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New Medicines Committee Briefing March 2016 oral capsules for treatment of acute withdrawal is to be reviewed for use within: Primary Care  Secondary Care 

Summary:

 Chlordiazepoxide is an with a UK marketing authorisation for use in the management of

acute alcohol withdrawal.

listed in the Joint Formulary for treatment of alcohol withdrawal include ,

, and .

 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).

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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 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 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 , 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, , vomiting, seizures and (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 . Delirium tremens (DT) usually occur between 48 and 72 hours after stopping drinking and consist of rapid heartbeat, and fever. By day 4-5, symptoms have significantly improved. Patients may also develop

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Wernicke-korsakoff syndrome, depression and electrolyte disturbances as well as disorders such as . 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 , or alternatively, . 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 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 Restriction: For the treatment of Generalised Anxiety Disorder (GAD) only Lorazepam Propranolol

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

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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  Patients with severe hepatic insufficiency  Patients planning a  Patients with  Patients with hyperkinesis.

Adverse Events Reported adverse effects of chlordiazepoxide include light-headedness and drowsiness, sedation, unsteadiness and ; 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 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 can result from high doses.

Rare adverse effects include numbed emotions, reduced alertness, fatigue, headache, , muscle weakness, vertigo, blurred vision, , gastrointestinal upsets, skin rashes, visual disturbances, changes in , and urinary retention.

Drug Interactions2 Potential for pharmacodynamic interactions with chlordiazepoxide Alcohol – chlordiazepoxide should not be used together with alcohol (enhanced 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, , , analgesics, anaesthetics, 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, , and rifampicin) induce the clearance and reduce the effect of chlordiazepoxide.

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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, , nabilone, , , tizanidine. Clozapine – serious adverse events reported when 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 Yes NICE Advice published 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 (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 15–25 units 30–49 units 50–60 units Severity of alcohol Very Severe SADQ dependence Moderate SADQ score 15-25 Severe SADQ score 30-40 score 40-60 15mg four 25 mg four 30mg four 40 mg four 50 mg four times a Day 1 (starting times a day times a day times a day times a day day 10 mg four 20 mg four 25 mg four 35 mg four 45 mg four times a Day 2 times a day times a day times a day times a day day 10 mg three 15 mg four 20 mg four 30 mg four 40 mg four times a Day 3 times a day times a day times a day times a day day 5 mg three 10 mg four 15 mg four 25 mg four 35 mg four times a Day 4 times a day times a day times a day times a day day 5 mg twice a 10 mg three 10 mg four 20 mg four 30 mg four times a Day 5 day times a day times a day times a day day 5 mg three 10 mg three 15 mg four 25 mg four times a Day 6 5 mg at night times a day times a day times a day day 5 mg twice a 5 mg three 10 mg four 20 mg four times a Day 7 day times a day times a day day 5 mg twice a 10 mg three 10 mg four times a Day 8 5mg at night day times a day day 5 mg three 10 mg four times a Day 9 5 mg at night times a day day 5 mg twice a 10 mg three times Day 10 day a day 5 mg three times a Day 11 5 mg at night day Day 12 5 mg twice a day Day 13 5 mg at night SADQ = Severity of Alcohol Dependence Questionnaire 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)

Day 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

Symptom triggered regimen7

CIWA-Ar Score Diazepam Lorazepam <10 Nil Nil 10-15 5mg hourly prn 0.5mg hourly prn ≥16 10mg hourly prn 1mg hourly prn

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. , 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, , lorazepam, ) 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 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

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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

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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 Safety  Mayo-smith et al report that benzodiazepines  A meta-analysis of harm by Holbrook et al are more effective than placebo in reducing the revealed no significant difference between occurrence of delirium tremens (DT) (risk benzodiazepines and alternative drugs in terms reduction of 4.9 cases of delirium per 100 of adverse events (common OR 0.67, 95% CI patients, P=0.04) and preventing seizures (risk 0.34–1.32 reduction of 7.7 seizures per 100 patients treated, P<0.001).  Amato et al report that there was a non- significant difference in adverse events between  Holbrook et al. report that benzodiazepines benzodiazepine and placebo (RR 3.28, 0.31 to were superior to placebo in reducing the signs 34.52) and symptoms of alcohol withdrawal syndrome as measured with the clinical institute  Amato et al report that there was a non- withdrawal assessment for alcohol (CIWA-Ar) significant difference in adverse events between score two days after the initiation of therapy benzodiazepine and other drugs (RR 3.28, 0.31 (OR 3.28, 95% CI 1.30-8.28). No difference in to 34.52) 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 0.04- 0.69)). 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

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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

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Cost analysis:

Cost per Cost per pack tablet Drug Formulation Pack Size (Primary (Primary care) care) excl.VAT excl.VAT 28 £3.22 £0.12 Chlordiazepoxide 5mg Capsules 100 £11.51 £0.12 10mg 28 £4.99 £0.18 Chlordiazepoxide Capsules 100 £17.81 £0.18

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)

Chlordiazepoxide* Diazepam** Lorazepam**

Very Moderate Severe Severe SADQ SADQ SADQ score 15- score score 25 30-40 40-60 £11.04 Course Cost Primary care (Ex. £3.84 - - £24.00 £0.55 £1.62 VAT) £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

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Symptom triggered regimen (Note: This is the regimen recommended for diazepam and lorazepam)

CIWA-Ar Score

Chlordiazepoxide* Diazepam** Lorazepam*** Day 1-4 20-30mg prn hourly. Max <10 Nil Nil 250mg daily 10-15 5mg 0.5mg ≥16 10mg 1mg Course Cost Primary £0.48 - £23.04 £0.04 - £1.92 £0.09 - £2.16 care (ex. VAT)

*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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References

1 Chlordiazepoxide. British National Formulary. https://www.medicinescomplete.com/mc/bnf/current/PHP2167- chlordiazepoxide-hydrochloride.htm?q=chlordiazepoxide&t=search&ss=text&p=1#_hit 2 Summary of product characteristics. Chlordiazepoxide. Kent pharmaceuticals. Last updated 11th 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-harmful- alcohol-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 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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