracts

Section B - Long Term Damage/Post Withdrawal Syndrome - Reference List

and Extracts

 

1. Introduction

 

Any drug acting upon the central nervous system (CNS) whether it is an

analgesic, stimulant or depressant has a potential for causing toxic

side effects, cognitive impairment, neurological disorders and dependence.

 

The benzodiazepines are depressants of the CNS and have five major

therapeutic actions, anxiolytic, hypnotic, muscle relaxant,

antiepileptic and amnesic i.e. they are very non-specific drugs.

Recipients of these drugs will be subject to all of these actions,

whether required or not, and to adverse reactions associated with each

therapeutic action. Over 500 different adverse reactions to the

benzodiazepines have been reported to the MCA (UK) and the FDA (USA)

and not surprisingly many are directly linked with the therapeutic

actions e.g. rebound anxiety, rebound insomnia, musculoskeletal

problems, epileptic fits and severe memory problems. Because of the

wide range of therapeutic actions, and the fat-soluble nature of the

benzodiazepines few parts of the body and brain are exempt from

adverse reactions. Some patients have dozens of these adverse

reactions occurring at the same time or over a given period. No wonder

many are mis-diagnosed as having schizophrenia, dementia, chronic

fatigue syndrome, or muscular dystrophy. It seems that they will

enhance any psychological or physical problem existing prior to

ingestion of these drugs, in addition to the many new problems they

create.

 

2. Elimination Half-life and Accumulation

 

Accumulation of the benzodiazepines in the body and brain is a severe

problem with long-term use of many of the benzodiazepines e.g.

diazepam, chlordiazepam, chlordiazepoxide, flunitrazepam and

flurazepam. This is a result of long elimination half-lives of up to

250 hours and of the formation of active metabolites giving levels for

diazepam about six times the daily dose in two weeks and eight times

in four weeks. For a given drug the half-life can vary by up to a

factor of three between individuals. Metabolic changes in the elderly

with kidney or liver problems cause much slower elimination rates e.g.

for diazepam half-lives of 400 hours have been measured leading to

very high accumulation levels (x20). The benzodiazepines without

active metabolites can also produce significant accumulation levels

e.g. nitrazepam and lorazepam with half-lives of 18 to 57 hours and 12

to 34 hours respectively producing levels of about 4 and 3 times the

daily dose respectively with an ingestion period of one week.

 

A severe consequence of the accumulation of and toxicity of

benzodiazepines is the effect on babies born to mothers who have

ingested these drugs. They readily cross the placenta and allowing for

the measured levels in the umbilical cord, the increased

bioavailability, and the weight of the foetus, the level of exposure

per unit weight of the foetus is many hundred times that of the daily

dose level of the mother. It is not surprising that many babies are

born addicted to these drugs, suffering from floppy infant syndrome

and other problems. There is sufficient evidence to postulate a causal

link between benzodiazepines (and some other drugs) and the Sudden

Infant Death Syndrome although the authorities are very quick and keen

to deny such a possibility.

 

3. Individual Variability and Dependence

 

There is a wide variability in the patterns of response to

benzodiazepines among individuals, in both therapeutic and adverse

reactions, both wanted and unwanted. Individual variability is

determined largely by genetic programming of drug metabolism and

responsiveness. A clear-cut example of these phenomena is the 30-fold

variation in plasma concentration in patients given the same oral dose

of diazepam. This variability is dependent on both genetic and

environmental factors such as race, sex, age, smoking, disease and

concomitant drug treatment. Wide inter-individual response to these

drugs was frequently recorded in research studies and clinical trials

in the 1960s, but has seldom been commented upon in recent decades.

 

There is one area where this variability has a strong impact i.e. the

probability of an individual becoming dependent on these drugs. It can

readily explain why some become dependent in a few weeks (shortest

recorded case - seven days) and others on similar doses may take more

than a year or more. This pattern is no different than that for

dependence to other drugs acting on the CNS, but the speed of onset

for benzodiazepines appears to be quicker than most, especially

alcohol (5 mg diazepam = 2 units of alcohol).

 

In essence, chronic dependence is the repeated taking of the drug to

alleviate the adverse reactions caused by that drug. In everyday terms

it is taking " the hair of the dog that bit you " . Those who are more

sensitive to unwanted adverse reactions will become more quickly

dependent on these drugs especially if the link between the drug and

adverse reaction is not recognised by the patient and the doctor (as

happens very frequently). There are " 101 " reasons why individuals

start taking drugs and continue to take them prior to chronic

addiction, but only one to explain how dependence occurs with drugs

having widely different and sometimes opposite therapeutic actions. In

other words - pharmaceutical actions cause adverse reactions -

therapeutic actions alleviate adverse reactions.

 

Resort to half baked ideas like personality traits and characteristics

is not necessary or appropriate. Such an explanation will be less than

satisfying to the members of the medical profession and the drugs

industry whose thinking is rooted in the 19th century, and revolves

around mental and moral issues. It is however far more acceptable to

the 13,000 BMA members dependent on alcohol, prescribed drugs and hard

drugs (BMA conference, Birmingham 1998).

