Download Chlordiazepoxide NMC Briefing Review Summary

New Medicines Committee Briefing
March 2016
Chlordiazepoxide oral capsules for treatment of acute alcohol withdrawal
is to be reviewed for use within:
Primary Care
Secondary Care


Summary:
 Chlordiazepoxide is an anxiolytic with a UK marketing authorisation for use in the management of
acute alcohol withdrawal.
 Anxiolytics listed in the Joint Formulary for treatment of alcohol withdrawal include diazepam,
escitalopram, lorazepam and propranolol.
 Chlordiazepoxide would provide an alternative to diazepam and lorazepam for patients who fail to
respond to first line treatments.
 Chlordiazepoxide is more expensive than generic diazepam (Note: Diazepam 10mg ≡ Chlordiazepoxide
25mg)
 Chlordiazepoxide would provide a long acting alternative to the short acting agents when preventing
withdrawal seizures.
 Chlordiazepoxide would contribute to a smoother withdrawal with fewer rebound symptoms.
 Chlordiazepoxide is less likely to be abused compared to rapid acting agents (diazepam and
lorazepam).
 Chlordiazepoxide is a schedule 4 controlled drug (CD Benz POM).
Page 1 of 14
Formulary application
Consultant submitting application:
Ediela Iliescu (Consultant Substance Misuse Pschyiatrist)
(North Staffordshire Combined Healthcare Trust)
Clinical Director supporting application: Derrett Watts (Consultant addiction Psychiatrist)
(North Staffordshire, Combined Healthcare Trust)
The application is a request for chlordiazepoxide to be considered for inclusion in the North
Staffordshire Joint Formulary for the treatment of alcohol withdrawal.
In support, the applicant states that chlordiazepoxide is well suited for the treatment of alcohol
withdrawal and can be used as an alternative to diazepam.
Dr Iliescu states that it is difficult to quantify the exact number of patients that commence
detoxification in the community. However, based on the figures provided by One Recovery in South
Staffordshire (Stafford, Tamworth, Burton and Cannock), it is estimated that approximately 500
hundred patients per year commence treatment for alcohol detoxification in the community.
In addition to the above, Dr Iliescu states that as chlordiazepoxide is long acting, use will lead to a
reduction in the number and length of hospital stays through effective symptom control.
Furthermore, chlordiazepoxide has a lower potential for abuse than diazepam as it is less well known
on the black market. Chlordiazepoxide is listed on the South Staffordshire Joint Formulary and is
already prescribed by experienced and trained staff in the management of acute alcohol withdrawal.
Background
Alcohol withdrawal is a potentially life threatening condition which can develop when a patient stops
drinking or significantly reduces their alcohol consumption after weeks, months or even years of heavy
drinking.
Patients can present with acute alcohol withdrawal or be admitted to hospital for another reason
which leads to an unplanned alcohol withdrawal episode. Alternatively, a patient may present wishing
to abstain from alcohol but has a high risk of acute alcohol withdrawal.
Symptoms occur as heavy prolonged drinking disrupts the brains neurotransmitters. Initially, alcohol
enhances the effect of Gamma-amino butyric acid (GABA) which promotes relaxation. However,
eventually chronic alcoholism suppresses GABA activity which requires a greater amount of alcohol to
produce the same desired effect (tolerance). In addition, to supressing GABA, alcohol also supresses
the activity of glutamate, a neurotransmitter which produces excitatory feelings. When heavy drinkers
stop suddenly, neurotransmitters previously supressed by alcohol are no longer supressed leading to
patients experiencing a rebound response leading to effects commonly associated with alcohol
withdrawal such as anxiety, irritability, agitation and seizures.
Symptoms range from excessive sweating, restlessness, agitation, mild anxiety, feeling nervous and
shaking to more severe complications such as anorexia, headache, nausea, vomiting, seizures and
delirium tremens (DTs). Symptoms usually occur eight hours after a fall in blood alcohol levels and
peak at day 2. Between 12 and 24 hours after stopping drinking, patients can experience auditory,
visual or tactile hallucinations which collectively is termed alcoholic hallucinosis. Delirium tremens (DT)
usually occur between 48 and 72 hours after stopping drinking and consist of rapid heartbeat,
confusion and fever. By day 4-5, symptoms have significantly improved. Patients may also develop
Page 2 of 14
Wernicke-korsakoff syndrome, depression and electrolyte disturbances as well as liver disorders such
as cirrhosis.
Management of acute alcohol withdrawal aims to prevent development of complications such as
seizures and delirium tremens. Furthermore, treatment aims to make management of withdrawal
more comfortable and produce an environment that allows abstinence to be produced and
maintained.
If symptoms are mild to moderate then patients may be treated as an outpatient. However, if
withdrawal symptoms are severe, presence of seizures or delirium tremens, previous detoxifications,
medical or psychiatric illness then hospital treatment may be necessary.
The NICE guidelines for the management of acute alcohol withdrawal recommend a benzodiazepine,
carbamazepine or alternatively, clomethiazole. Dosage regimens which should be considered are
either a standard fixed dose or symptom-triggered. NICE advises that for community based withdrawal
programmes, a fixed dose medication regimen is used whilst programmes for inpatient or residential
settings can be either fixed dose or symptom-triggered regimens.
Current formulary status
4.1.2
Anxiolytics
Diazepam
Escitalopram
Lorazepam
Propranolol
Restriction: For the treatment of Generalised Anxiety Disorder (GAD) only
Therapeutic class and mode of action
Chlordiazepoxide is a benzodiazepine. Chlordiazepoxide acts on benzodiazepine allosteric sites that are
part of the gamma-aminobutyric acid (GABA)A receptor/ion-channel complex which results in an
increased binding of the inhibitory neurotransmitter GABA to the GABAA receptor thereby producing
inhibitory effects on the central nervous system and body.
Licensed indication
Short term treatment of acute alcohol withdrawal.
Dosage and administration
The recommended dose for moderate alcohol withdrawal by mouth is 10 to 30 mg four times a day
reducing gradually over 5-7 days as per local protocol for titration regimens. The recommended dose
for acute alcohol withdrawal in severe dependence is 10-50mg four times a day and 10-40mg as
required for the first 48 hours reducing gradually over the following 7-10 days as per local protocol.
Maximum 250mg per day. 1
Page 3 of 14
Safety and adverse effects2
Contraindications
Hypersensitivity to the active substance or to any of the excipients
The use of chlordiazepoxide is contraindicated in:

