Benzodiazepines(BZDs) are a type of psychotropic drug: i.e. they affect
the mind and can alter mood. They are generally known as minor
tranquillisers and were introduced initially as anxiolytics (drugs to
relieve anxiety). Librium was the first to be marketed, and was hailed
as a good alternative to barbiturates which were recognised as being
potentially fatal. By the late 1960s, a number of other BZDs were
available and they became hugely popular as treatment for anxiety and
insomnia, especially as they were thought to be non-addictive. Nowadays,
of course, it has been recognised that BZDs are in fact tremendously
addictive and are a leading cause of dependence on prescription drugs.
For this reason, their use in chronic pain is controversial.

In the context of chronic pain, BZDs are quite commonly prescribed for 4
main reasons:
1. to treat anxiety/agitation secondary to chronic pain (ANXIOLYTIC)
2. to treat sleep disturbance due to pain (HYPNOTIC)
3. to treat muscle spasm or spasticity (MUSCLE RELAXANT)
4. as potentiators of opiate drugs.(ADJUNCTIVE ANALGESIC)

TYPES OF BZDs
Basically, it is helpful to divide the group into long-acting drugs and
short-acting drugs. This will be helpful in understanding both dosage
regime and adverse effects/withdrawal.

SHORT-ACTING LONG-ACTING
Alprazolam (Xanax) Chlordiazepoxide (Librium)
Lorazepam (Ativan) Clonazepam (Klonopin)
Oxazepam (Serax) Chlorazepate (Tranxene)
Temazepam (Restoril) Fluorazepam (Dalmane)
Triazolam (Halcion) Halazepam (Paxipam)
Diazepam (Valium) Prazepam (Centrax)


HOW DO THEY WORK?
BZDs affect specific benzodiazepine receptors in the nervous system that
are part of the GABA neurotransmitter system. GABA (gamma-amino-butyric
acid) is the major inhibitory neurotransmitter.
BZDs cause sedation, striated (skeletal) muscle relaxation, and have
anxiolytic(anti-anxiety) and anticonvulsant properties.
Most BZDs are broken down into active metabolites, which may have longer
half-lives than the original compound. They are absorbed in the stomach
and small intestine, and are highly fat-soluble, so may accumulate in
fatty tissue. They are excreted through sweat, saliva, urine, faeces and
breast milk.

EFFECTS OF BZDs ON SLEEP:
BZDs decrease sleep latency (time taken to fall asleep) and reduce
number of awakenings; overall REM(dream) sleep is reduced but there may
be more REM cycles late in sleep. Total sleep duration increases.
"Rebound" may happen within a short time of starting drugs like Halcion:
this worsens the insomnia.


WHICH BZD?
In the context of this article, the main relevant BZD is clonazepam, but
I will mention a few others briefly as they may also have been
prescribed and the issues of dependence are of great importance
especially if the use of a BZD can be readily avoided.

Clonazepam (Klonopin/Rivotril):
? muscle relaxant: may be used to treat myoclonus (muscle jerks)
especially nocturnal myoclonus Clonazepam has also been found to reduce
involuntary muscle hyperactivity which may arise due to chronic high
dose opiate therapy.( )
? anticonvulsant : 1mg initially at night for 4 weeks, increased over
2-4 weeks to a maintenance dose of 4-8mg daily in divided doses. May
decrease in effectiveness after months of continuous therapy.
? pain relief: it has been used for trigeminal neuralgia with some
success

Diazepam (Valium):
? short-term relief of mild to moderate anxiety.
? to relieve muscle spasms. (dose 2-15mg daily in divided doses up to
60mg daily if necessary)
? to help control epilepsy (usually acute attacks)
? used to treat symptoms of acute alcohol withdrawals

Librium:
Relief of mild anxiety and tension, it also reduces tension states
associated with:
? muscle spasm
? tension headache
? pre-menstrual syndrome (PMS)
? insomnia

Librium is also used to treat symptoms of alcohol withdrawal.

Alprazolam (Xanax): dosage: 0.25mg to 1.5mg daily.
? A study of cancer patients( ) found that it was helpful in relieving
neuropathic pain
? Used primarily for short-term relief of mild to moderate anxiety and
nervous tension
? symptoms of PMS
? tinnitus
? essential tremor
Ashton ( ) has expressed the opinion: "Alprazolam has been widely used,
particularly in the US, but is not recommended in the UK, especially for
long term use."
Peter Breggin MD wrote the following in his book "Brain-Disabling
Treatments in Psychiatry:Drugs, Electroshock and the Role of the FDA" in
1997 ( )
"Studies of Xanax show that most patients develop withdrawal symptoms
during routine treatment lasting only 8 weeks."
Within 2-4 weeks tolerance can develop to the sedative effect of minor
tranquillisers taken at night for sleep.
Short-acting BZDs can produce especially severe withdrawal symptoms
(this includes Xanax, Halcion, Ativan, Restoril and Serax).