 

4. Toxicity

 

The toxicity of drugs can be related to total dosage i.e. the larger

the dose the greater the toxic effects e.g. overdose and death. Most

drugs can produce toxic reactions in the normal or therapeutic range,

especially those that accumulate in the body with repeated doses.

Toxic effects due to overdose are generally a harmful extension of the

drugs normal pharmacological reaction and are largely predictable and

preventable. Toxic reactions that occur with normal doses are often

unrelated to known pharmacology and are responsible for most of the

adverse reactions reported for the benzodiazepines.

 

Toxicity resulting from a drug may be divided into four types (Spilker

B., 1992):

 

Type 1. Toxicity results from an excess of an undesired

pharmacological effect. Many of the benzodiazepines adverse reactions

are in this category because in general they are presented for only

one of the main therapeutic actions e.g. if diazepam is prescribed as

a muscle relaxant then the dependence, withdrawal, memory problems,

fits, anxiety, etc. are of this type.

 

Type 2. Toxicity results from an excess of a desired beneficial

pharmacological effect for which the drug is used e.g. hangover effect

for hypnotics.

 

Type 3. Toxicity results from effects not observed at therapeutic

doses. These are generally predictable and observed in overdose e.g.

coma. The safety index of a drug is defined as the ratio between the

minimum toxic dose and the maximum effective dose, the larger the

ratio the greater the safety. The barbiturates generally have a higher

value than the benzodiazepines (but not as high as the blown up

estimates of the drug industry) but the individual variability of the

benzodiazepines has caused deaths at a few times the therapeutic dose.

 

Type 4. Toxicity is unexpected (paradoxical reactions). These are

idiosyncratic events and often may be the opposite of the intended and

anticipated response. For some drugs these occur at low rates but for

the benzodiazepines they occur relatively frequently e.g. rebound

anxiety, rebound insomnia, muscular tension, aggression and hostility.

These occur so frequently that they can no longer be described as

unexpected.

 

Adverse Reactions and Events

 

Adverse reactions include any undesirable effects that occur e.g.

 

1.

 

Physical symptoms

2.

 

Psychological symptoms

3.

 

Physical signs

4.

 

Laboratory values from tests and biological samples

5.

 

Laboratory values from tests on the patient's EEG etc.

6.

 

Other factors relating directly to deterioration of the quality

of life and social interactions

 

The frequency of toxic adverse reactions is not given in data sheets

or literature in the UK. Their frequencies are given in some

international data sheets e.g. the Spanish data sheets (data supplied

by the drug companies) give a wide range of adverse reactions for many

benzodiazepines. These reactions include:

 

*

 

Greater than 25%: drowsiness, confusion and ataxia.

*

 

From 10 - 25%: sedation, depression, disorientation, dysphagia,

dysarthia, poor concentration, trembling, changes in libido,

incontinence, nausea, vomiting, diarrhoea and hyper salivation.

*

 

From 1 - 9%: hepatitis, dermatitis, urticaria, puritis,

leucopoenia, anterograde amnesia, paradoxical excitation, changes in

vision, diplopia, nystagmus, hearing changes and eosinophilia.

*

 

Less than 1 %: respiratory depression, hypertension,

hypotension, bradycardia, tachycardia and palpitations.

 

5. Toxic Poisoning

 

It is interesting to note that the most frequently reported adverse

reactions in Canada (about 50% of adverse reactions for single

benzodiazepine ingestion) is encephalopathy i.e. organic brain

disease. One of the manifestations of this illness is toxic psychosis

or toxico mania which the World Health Organisation has defined as a

chronic state of intoxication produced by repeated consumption of a

drug harmful to the individual or to society.

 

The characteristics are:

 

1.

 

Uncontrollable desire or necessity to continue consuming the

drug and try to get it by all means.

2.

 

Tendency to increase the dose.

3.

 

Physical and psychic dependence as a result.

 

Many long-term therapeutic addicts will readily identify with toxico

mania, especially those addicted to long half-life benzodiazepines.

This aspect of the benzodiazepine problem which put simply is toxic

poisoning produces an altered state of consciousness with an altered

state of perception of self, others and one's environment and

relationships* In many ways this syndrome is similar to that produced

by chemical poisoning e.g. organo-phosphates. The lack of

self-awareness can take many years to change, often requiring much

information, knowledge and counselling to achieve it. *nb after

discontinuation of drugs many have an enduring personality change.

 

6. Medical Literature

 

The medical literature contains thousands of papers on toxic effects

and resulting adverse reactions and effects. Listed below are some of

the topics in the VOT archives with the number of papers in brackets:

 

1.

 

Dependence and withdrawal (500)

2.

 

Adverse reactions, side-effects and paradoxical reactions (220)

3.

 

Cognitive impairment, memory and brain problems (140)

4.

 

Pregnancy, neonates, infants (120)

5.

 

Toxicity, poisoning, suicides, deaths (100)

6.