Patients with acute pulmonary insufficiency: respiratory depression: sleep apnoea.

Patients with phobic and obsessional states

Patients with chronic psychosis

Patients with severe hepatic insufficiency

Patients planning a pregnancy

Patients with myasthenia gravis

Patients with hyperkinesis.
Adverse Events
Reported adverse effects of chlordiazepoxide include light-headedness and drowsiness, sedation,
unsteadiness and ataxia; these are usually dose related but, even after a single dose, may persist into
the following day. The elderly are particularly sensitive to the effects of central depressant drugs and
may experience confusion, especially if organic brain changes are present; the dosage of
chlordiazepoxide should not exceed one-half that recommended for other adults. Other adverse
effects include dependence, confusion, restlessness, agitation, irritability, aggressive outbursts,
delusion, nightmares, hallucinations, inappropriate behaviour, tremor, dysarthria, salivation changes,
incontinence, and thrombocytopenia / other blood disorders. Depressions and amnesia can result
from high doses.
Rare adverse effects include numbed emotions, reduced alertness, fatigue, headache, dizziness,
muscle weakness, vertigo, blurred vision, hypotension, gastrointestinal upsets, skin rashes, visual
disturbances, changes in libido, and urinary retention.
Drug Interactions2
Potential for pharmacodynamic interactions with chlordiazepoxide
Alcohol – chlordiazepoxide should not be used together with alcohol (enhanced sedative effects which
affect the ability to drive or operate machinery).
Antiepileptics – concurrent use with chlordiazepoxide may lead to side effects and toxicity.
Sodium oxybate – chlordiazepoxide enhances the effect of sodium oxybate.
Centrally acting drugs – enhancement of central depressive effect may occur if chlordiazepoxide is
combined with neuroleptics, antipsychotics, tranquillisers, antidepressants, hypnotics, analgesics,
anaesthetics, barbiturates and sedative antihistamines.
Cytochrome P450 inhibitors – (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin,
nefazadone, saquinavir, nelfinavir, indinavir, atanazavir, and telithromycin) may reduce clearance of
and potentiate the effect of chlordiazepoxide.
Cytochrome P450 inducers – (e.g. bosentan, carbamazepine, efavirenz, phenobarbital and rifampicin)
induce the clearance and reduce the effect of chlordiazepoxide.
Page 4 of 14
Narcotic analgesics - Enhancement of the euphoria may occur when given with chlordiazepoxide
leading to an increased psychological dependence.
Other drugs enhancing the sedative effect of chlordiazepoxide: cisapride, lofexidine, nabilone,
disulfiram, baclofen, tizanidine.
Clozapine – serious adverse events reported when benzodiazepines used with clozapine. Avoid
concomitant use.
Antihypertensives, vasodilators & diuretics - Enhanced hypotensive effect when chlordiazepoxide
given with ACE-inhibitors, alpha-blockers, angiotensin II receptor antagonists, calcium channel
blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil,
sodium nitroprusside and diuretics.
Dopaminergics – chlordiazepoxide may possibly antagonise the effect of levodopa.
Presentation
5mg capsules: Polypropylene tablet containers with low density polyethylene caps. Pack sizes: 28, 30,
56, 60, 100 and 500 capsules. White opaque PVC/PVdC 250μm / 40 gsm film and 20μm aluminium foil
Pack sizes: 28, 30 and 100 capsules
10 mg capsules: Polypropylene tablet containers with low density polyethylene caps. Pack sizes: 28,
30, 56, 60, 100 and 500 capsules. White opaque PVC/PVdC 250µM/40gsm film and 20µm aluminium
foil. Pack sizes: 28, 30 and 100 capsules. 5mg and 10mg capsules require storage below 25oC.
Guidance and Evidence Summary
NICE Guidance published
NICE Advice published
Yes
Yes
NICE advice is not NICE Guidance: it reviews the strengths and weaknesses of the relevant evidence to
provide useful information for those working on the managed entry of new medicines for the NHS.
There is NICE guidance on alcohol use disorders: diagnosis and management of physical complications
(CG100)3 and alcohol use disorders: diagnosis, assessment and management of harmful drinking and
alcohol dependence (CG115)4. These guidelines recommend fixed dose-regimens of benzodiazepines
for community settings or a symptom-triggered regime using benzodiazepines for inpatient assisted
withdrawals (Note: In the presence of liver impairment, NICE recommend a benzodiazepine which
requires limited liver metabolism such as lorazepam with monitoring of liver function). In addition to
the above, there is also NICE advice relating to alcohol use disorders: sample chlordiazepoxide
regimens for use in managing alcohol withdrawal5. This tool provides chlordiazepoxide dosing