Oxazepam:
? for anxiety: 15-30mg daily. Note it is short-acting and may have a
delayed onset of action.

ZOPICLONE: (Imovane)
Zopiclone, is a short-acting hypnotic agent. It belongs to a novel
chemical class which is structurally unrelated to existing hypnotics :
it is a cyclopyrrolone derivative,. However, zopiclone is similar to
benzodiazepines in its pharmacological profile.
It may be prescribed to help with disturbed sleep due to pain. It is
useful for insomnia characterized by difficulty in falling asleep,
frequent nocturnal awakenings and/or early morning awakening.
However, as with BZDs, it carries a high risk of dependence. Withdrawal
may result in rebound insomnia. It should only be used on a short-term
basis.

ADVERSE EFFECTS:
Clonazepam:
The most frequently occurring adverse effects of clonazepam are due to
central nervous system depression. Drowsiness occurs in approximately
50% of patients and ataxia(drunken gait) in approximately 30%. Behaviour
problems have been noted in approximately 25% of patients and increased
salivation in 7%. Often, the sedative side-effects subside after a time.

Behavioural problems include aggression, agitation, irritability,
hyperactivity, restlessness, depression/euphoria,
forgetfulness/confusion.
? Less common / rare side effects:
Nausea/vomiting; constipation, indigestion, increased/decreased
appetite, dry mouth/increased salivation
Difficulty urinating/enuresis (bedwetting)
Altered libido
Muscle/bone pain; muscle weakness; involuntary movement
Vertigo
Weight loss/gain
Hair loss or hirsutism ; rash/itching
Headache
Palpitations ; shortness of breath; fever
Hallucinations

PROBLEMS WITH OTHER BZDS:
Other problems may include paradoxical effects such as nightmares (may
occur with use of flurazepam and nitrazepam espec. in first week)
More seriously, drugs like Halcion and Xanax have been implicated in
"dyscontrol": increased violent activities (against the self and
others); decreased inhibition, increased anxiety, excessive
extroversion similar to that seen with alcohol and other CNS
depressants. Other kinds of behavioral changes have been reported, for
example, bizarre behavior, agitation, hallucinations, depersonalization.
In depressed patients, there may be a worsening of depression, including
increased suicide risk.
Adjustment of the dose (up or down) usually reduces the problem.


PARADOXICAL EFFECTS
Although there is considerable debate as to the exact number of people
who develop a "paradoxical reaction", it is estimated that somewhere in
the order of 5% may be involved. Basically, this is when the drugs cause
effects which are the opposite to those one would normally expect.
Such reactions include:
? Increased aggression
? Depression /suicidal ideation
? Derealisation/depersonalisation (bizarre "disconnected" feelings)
? Hallucination/illusions
? Other psychotic processes


LONG TERM ADVERSE EFFECTS:
It is well recognised nowadays that use of benzodiazepine drugs can
quickly lead to dependence, even at therapeutic doses, after only a
brief period of use.
However, the issues about long-term adverse effects on memory, mood and
personality are still contentious, with some experts maintaining that
dependency is the sole long-term problem, whereas others have described
clear correlations between the chronic consumption of BZDs and poor
mental health. The most common problems are chronic depression,
obsessive-compulsive disorder, phobias and personality changes.

WITHDRAWAL:
As already stressed, benzodiazepines are highly addictive and if
discontinued abruptly, but withdrawal symptoms tend to occur only in
about 50% of people. There is a wide range of symptoms. Withdrawal
symptoms after stopping a long-acting BZD may not develop for up to 3
weeks after last does, whereas with short-acting they occur within a few
hours (hence the possibility of inter-dose withdrawal symptoms.)

REBOUND PHENOMENON: "Rebound" means that the original problem returns at
a higher level. It might mean that sleeping disturbance is raised to
total insomnia.
Generally, the course of withdrawal is influenced by the duration of BZD
use and what dose has been taken. The full range of withdrawal symptoms
tend to cluster into 2 phases:
The initial phase can last for 6 weeks, the secondary for up to 12
months. Psychological problems tend to more resistant. Short-term high
dose users experience symptoms which start to peak early and are intense
whereas long-term low dose users tend to have more protracted extended
withdrawals. Seizures may occur during withdrawal from either short or
long term abuse, the risk of fitting being higher if there is a history
of fitting or if other CNS depressants have been taken.

DRUG INTERACTIONS:
BZDs are central nervous system depressants and will therefore
accentuate the effects of other CNS depressants, including alcohol. A
variety of other drugs can also interact with BZDs.