 

Driving problems, accidents, injuries (80)

7.

 

Elderly (60)

 

Many of these papers were published in the 1960s and 1970s and they

contain most of the information on benzodiazepine problems that has

only recently been accepted and included in data sheets and patient

information leaflets. Some problems are still not included. On the

other hand most information was published in overseas adverts,

journals and data sheets.

 

Sections A and B contain a selection of extracts from representative

and key papers on cognitive impairment, long-term damage and the post

withdrawal syndrome.

 

Section A

 

Cognitive Impairment and Long-Term Damage

 

The many papers published in the 1960s and early to mid 1970s on this

subject were largely single dose therapeutic dose studies or low-dose

studies for periods of a few weeks. They showed a range of deficits in

cognitive function, psychomotor performance and short-term memory

problems with no development of tolerance. It was not until the late

1970s and early 1980s (when therapeutic dose dependency was belatedly

accepted), that cognitive function and other tests on long-term

benzodiazepine users (up to 10 years) were studied both during use and

in acute withdrawals. From the mid 1980s to mid 1990s there was an

increasing number of studies looking at damage after long-term use and

at follow-up periods after discontinuation of up to six years. Several

of these studies involve CT scans of the brain looking for structural

changes.

 

Summary

 

1.

 

Benzodiazepines produce impairment of cognitive functioning and

psychomotor performance e.g. reaction time, vigilance, arousal,

judgement, reasoning, speed and accuracy of information processing,

visual spatial ability, co-ordination, short-term and post drug

long-term memory, 'blackouts' and learned tasks.

2.

 

These effects are independent of abuse, dependency,

non-dependency, normal, healthy, young or old subjects. Impairment

increases with chronic use. Development of tolerance to these effects

is very slow.

3.

 

CT brain scans show a difference in ventricular cerebral spinal

fluid space dimensions between benzodiazepine users and non-users, and

also between high and low benzodiazepine users.

4.

 

The functional brain damage causes increased morbidity,

increased mortality and social deterioration.

5.

 

Subjects are generally not aware of their reduced capacity or

the fact that they are not functioning well in every day life.

6.

 

In general much of the impairment is slowly reversible. Some

aspects show improvement after six years, some are semi-permanent or

permanent.

 

Key papers: 1, 4, 10,12, 17, 20, 21, 24, 25, 28, 29, 37, 38, 40.

 

Benzodiazepines - Section A

Cognitive Impairment/Long-Term Damage

 

References and extracts

 

1.

 

Di Mascio A. et al. (1968) Behavioural Toxicity of Psychotropic

Drugs Connecticut Med. 32, 8, 617-620. Reaction time, judgement,

concentration and visual acuity are impaired by benzodiazepines.

2.

 

Kleinknecht R. (1975) Review of Effects of Diazepam on Cognitive

and Psychomotor Performance. J. Nerv. Mental Dis.161, 399-411. 23

studies (1970-75) Mainly young healthy volunteers after a few days

ingestion showed impairment in 6 areas of cognitive function.

3.

 

Liljequist R. et al. 1978 Effects of Diazepam and Chlorpromazine

on Memory Functions in Man. Europe J. Clin. Pharmacol.13, 339-343.

Single doses, 2 weeks treatment. Impairment of acquisition, reaction

time, co-ordination and memory. Impaired transfer from short to long

term memory.

4.

 

Grant I. (1978) Organic Impairment in Poly Drug Users, Risk

Factors. Amer. J. Psychiatry,135, 2, 178-184. Extensive use (up to 10

years) of CNS depressants (incl. Benzodiazepines) causes

neuropsychological impairment detectable 3 months after cessation of

drug taking and may be long lasting.

5.

 

Lucki I. et al. (1980) Chronic use of Benzodiazepines and

Psychomotor and Cognitive Test Performance. Psychopharmacology, 88,

426-433. Behavioural and cognitive tests on chronic users (5yrs) gave

results that are similar or worse than a control group with diagnosed

anxiety disorders (no pills). [so much for the effectiveness of

benzodiazepines - RFP]

6.

 

Hendler N. et al. (1980) Comparison of Cognitive Impairment due

to Benzodiazepines and Narcotics. Amer. J. Psychiatry,137, 828-830.

Cognitive impairment due to benzodiazepines is marked, no effect due

to narcotics at clinical doses.

7.

 

Bergman H. et al. (1980) Neuropsychological Impairment and

Exclusive Abuse of Sedatives or Hypnotics. Amer. J. Psychiatry,137, 2,

215-17. Chronic use for 5 to 10 or more years. Tests 3 to 10 months

after withdrawal showed significant decrease in neuropsychological

performance and intellectual impairment compared with a control group.

8.

 

Scharf M. (1982) Lorazepam, Efficacy, Side Effects and Rebound

Phenomena. Clin. Pharmacol. Ther., 31, 2,175-179. Lorazepam (4mg) used

in 18-night sleep study with insomniacs. Rebound insomnia, rebound

anxiety, severe hangover and impaired functioning, including

anterograde amnesia.