regimens for alcohol withdrawal and is brought about by generalised recommendations in the British
National Formulary and a lack of national guidance. The regimes are outlined below:
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Fixed Dose regimen for chlordiazepoxide dosing in acute alcohol withdrawal
Daily alcohol
consumption
Severity of
alcohol
dependence
15–25 units
30–49 units
Day 7
Moderate SADQ score 15-25
15mg four
25 mg four
times a day
times a day
10 mg four
20 mg four
times a day
times a day
10 mg three
15 mg four
times a day
times a day
5 mg three
10 mg four
times a day
times a day
5 mg twice a
10 mg three
day
times a day
5 mg three
5 mg at night
times a day
5 mg twice a
day
Day 8
5mg at night
Severe SADQ score 30-40
30mg four
40 mg four
times a day
times a day
25 mg four
35 mg four
times a day
times a day
20 mg four
30 mg four
times a day
times a day
15 mg four
25 mg four
times a day
times a day
10 mg four
20 mg four
times a day
times a day
10 mg three
15 mg four
times a day
times a day
5 mg three
10 mg four
times a day
times a day
5 mg twice a 10 mg three
day
times a day
5 mg three
5 mg at night times a day
5 mg twice a
day
Day 1 (starting
Day 2
Day 3
Day 4
Day 5
Day 6
Day 9
Day 10
Day 11
Day 12
Day 13
SADQ = Severity of Alcohol Dependence Questionnaire
50–60 units
5 mg at night
Very Severe SADQ
score 40-60
50 mg four times a
day
45 mg four times a
day
40 mg four times a
day
35 mg four times a
day
30 mg four times a
day
25 mg four times a
day
20 mg four times a
day
10 mg four times a
day
10 mg four times a
day
10 mg three times
a day
5 mg three times a
day
5 mg twice a day
5 mg at night
a Dose of chlordiazepoxide in excess of 30 mg four times a day should be prescribed only in severe
alcohol dependence. The patient’s response to treatment should always be regularly and closely
monitored.
b Doses in excess of 40 mg four times a day should be prescribed only if there is clear evidence of very
severe alcohol dependence. Such doses are rarely necessary in women and children and never in older
people or if there is liver impairment.
Symptom triggered regimen for chlordiazepoxide dosing in acute alcohol withdrawal
On days 1–4, chlordiazepoxide 20–30 mg as needed up to hourly, based on symptoms (including pulse
rate greater than 90 per minute, diastolic blood pressure greater than 90 mmHg or signs of
withdrawal).
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Fixed Dose regimen for diazepam and lorazepam dosing in acute alcohol withdrawal6
(Note: Fixed dose regimens using diazepam and lorazepam are no longer recommended)
Diazepam
Lorazepam
Day 1
10mg QDS
2mg TDS
Day 2
10mg TDS
2mg TDS
Day 3
10mg BD
1mg TDS
Day 4
10mg ON
1mg BD
Day 5
10mg ON
1mg ON
Diazepam
Lorazepam
<10
Nil
Nil
10-15
5mg hourly prn
0.5mg hourly prn
≥16
10mg hourly prn
1mg hourly prn
Day
Symptom triggered regimen7
CIWA-Ar Score
Efficacy
a) Meta-analyses
This evidence summary is based on three meta-analyses and a number of randomised controlled trials
(RCTs) which examined the safety, effectiveness and risk benefit of benzodiazepines in comparison
with placebo, other pharmacological agents and between benzodiazepines themselves.
Mayo-Smith et al8 conducted a meta-analysis of six prospective, placebo controlled trials from the
1960s to 1980s involving three different benzodiazepines and concluded that benzodiazepines are
more effective than placebo in reducing the occurrence of DT (risk reduction of 4.9 cases of delirium
per 100 patients, P=0.04) and in seizure prophylaxis (risk reduction of 7.7 seizures per 100 patients
treated, P=0.003). The different subclasses of benzodiazepines all appear to be equally effective in
reducing signs and symptoms of alcohol withdrawal. However, there was some evidence that longer
acting benzodiazepines (chlordiazepoxide vs. lorazepam, chlordiazepoxide vs. alprazolam, diazepam
vs. lorazepam) are better at reducing the incidence of seizures (6.7 cases per 100 patients, 95% CI -13
to -0.0, P=0.07) Mayo-smith et al. also investigated the abuse potential amongst the different
benzodiazepines (alprazolam, chlordiazepoxide, diazepam, halazepam, lorazepam, oxazepam) and
found 4 trials, the results of which were that agents with a rapid onset of action such as diazepam and
lorazepam were more likely to be abused than longer acting agents such as chlordiazepoxide.
However, no statistical analysis is provided with this information.
A second meta-analysis was authored by Holbrook et al.9 and included three randomized,
placebo-controlled trials from the 1980s with a total of 112 patients and three benzodiazepines10,11,12.
Benzodiazepines were superior to placebo in reducing the signs and symptoms of alcohol withdrawal
syndrome as measured with the clinical institute withdrawal assessment for alcohol (CIWA-Ar) score
two days after the initiation of therapy (OR 3.28, 95% CI 1.30-8.28). Review of the individual
benzodiazepines (chlordiazepoxide, diazepam and lorazepam) used in these placebo controlled
trials did not suggest differences in efficacy among them. However, again no statistical analysis is
present with this investigation. Data on comparisons between benzodiazepines and other drugs,
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including α-blockers, carbamazepine and clonidine could not be pooled, but none of them were found
to be superior to benzodiazepines (No statistical analysis present).
In a more recent meta-analysis, Amato et al.13 included three randomized, placebo- controlled trials
from the 1970s and 1980s with a total of 324 patients in which benzodiazepines were compared with
placebo14,15,16. Their analysis showed that benzodiazepines perform significantly better in seizure
prophylaxis with a RR of 0.16 (95% CI 0.04-0.69). When benzodiazepines were compared with other
drugs (7 studies, 523 patients), incidence of alcohol withdrawal seizures was less in the benzodiazepine
treatment arm than with other drugs (RR 1.70, 0.39 to 7.37) but again, the result was not statistically
significant. Similarly, the incidences of alcohol withdrawal delirium in the benzodiazepine arm was less
than in the other drugs arm (8 studies, 893 participants, RR 0.65 0.21 to 1.98), the result was not
statistically significant.
A number of randomised controlled trials have evaluated the efficacy of chlordiazepoxide against
other benzodiazepines. Jauhur et al. conducted a randomised controlled trial (n=23) which compared
the effect of multiple dose chlordiazepoxide (n=9) vs. single dose diazepam (n=11) in patients with
acute alcohol withdrawal.17 Patients were randomised to either chlordiazepoxide 80mg four times a
day for 8 days vs. diazepam 40mg once a day and placebo three times a day. 3 patients were
withdrawn at the time of assessment, one had a subdural haematoma, one had manifest agitation felt
to be a feature of psychosis, and one patient took immediate self-discharge prior to medication being
administered. The mean pulse rate in both groups showed no significant difference on days 1, 2, 5 or 8
although significance was noted on day 6 (P < 0.05) and day 7 (P < 0.05). Both medications were
effective with withdrawal symptoms.
Kumar et al. (2009) also conducted a RCT of 100 participants, all of which were male (age range: 18-55
years of age).18 Patients were randomised to either chlordiazepoxide (n=50) or lorazepam (n=50).
Dosage was Lorazepam 2mg four times a day vs. chlordiazepoxide 20mg morning and noon plus 40mg
at night. Efficacy was assessed using a CIWA-AR score, presence of delirium and seizures. One
chlordiazepoxide patient developed withdrawal delirium. Lorazepam and chlordiazepoxide showed
similar efficacy in reducing symptoms of alcohol withdrawal as given by the CIWA-AR scores. During
withdrawal irritability(x2 34.89, 1df p<0.001 , dizziness (x2 16.07 1df, p<0.001), and brisk reflexes (x2
6.40, 1df p<0.02), were statistically significantly more common with lorazepam than with
chlordiazepoxide (2.9% vs. 0.4%, 0.9% vs. 0.0%, 0.8% vs. 0.2%) and palpitations were more common
with chlordiazepoxide (0.9% vs. 0.0%) (x2 16.07, 1df p<0.001).
Day et al. conducted a study of chlordiazepoxide vs. diazepam in 23 patients (61% male, mean age 45))
who met the ICD-10 criteria for alcohol dependence for 4 months.19 Participants were randomised to
receive diazepam 10 or 20mg daily depending on CIWA-AR score (n=11) or chlordiazepoxide 30mg four
times a day on day 1 tapered to 0 (n=12). A total of 16 patients (10 men, 6 women) were excluded
from the study: 5 were unable or unwilling to give informed consent to take part in the trial; 4 had
severe current mental health problems; 3 had alcohol related liver disease; 2 had completed their
detoxification prior to admission; 1 was dependent on cocaine; and 1 was excluded owing to the lack
of a trained CIWA-Ar rater at the time of admission. Baseline characteristics were similar in both
groups. The intervention group received a mean dose of 74 mg of diazepam (equivalent to 222 mg
chlordiazepoxide), compared with 700 mg of chlordiazepoxide in the control group (P<0.001). Primary
outcome was seizures. The mean length of the detoxification period (as defined by administration of
medication) was 8.2 hours, compared with 242 hours in the control group (P<0.001). However, despite
Page 8 of 14
these differences, there was little difference in the severity of alcohol withdrawal between the two
groups throughout the 10 days studied. The intervention group reported a lower median level of
adverse symptoms than did the group receiving the traditional detoxification (14.0 v. 29.5, P=0.267).
Overall, in the three meta-analyses, compared with placebo, benzodiazepines were better than