9.

 

Petursson H. et al. (1983) Psychometric Performance during

Withdrawal from Long-Term Benzodiazepine Treatment.

Psychopharmacology, 81, 345-349. Chronic use of benzodiazepines

results in selective and chronic psychological deficits including fine

motor control and co-ordination. Rebound effects measured during

withdrawal. Likelihood of cerebellar damage.

10.

 

Block R.I. et al. (1984) Alprazolam and Lorazepam Effects on

Memory Acquisition and Retrieval Processes. Pharmacol. Biochem. and

Behaviour, 20, 233-241. Both benzodiazepines produced marked memory

impairment of acquisition and retrieval for long term memory (pre

drug). [This study supports the anecdotal reports of hundreds who

claim that their retrograde memory was impaired for many years after

stopping the benzodiazepines - RFP]

11.

 

Romney D.M. et al. (1984) A Brief Review of the Effects of

Diazepam on Memory. Psychopharmacol. Bull., 20, 313-315. Review of

about 30 papers. Supports memory loss is due to a consolidation

process of impairment i.e. short- to long-term memory transfer.

Queries use of psychotherapy whilst patient is on diazepam.

12.

 

Lader M. et al. (1984) Computerised Axial Brain Tomography in

Long-Term Benzodiazepine Users. Psychological Med., 14, 203-206.

Benzodiazepine users have larger ventricular brain ratio than control

group.

13.

 

Angus W.R. (1984) Effects of Diazepam on Patients Memory. J.

Clin. Psychopharmacol., 4, 4, 203-206. Has detrimental effect on short

term and long term memory. It interferes with consolidation process of

information transfer i.e. short- to long-term storage. Dose 5-30

mgs/dly, patients 21-74 yrs.

14.

 

Mac D.S. et al. (1985) Anterograde Amnesia with Oral Lorazepam.

J. Clin. Psychiatry, 46,137-138. Young healthy volunteers, 2mg

Lorazepam, single dose. Deleterious effect on short-term recall of

verbal information.

15.

 

Lucki I. et al. (1985) Psychomotor Performance Following

Long-Term Use of Benzodiazepines. Psychopharmacol. Bull., 21, 93-96.

Chronic users (6yrs) for 5 different benzodiazepines on equivalent of

10-30 mgs. dly of Valium, compared with a group of anxious patients

not on benzodiazepines. Very little difference except for impairment

of delayed recall for Benzodiazepine users. [benzodiazepines

ineffective - RFP]

16.

 

Pomara M. et al. (1985) Increased Sensitivity of the Elderly to

the Central Depressant Effects of Diazepam. J. Clin. Psychiatry, 46,

5,185-187. Groups of old and young healthy volunteers. Single 2.5 mg

dose. Impaired immediate and delayed recall memory and psychomotor

performance for elderly is much greater than for the young.

17.

 

Curran H.V. (1986) Tranquillising Memories. A Review of the

Effects of Benzodiazepines on Human Memory. Biolog. Psychology,

23,179-213. Review of 1973 - 1985 papers, about 90 papers on 20

different benzodiazepines. Most studies are short-term of single dose.

All show amnesic problems and cognitive deficits.

18.

 

Cole S.O. (1986) Effects of Benzodiazepines on Acquisition and

Performance: A Critical Assessment. Neuroscience and Biobehaviour

Revs., 10, 265-272. Review of up to 100 papers. Benzodiazepine

produced impairment of learned tasks (behaviour) as well as an

acquisition impairment of different (new) tasks.

19.

 

Brosan L. et al. (1986) Performance Effects of Diazepam During

and After Prolonged Administration. Psycholog. Med., 16, 561-571.

Repeated doses for 3 weeks. Reduced performance while on drug and for

3 weeks afterwards e.g. reduced reaction time and reasoning.

20.

 

Borg S. (1986) Dependence and other Long-Term Effects Associated

with Benzodiazepines. Lakartidningen, 83; 321-326. Withdrawal symptoms

occur after 1-2 weeks of benzodiazepine ingestion, 15% become

dependent with short term use (weeks). Benzodiazepines cause

functional brain damage similar to that seen with alcohol abuse.

Increased mortality and marked social deterioration. Whether brain

damage is permanent requires further research.

21.

 

Borg S. (1987) Sedative Hypnotic Dependence: Neuropsychological

Changes and Clinical Course. Nord. Psyhiatr. Tidsskr., 41,

Suppl.15,17-19. Neuropsychological impairment present in patients,

independent of abuse, dependence or non-dependence. Impairment still

present after abstinence of 1, 4 and 6 years.

22.

 

Smiley A. (1987) Effects of Minor Tranquillisers and

Antidepressants on Psychomotor Performance. J. Clin. Psychiatry, 48,

Suppl.12, 22-28. Review of studies of the effects of benzodiazepines

on tracking, reaction time, vigilance and divided attention. Diazepam

clearly impairs performance for several hours after dosing. No

evidence of tolerance for up to 3 weeks. Effects are the same for

groups of anxious and normal subjects.