placebo in achieving seizure and delirium control and reducing the symptoms of alcohol withdrawal.
When compared with alternative drugs, benzodiazepines demonstrate a non-significant tendency to
deliver better seizure and delirium control, fewer adverse effects and a lower dropout rate. Trials
comparing different benzodiazepines have failed to produce evidence in favour of one benzodiazepine
over any other in the treatment of alcohol withdrawal syndrome.
There are, nonetheless, several considerations which may guide the choice of benzodiazepine. The
longer-acting drugs in this class may provide a smoother course of withdrawal and are more effective
in seizure control.
Saitz et al. assessed the effect of an individualized treatment regimen on the intensity and duration of
medical treatment for alcohol withdrawal in 101 patients.20 They investigated the effect of
chlordiazepoxide four times a day with additional medication as needed (fixed therapy schedule)
against a treatment regimen that provided chlordiazepoxide only in response to the development of
signs and symptoms of alcohol withdrawal (symptom triggered therapy). Outcomes were duration of
medical treatment and total amount of chlordiazepoxide administered. The results of the study found
that the median duration of treatment in the symptom-triggered group was 9 hours compared with 68
hours in the fixed schedule group (P<0.001). When determining the total amount of chlordiazepoxide
administered between the two regimens, it was found that the symptom-triggered group received
statistically significantly less (100mg) than fixed schedule group (425mg, P<0.001). The study found no
significant difference in severity of withdrawal during treatment or incidence of seizures or delirium
tremens between the two regimens using chlordiazepoxide.
Safety
Holbrook et al conducted a meta-analysis of harm in patients being treated for alcohol withdrawal
which revealed no significant difference between benzodiazepines and alternative drugs in terms of
adverse events (common OR 0.67, 95% CI 0.34–1.32). Data was pooled for meta-analysis of harm
(adverse effects and dropout rates). Three studies (representing a total 148 patients) reported on the
number of patients who had an adverse event. The common odds ratio (0.67, 95% CI 0.34–1.32)
suggested no difference between benzodiazepines and the alternative drugs examined. Data on study
dropout rates could be combined from 5 trials (representing a total 633 patients). The common odds
ratio (0.68, 95% CI 0.47–0.97) indicated that fewer patients in the benzodiazepine group than in the
alternative drug group dropped out within the first 7 days of treatment.
Amato et al reported on 2 studies consisting of 71 participants and found more adverse events in the
benzodiazepine treatment group (RR 3.28, 0.31 to 34.52) compared to placebo, however, this result
was not statistically significant. Dropout due to adverse events from 2 studies totalling 86 participants
(benzodiazepine vs. placebo) led to a RR 0.36 (0.02 to 8.03), a result which is not statistically
significant. When comparing, benzodiazepines vs. other drugs (18 studies, 919 participants) there was
more adverse events in benzodiazepine group (RR 1.31, 0.99 to 1.72). These same studies were also
used to compare adverse events between benzodiazepines and other drugs (7 studies, 340
participants) there were two severe life threatening events in the benzodiazepine group. In
Page 9 of 14
comparison, there was only 1 in the other drugs group (RR 1.95, 0.25 to 15.28) but the result was not
statistically significant.
Another issue influencing the choice of benzodiazepine is the safety in patients with cirrhotic and
other liver diseases. Both diazepam and chlordiazepoxide have a complex metabolism in the liver with
active metabolites prolonging the half-lives of both drugs. Decreased liver function enhances and
lengthens their sedative effects. In contrast, the shorter acting lorazepam has a simpler metabolism, is
less influenced by cirrhosis of the liver and has only inactive metabolites. Consequently, the behaviour
of lorazepam is more predictable in patients with hepatic dysfunction. Another potential risk with
diazepam is the fact that it is more lipophilic than lorazepam and chlordiazepoxide. This characteristic
results in a rapid onset of action because of a swift distribution into the brain and is therefore more
likely to be abused.
The safety and efficacy results are summarised, in the table, below
Efficacy
 Mayo-smith et al report that benzodiazepines
are more effective than placebo in reducing the
occurrence of delirium tremens (DT) (risk
reduction of 4.9 cases of delirium per 100
patients, P=0.04) and preventing seizures (risk
reduction of 7.7 seizures per 100 patients
treated, P<0.001).