23.

 

Golombok S. et al. (1987) A Follow Up Study of Patients Treated

for Benzodiazepine Dependence. Br. J. Med. Psychol., 60,141-149.

Examination of patients from 1-5 years after discontinuation, 54% had

withdrawn successfully in spite of continuing psychiatric symptoms.

24.

 

Schmauss C. et al. (1987) Enlargement of Cerebral Spinal Fluid

Spaces in long Term Benzodiazepine Users. Psychological Med.,17,

869-873. Large difference in CSF spaces between high and low dose

benzodiazepine users for 5-6 years.

25.

 

Lader M. (1987) Long-Term Benzodiazepine Use and Psychological

Functioning. The Benzodiazepines in Current Clinical Practice. Roy.

Soc. Med., 1987, 55-59. Patients perform poorly on tasks involving

visual spatial ability and sustained attention. They are not aware of

their reduced ability. Only after they have withdrawn do they realise

that they have been functioning below par.

26.

 

Larson E. et al. (1987) Adverse Drug Reaction Associated with

Global Cognitive Impairment in Elderly Persons. Anns. of Inst. Med.,

107, 169-173. Patients on long-term/long half-life benzodiazepines

diagnosed with dementia. After discontinuation 30% re-diagnosed i.e.

no dementia after 1 year follow up.

27.

 

Lavender S. (1988) Psychophysiology and Anxiety: Current Issues

and Trends. Pharmacological Treatment of Anxiety,145-51.

Benzodiazepine induced neurophysiological impairment, in worst cases

permanent.

28.

 

Golombok S. et al. (1988) 'Impairment in Long Term

Benzodiazepine Users' Psychological Med.,18, 365-374 Patients on

benzodiazepines not functioning well in everyday life and not aware of

reduced ability. Recognition of below par functioning after

withdrawal. Cognitive impairment greater with chronic medication.

29.

 

Bergman H. et al. (1989) Dependence on Sedative Hypnotics,

Neuro-Psychological Impairment, Field Dependence and Clinical Course

in a 5 yr Follow Up Study. Br. J. Addiction, 84, 547-553. Cerebral

disorders present 4-6 years after drug discontinuation - permanent? CT

scans show dilation of ventricular system in brain.

30.

 

Danion J.M. et al. (1989) Diazepam Induces a Dissociation

Between Explicit and Implicit Memory. Pharmacology, 99, 238-243.

Healthy volunteers, double blind study. Diazepam impairs explicit

memory (new events/recent information) but not implicit (knowledge

based memory). Organic Amnesia like Korsakoff's Syndrome.

31.

 

Penetor D.M. et al. (1989) Triazolam Impairs Learning and Fails

to Improve Sleep in a Long-Range Aerial Deployment. Aviation, Space

and Envir. Med., June, 594-597. Ability to recall recent verbal

information impaired 8 hrs after ingestion of triazolam.

32.

 

Curran H.V. (1991) Benzodiazepines, Memory and Mood: A Review.

Psychopharmacol., 105,1-8. Effect of benzodiazepines on anxiety,

cognitive function and arousal. Detailed discussion on memory

processes affected by benzodiazepines. Slow tolerance to memory

impairment, i.e. tolerance not fully developed.

33.

 

Lader M. (1992) Benzodiazepines and Memory Loss: More Than Just

Old Age. Prescriber, 3,13. Benzodiazepines cause memory losses, or

'blackouts'. They impair speed and accuracy of information processing.

34.

 

Slazman C. et al. (1992) Cognitive Impairment Following

Benzodiazepine Discontinuation in Elderly Nursing Home Residents.

Intl. J. Geriatric Psychiatry, 7, 89-93. Group of patients on short

half-life benzodiazepines for 18 months. After 1 year discontinuation

impairment in short-term memory and alertness. Impairment slowly

reversible.

35.

 

Bowen J.D. (1993) Drug Induced Cognitive Impairment. Drugs and

Ageing 3 (4), 349-357. Benzodiazepines have a high risk of cognitive

impairment. A common cause of delirious and a confounding factor in

dementia.

36.

 

Anon (1993) Learning and Memory Impairment in Older Detoxified

Benzodiazepine Dependant Patients. Mayo Clinic Proc., 68, 731-737.

Benzodiazepines have an accumulative effect on memory that did not

necessarily diminish with time after detoxification.

37.

 

Moodley P. et al. (1993) Computed Axial Brain Tomograms in Long

Term Benzodiazepine Users. Psychiatric Research, 48,135-144.

Differences in the density of some areas of the brain between

benzodiazepine and non-benzodiazepine users.

38.

 

Tata P.R. et al. (1994) Lack of Cognitive Recovery Following

Withdrawal from Long-Term Benzodiazepine Use. Psycholog. Med., 24,

202-213. Modest recovery of cognitive deficits after 6 months

cessation of benzodiazepines compared with pre and post withdrawal and

a follow up.

39.

 

Binnie C. (1994) Cognitive Impairment - Is It Inevitable?

Seizure, 3 Supple. A. 17-22. Most anti-epileptic drugs, including

benzodiazepines, cause cognitive impairment.

40.

 

Patten S.B. et al. (1994) Neuropsychiatric Adverse Drug

Reactions. From Canadian Adverse Data Base (65-94) Intnl. J.

Psychiatry in Med., 24 (24), 45- 62. Over half of all reports (for

single benzodiazepines) were for encephalopathy (organic brain disorder).

41.

 

Tonne U. et al. (1995) Neuropsychological Changes During Steady

State Drug Use. Acta Psychiatr. Scand., 91, 299-304.

Neuropsychological deficits only partly reversible on discontinuation

at 1 yr follow up.

42.

 

Anon (1996) Intellectual Impairment and Acquired Intellectual

Deterioration in Sed/Hyp Drug Dependent Patients. Dept. of Psychology

and Psychiatry Clinic, Stockholm University, Sweden. Every second

patient on sed/hyp drugs showed signs of intellectual impairment.

 

Section B

 

Long-Term Damage and The Post Withdrawal Syndrome (PWS)

 

The existence of the post withdrawal syndrome is recognised and

accepted for other drugs like the barbiturates, opiates and alcohol.

(See references 3, 20, 26). Its occurrence is routine enough for it

seldom to be commented upon. Although many alcoholics and hard drug

addicts receive primary treatment for four to ten weeks, a minority

need and receive residential treatment and rehabilitation for up to 12

months. It would be appropriate if similar opportunities were

available to benzodiazepine therapeutic addicts. There is a desperate

need for them.

 

Just as there was (and is) a strong resistance from the medical

profession and the drug companies to recognising and accepting

therapeutic dose dependence there was (and is) a similar reaction to

the benzodiazepine post withdrawal syndrome. There is a strong

knee-jerk reaction geared to diverting the blame from the drugs and

prescribing practices onto the patients. A range of speculative

reasons is offered e.g. the symptoms are a return of the original

complaint, latent mental problems exposed by the drugs and the old

chestnut, personality disorders.

 

Contrary to these myths are the following:

 

1.

 

Few if any studies have actually checked the original records

for prescribing diagnosis, most information is anecdotal. The best

evidence there is suggest that at least 85% of prescriptions are given

for non psychiatric disorders.

2.

 

There is no evidence that personality traits or characteristics

predispose anyone to dependence (Royal College of Psychiatrists,

1987). The few before, during and after dependency studies show no

correlation.

3.

 

All aspects of drug dependency can be fully explained by

biochemical factors (World Health Organisation 1993).

4.

 

The claim that drugs expose latent problems is unprovable,

unsustainable and unscientifc. What is provable is that psychoactive

drugs cause psychiatric disorders and marked changes in personality.

 

From the mid-1980s to the mid-1990s there was an increasing number of

papers studying this syndrome up to five years after discontinuation

of drug taking. These studies were sometimes in parallel with

investigations of the nature of long-term damage and conclude that it

is an iatrogenic condition. In addition, there is a significant

overlap between the syndrome, acute withdrawals and long-term

ingestion of benzodiazepines, clearly establishing a link between the

post withdrawal syndrome and adverse reactions caused by these drugs.

 

Summary

 

1.

 

There is a very wide range of physical and psychological

symptoms for example: paranoia, delusions, shaking and trembling,

paraesthesiae, depression, behavioural disorders, unstable mood,

headache, irritability, insomnia, anxiety, malaise, poor

concentration, gastrointestinal problems, abdominal discomfort,

depersonalisation, derealisation, emotional instability, sensory

disturbances, perceptual changes, auditory changes, tinnitus,

vulnerability to stress, unsteadiness, neck tension, neuro-muscular

problems, " bursting head " , phobias, panic, obsessive features and

palpitations.

2.

 

The post withdrawal syndrome is largely responsible for relapse

- from 30 to 70% in different studies, up to five years after

discontinuation.

3.

 

The studies have established that the PWS is:

*

 

Linked with biological abnormalities - up to 3.5 years

*

 

Is reversed for short periods by flumazenil, an

antagonist, up to five years.

*

 

Associated with a non-reversal of tolerance up to 3.5 years.

*

 

Linked with permanent changes to the central nervous system.

4.

 

Patients with a history of benzodiazepine dependence are

unlikely to respond normally to these drugs after discontinuation.

5.

 

There is a 1:1 correspondence between long-term damage and the

post withdrawal syndrome.

6.

 

Careful management of the PWS is required and should include

help from doctors, family, friends, support groups, stress management,

cognitive behavioural therapy, knowledge and information - to help the

patient come to term with the patients changed life situation.

7.

 

At least 30% of benzodiazepine dependent patients experience the

PWS rising to nearly 100% for long-term chronically dependent patients.

 

Key papers: 4, 5, 6, 7, 10, 18, 24, 25, 27, 28.

 

Little has changed

 

" Physicians pour drugs of which they know little to cure diseases of

which they know less, into humans of whom they know nothing. " Voltaire

(1694-1778)

 

References and extracts

 

1.