Holbrook et al. report that benzodiazepines
were superior to placebo in reducing the signs
and symptoms of alcohol withdrawal syndrome
as measured with the clinical institute
withdrawal assessment for alcohol (CIWA-Ar)
score two days after the initiation of therapy
(OR 3.28, 95% CI 1.30-8.28). No difference in
efficacy between chlordiazepoxide, diazepam
and lorazepam was found.

Dropout rates as reported by Holbrook et al
state that more patients in the alternative drug
group dropped out within the first 7 days of
treatment compared to the benzodiazepine
group.

Amato et al. report that benzodiazepines
perform significantly better than placebo in
preventing a seizure (RR of 0.16 (95% CI 0.040.69)). Comparison between different
benzodiazepines did not produce statistically
significant results. However, chlordiazepoxide
performed better.

Jauhur et al. reported no significant difference
in efficacy between chlordiazepoxide and
Safety

A meta-analysis of harm by Holbrook et al
revealed no significant difference between
benzodiazepines and alternative drugs in terms
of adverse events (common OR 0.67, 95% CI
0.34–1.32

Amato et al report that there was a nonsignificant difference in adverse events between
benzodiazepine and placebo (RR 3.28, 0.31 to
34.52)

Amato et al report that there was a nonsignificant difference in adverse events between
benzodiazepine and other drugs (RR 3.28, 0.31
to 34.52)
Page 10 of 14
diazepam.

Kumar et al. found no difference in CIWA-AR
scores between lorazepam and
chlordiazepoxide. Withdrawal irritability,
dizziness and brisk reflexes were statistically
significantly more common with lorazepam than
with chlordiazepoxide whilst palpitations were
more common with chlordiazepoxide.

Day et al. report that lower doses of diazepam
was required for detoxification compared to
chlordiazepoxide. In addition, the detoxification
period for diazepam was 8.2 hours, compared
with 242 hours in the chlordiazepoxide group;
there was little difference in the severity of
alcohol withdrawal between the two groups
throughout the 10 days studied.

Saitz et al. state that no significant difference in
severity of withdrawal during treatment or
incidence of seizures or delirium tremens
between symptom triggered and fixed dose
regimens using chlordiazepoxide.
Considerations
SMC recommended use within NHS Scotland
NO
Not reviewed
All Wales Medicines Strategy Group (AWSG)
NO
Not reviewed
Regional Drug and Therapeutic Centre (RDTC):
NO
Not reviewed
MTRAC
NO
Not reviewed
Cochrane Review:
NO
Not reviewed
Page 11 of 14
Cost analysis:
Drug
Formulation
Pack Size
Cost per
pack
(Primary
care)
excl.VAT
£3.22
£11.51
£4.99
£17.81
Cost per
tablet
(Primary
care)
excl.VAT
£0.12
£0.12
£0.18
£0.18
Chlordiazepoxide
5mg Capsules
Chlordiazepoxide
10mg
Capsules
28
100
28
100
Chlordiazepoxide
10mg tablets
100
£49.50
£0.50
Diazepam
5mg tablets
28
£1.05
£0.04
Diazepam
10mg tablets
28
£1.30
£0.05
Lorazepam
1mg tablets
28
£2.65
£0.09
Lorazepam
2.5mg tablets
28
£3.46
£0.12
Course cost
Fixed Dose regimen for chlordiazepoxide, diazepam and lorazepam dosing in acute alcohol withdrawal21
(Note: Fixed dose regimens using diazepam and lorazepam are no longer recommended)
Course Cost Primary care (Ex.
VAT)
Chlordiazepoxide*
Very
Moderate Severe
Severe
SADQ
SADQ
SADQ
score 15- score
score
25
30-40
40-60
£11.04
£3.84 £24.00
£8.16
£14.88
*chlordiazepoxide cost calculated based on using 5mg capsules
**diazepam cost calculated based on using 10mg tablets
***lorazepam cost calculated basing on using 1mg tablets
Page 12 of 14
Diazepam**
Lorazepam**
£0.55
£1.62
Symptom triggered regimen (Note: This is the regimen recommended for diazepam and lorazepam)
CIWA-Ar Score
Day 1-4
Chlordiazepoxide*
20-30mg prn hourly. Max
250mg daily
<10
10-15
≥16
Course Cost Primary
care (ex. VAT)
£0.48 - £23.04
*Chlordiazepoxide cost calculated based on using 5mg capsules
**diazepam cost based on using 5mg tablets
***lorazepam cost based on using 1mg tablets
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Diazepam**
Nil
Lorazepam***
Nil
5mg
10mg
£0.04 - £1.92
0.5mg
1mg
£0.09 - £2.16
References
1
Chlordiazepoxide. British National Formulary. https://www.medicinescomplete.com/mc/bnf/current/PHP2167chlordiazepoxide-hydrochloride.htm?q=chlordiazepoxide&t=search&ss=text&p=1#_hit
th
2
Summary of product characteristics. Chlordiazepoxide. Kent pharmaceuticals. Last updated 11 January 2013
http://www.medicines.org.uk/emc/medicine/26299
3
NICE Guidance. Alcohol use disorders: Diagnosis and management of physical complications. Clinical Guideline
100. 2010. http://www.nice.org.uk/guidance/cg100
4
NICE Guidance. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol
dependence. 2011.
http://www.nice.org.uk/guidance/cg115
5
NICE Guidance. Alcohol use disorders: sample chlordiazepoxide dosing regimens for use in managing
alcohol withdrawal. https://www.nice.org.uk/guidance/cg115/resources/alcohol-dependence-and-harmfulalcohol-use-sample-chlordiazepoxide-dosing-regimens-for-use-in-managing-alcohol-withdrawal-136383229
6