 

Tyrer P. et al. (1983) Gradual Withdrawal of Diazepam after

Long-Term Therapy. Lancet i,1482 - 86. At six months follow-up 19 out

of 41 patients relapsed, three became seriously ill (?), others had

developed paranoia and delusions.

2.

 

Ashton H. (1984) Benzodiazepine Withdrawal: An Unfinished Story.

British Medical Journal 288,1135-1140. Patients assessed every one -

two weeks in withdrawal. Wide range of persisting symptoms, up to at

least six months.

3.

 

Jaffe J.H. (1986) Drug Addiction and Drug Abuse. The

Pharmaceutical Basis of Therapeutics, 7th Edit. New York, McMillan

1985 chapter 23, 532-81. Depressive states, unstable mood and insomnia

are common during the months following withdrawal of alcohol and opioids.

4.

 

Ashton H. (1986) Adverse Effects of Prolonged Benzodiazepine

Use. Adverse Drug Reaction Bull.,118, 440-443. Acute withdrawal is

followed by a prolonged period (many months) of gradually diminishing,

mixed psychological and somatic symptoms. The illness produced by the

protracted syndrome may be more severe than that for which the

benzodiazepines were originally prescribed.

5.

 

Ashton H. (1987) Benzodiazepine Withdrawal: Outcome in 50

Patients. Br. J. Addiction, 82, 665-71. Patients assessed from 10 - 42

months after withdrawal. 48% had slight symptoms, 22% had moderate

symptoms, 16% had severe symptoms interfering with life, 6% were

polysymptomatic and on other medication, 8% had relapsed on

benzodiazepines.

6.

 

Higgit A. et al. (1988) The Natural History of Tolerance to the

Benzodiazepines. Psychological Med. Monograph Supple.,13 Cambridge

University Press. 'It is no longer debated that tolerance develops

over periods of 6 months! Tolerance is still present in patients off

benzodiazepines for 5 - 42 months. Low single dose challenge to

patients precipitated withdrawal symptoms. It is unlikely that

patients with a history of benzodiazepine dependence will respond

normally to these drugs'. The presence of permanent changes to the CNS

is indicated.

7.

 

Marks J. (1988) Techniques of Benzodiazepine Withdrawal in

Clinical Practice. Med. Toxicology, 3, 324-333. Post withdrawal

syndrome of many months consists of a fluctuating malaise, poor

concentration, abdominal discomfort, depersonalisation, derealisation

and emotional liability. Management of the PWS requires various forms

of help to come to terms with the patients' life situation, e.g. help

from doctors, family friends, support groups and stress management.

8.

 

Busto U. et al. (1988) Protracted Tinnitus after Discontinuation

of Long Term Therapeutic Use of Benzodiazepines. J. Clin.

Psychopharmacol., 8, 359-61. Sensory disturbances of long term

duration are among the most distinctive clinical features of

benzodiazepine withdrawal syndrome. Tinnitus present 1 year after

discontinuation.

9.

 

Montgomery S.A. et al. (1988) Benzodiazepines: Time To Withdraw.

Journal of the Royal College of General Practioners 1988; 38: 146-147.

After withdrawal patients remain vulnerable to stress for at least 6

months.

10.

 

Higgit A. et al. (1990) The Prolonged Benzodiazepine Withdrawal

Syndrome; Anxiety or Hysteria? Acta. Psychiatr. Scan., 82,165-168. PWS

is a genuine iatrogenic condition. 30% of dependent patients get it.

Tests point to biological abnormalities. Patients discontinued and

tested after 5 to 42 months.

11.

 

Roche Products Ltd. (ca.1990) Benzodiazepines and your Patients:

A Management Programme (Sent to prescribers on request). The post

withdrawal syndrome can manifest itself as fluctuating levels of

malaise, lack of concentration, abdominal discomfort,

depersonalisation and emotional liability. If post withdrawal symptoms

occur good support from the general practitioner over at least the

first year reduces the risk of relapse.

12.

 

Holm M. (1990) One Year Follow up of Users in General Practice.

Danish Med. Bull., 188-191. First time users more likely to

discontinue in one year (55%) than long term users (12%).

13.

 

Holton A. (1990) Five Year Outcome In Patients Withdrawn from

Long Term Treatment with Diazepam. BMJ,1241-1242. High level of

relapse (75%), taking benzodiazepines for insomnia, anxiety and stress.

14.

 

Ashton H. (1991) Protracted Withdrawal Symptoms. J. Substance

Abuse Treatment, 8,19-28. Persistent symptoms may last for many months

and are related to long-term benzodiazepine use. Delayed or slow

reversal of tolerance may account for some protracted withdrawal

symptoms. The possibility is that benzodiazepines produce slowly

reversible functional changes in the CNS and cause structural neuronal

damage.

15.

 

Lader M. (1991) Benzodiazepine Problems. Br. J. Addiction, 86,

823-828. Persisting symptoms - unsteadiness, neck tension, 'bursting'

head, perceptual distortion, muscle spasm, anxiety, phobias, panic,

obsessive and depressive features.