Muncie H.L, Yasinian Y, Oge L. Outpatient Management of Alcohol Withdrawal Syndrome. Am Fam
Physician. 2013 Nov 1;88(9):589-595. http://www.aafp.org/afp/2013/1101/p589.html
7
Acute alcohol withdrawal. Bedside guidelines. University hospital of North Midlands NHS Trust.
http://uhns/media/325887/131018%202013-14%20withdrawal%20guidelines.pdf
8
Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based
practice guideline. American Society of Addiction Medicine
Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA. 1997
Jul 9;278(2):144-51.
9
Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of
acute alcohol withdrawal. CMAJ. 1999 Mar 9;160(5):649-55.
10
Sellers EM, Naranjo CA, Harrison M, Devenyi P, Roach C, Sykora K. Diazepam loading: simplified treatment of
alcohol withdrawal. Clin Pharmacol Ther. 1983 Dec;34(6):822-6.
11
Burroughs AK, Morgan MY, Sherlock S. Double-blind controlled trial of bromocriptine, chlordiazepoxide and
chlormethiazole for alcohol withdrawal symptoms. Alcohol Alcohol. 1985;20(3):263-71.
12
Naranjo CA, Sellers EM, Chater K, Iversen P, Roach C, Sykora K. Nonpharmacologic intervention in acute alcohol
withdrawal. Clin Pharmacol Ther. 1983 Aug;34(2):214-9.
13
Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev.
2010 Mar 17;(3):CD005063.
14
Kaim SC, Klett CJ, Rothfeld B. Treatment of the acute alcohol withdrawal state: a comparison of four drugs. Am
J Psychiatry. 1969 Jun;125(12):1640-6.
15
Sellers EM, Naranjo CA, Harrison M, Devenyi P, Roach C, Sykora K. Diazepam loading: simplified treatment of
alcohol withdrawal. Clin Pharmacol Ther. 1983 Dec;34(6):822-6.
16
Naranjo CA, Sellers EM, Chater K, Iversen P, Roach C, Sykora K. Nonpharmacologic intervention in acute alcohol
withdrawal. Clin Pharmacol Ther. 1983 Aug;34(2):214-9.
17
Jauhar. P, Anderson. J, Is daily single dosage of diazepam as effective as chlordiazepoxide in divided doses in
alcohol withdrawal- a pilot study. S http://dx.doi.org/10.1093/alcalc/35.2.212
18
Kumar, CN. Andrade, C. Murthy P. A Randomized, Double-Blind Comparison of Lorazepam and
chlordiazepoxide in Patients With Uncomplicated Alcohol Withdrawal. Journal of Studies on Alcohol and Drugs,
70(3), 467–474 (2009). http://dx.doi.org/10.15288/jsad.2009.70.467
19
Day ED, Evaluation of a symptom-triggered front-loading detoxification technique for alcohol dependence: a
pilot study. Psychiatric Bulletin (20 04). http://pb.rcpsych.org/content/pbrcpsych/28/11/407.full.pdf
20
Richard Saitz et al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial.
JAMA. 1994;272(7):519-523.
21
Muncie H.L, Yasinian Y, Oge L. Outpatient Management of Alcohol Withdrawal Syndrome. Am Fam
Physician. 2013 Nov 1;88(9):589-595. http://www.aafp.org/afp/2013/1101/p589.html
Produced by
Stephen Morrow
Specialist Rotational Clinical Pharmacist
University Hospital of North Midlands NHS Trust
e-mail: [email protected]
Produced for use within the NHS. Not to be reproduced for commercial purposes.
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