16.

 

Rickels et al. (1991) Long Term Benzodiazepine Users - 3 Years

after Participation in a Discontinuation Program. Am. J.

Psychiatry,148, 6., 757-761. Anxiety and/or depression in patients who

had discontinued benzodiazepines for 3-5 years was less than that (but

still significant) in patients who continued to take benzodiazepines

[benzodiazepines cause depression and anxiety - RFP].

17.

 

Tyrer P. (1991) The Benzodiazepine Post Withdrawal Syndrome.

Stress med., 7,1-2. Feelings of tension, threat, bodily feelings,

unsteadiness, shaking, palpitations, gastrointestinal symptoms,

agoraphobia. There is a considerable overlap between symptoms of the

post withdrawal syndrome and the acute withdrawal syndrome.

18.

 

Lader M. (1992) Pilot Study of the Effects of Flumazenil on

Symptoms Persisting after Benzodiazepine WithdrawaI. J.

Psychopharmacology, 6. 357- 363. Patients off benzodiazepines for 1

month to 5 years had persisting benzodiazepine withdrawal symptoms

significantly lessened. Symptoms include clouded thinking, tiredness,

muscular symptoms, neck tension, cramps, shaking, pins and needles,

burning skin, pain and sensations of bodily distortion and mood

disorder. The benefits lasted several hours to several days.

19.

 

Higgit A. et al. (1992) Withdrawal from Benzodiazepines and the

Persistent Benzodiazepine Withdrawal Syndrome. In Granville Crossman

(ed) Recent Advances in Clin. Psychiatry: No. 8, London, Churchill

Levingstone,1992, 49-59. 30% of patients experiencing acute

withdrawals continue with the persistent withdrawal syndrome.

Cognitive processes linked to high risk of PWS. [impaired cognitive

processes induced by benzodiazepine ingestion - RFP].

20.

 

Landry M.J. et al. (1992) Benzodiazepine Dependence and

Withdrawal, Identification and Management. J. Amer. Board Fam. Pract.,

5(2),167-75. A prolonged sub acute low dose benzodiazepine withdrawal

syndrome can last for months or even years.

21.

 

Eduards R. (1993) Benzodiazepines and Dependence. Statens

Offentliga Utredninger, 5,135-140. Duration of withdrawal phenomena;

recent figures of over 1 year have been proposed. It is well

recognised that withdrawal syndromes from barbiturates, narcotics and

other psychoactive drugs may also be similarly prolonged.

22.

 

Lader M. (1994) Anxiety or Depression During Withdrawal of

Hypnotic Treatments. J. Psychosomatic Res.,18, Suppl. 1,113-123.

Hypnotic withdrawal. Persistent withdrawal syndrome dominated by

anxiety (generalised, phobic or both), phobic behavioural disorder and

panic attacks. Many of the litigants involved in the UK court case

suffered form prolonged disabilities of this type.

23.

 

Geller A. (1994) Management of Protracted Withdrawal. Amer. Soc.

of Addiction, Ch.2,1-6. Persistent symptoms - impaired concentration,

derealisation, depersonalisation, headaches, sleep disturbances,

tension, irritability and lack of energy.

24.

 

Ashton H. (1995) Protracted Withdrawal from Benzodiazepines; The

Post Withdrawal Syndrome. Psychiatric Annals, 25,174-179. A

substantial minority of patients have a PWS including perceptual

symptoms and gastrointestinal symptoms gradually receding, lasting at

least one year and occasionally permanent.

25.

 

Ashton H. (1995) Toxicity and Adverse Consequences of

Benzodiazepine Use. Psychiatric annals, 25,158-165. Some symptoms

decline more slowly merging into a period of increased vulnerability

to stress lasting many months. Protracted symptoms include prolonged

anxiety and depression, gastrointestinal disturbances, tinnitus,

neuromuscular abnormalities and paraesthesiae.

26.

 

Okada C. (1995) Treating the Patient with Benzodiazepine

Addiction. Hospital Update Sept. 396-401. A small proportion of

patients report significant withdrawal symptoms up to 3 years

following withdrawal.

27.

 

O'Brien C. P. et al.(1996) Myths About the Treatment of

Addiction. Lancet, 1996, 347, 237-240. Addiction drugs produce changes

in brain pathways that endure long after drug taking stops. The

associated medical, social and occupational difficulties that develop

during addiction do not disappear with detoxification. Protracted

brain changes, personal and social difficulties put the former addict

at great risk. Treatments for addiction should be regarded as

long-term. [A paper refuting the myths - RFP].

28.

 

Roche Products Ltd. (ca.1990) Benzodiazepines and your Patients:

A Management Programme (Sent to prescribers on request). The post

withdrawal syndrome can manifest itself as fluctuating levels of

malaise, lack of concentration, abdominal discomfort,

depersonalisation and emotional liability. If post withdrawal symptoms

occur good support from the general practitioner over at least the

first year reduces the risk of relapse.

 

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