1. Medications used for alcohol use disorders in primary care Dr Martyn Hull Lead GPSI in substance misuse Ridgacre Medical Centres, Birmingham

2. Medication can play a role in a number of facets of alcohol treatment It is key to recognise – via thorough assessment – the indications and suitability for treatment in a primary care setting NICE give clear guidance on the potential indications, and their management It is useful to understand the management of these conditions in an acute setting

3. Indications for medication in the acute setting Acute alcohol withdrawal Delerium tremens Wernicke’s encephalopathy Alcohol-related liver & pancreatic disease

4. NICE - Acute alcohol withdrawal Admission to hospital For people in acute alcohol withdrawal with - or who are at high risk of developing - alcohol withdrawal seizures or delirium tremens, offer admission to hospital for medically assisted alcohol withdrawal For young people (under 16 years) Vulnerable groups For people who are alcohol dependent but not admitted to hospital, offer advice to avoid a sudden reduction in alcohol intake and information about how to access local alcohol services This can be managed by specialist services or in primary care, though there needs to be adequate support

5. NICE - Treatment for acute alcohol withdrawal Treat the symptoms of acute alcohol withdrawal: Consider offering a benzodiazepine or carbamazepine Clomethiazole may be offered as an alternative, however, it should be used with caution, and in inpatient settings only Follow a symptom-triggered benzodiazepine regimen for people in acute alcohol withdrawal who are: in hospital or in other settings where 24-hour assessment and monitoring are available

6. NICE - Management of delirium tremens Oral lorazepam is first-line treatment If symptoms persist or oral medication is declined, give parenteral lorazepam, haloperidol or olanzapine If DTs develops in a person during treatment for acute alcohol withdrawal, review their withdrawal drug regimen

7. NICE - Management of alcohol withdrawal seizures In people with alcohol withdrawal seizures, consider offering a quick-acting BDZ (such as lorazepam) to reduce the likelihood of further seizures If alcohol withdrawal seizures develop in a person during treatment for acute alcohol withdrawal, review their withdrawal drug regimen Do not offer phenytoin to treat alcohol withdrawal seizures

8. NICE - Wernicke's encephalopathy Offer thiamine to people at high risk of developing, or with suspected, Wernicke's encephalopathy Offer prophylactic oral thiamine to harmful or dependent drinkers: if they are malnourished or at risk of malnourishment or if they have decompensated liver disease or if they are in acute withdrawal or before and during a planned medically assisted alcohol withdrawal Offer prophylactic parenteral thiamine (Pabrinex) – for 5 days - followed by oral thiamine to harmful or dependent drinkers: if they are malnourished or at risk of malnourishment or if they have decompensated liver disease and in addition they attend an emergency department or are admitted to hospital with an acute illness or injury Maintain a high level of suspicion for the possibility of Wernicke's encephalopathy, particularly if the person appears intoxicated

9. All patients should be prescribed oral vitamins for at least four weeks prior to detoxification commencement and for at least six weeks after the detoxification ends There is no clear evidence for the best oral supplementation regime, though a common regime is: Thiamine tablets 100mg three times a day, or 50mg four times a day Vitamin B Co strong tablets two tablets four times a day It is good practice for all alcohol dependent patients to be prescribed oral supplementation to protect against the harms relating to unplanned detoxifications, though note poor adherence and bioavailability (enteropathy)

10. Indications for medication in primary care Community alcohol detoxification Maintenance of abstinence Reduction in harmful drinking

11. Medically assisted alcohol withdrawal in the community Alcohol withdrawal syndrome develops when consumption is abruptly stopped or substantially reduced Symptoms and signs appear within 6-8 hours: anxiety, tremor, sweating, nausea, tachycardia, and hypertension Usually peaking over 10-30 hours and subsiding within 2-3 days Seizures may occur in the first 12-48 hours (but rarely after this) Delirium tremens is a serious condition that occurs 48-72 hours after cessation of drinking, characterised by: coarse tremor, agitation, fever, tachycardia, profound confusion, delusions (characteristically frightening), auditory and visual hallucinations, and possibly hyperpyrexia, ketoacidosis, and circulatory collapse

12. Minor degrees of alcohol withdrawal are common and can be managed with information, reassurance, and adequate fluid intake BUT alcohol withdrawal syndrome is potentially life threatening Long acting BDZs (chlordiazepoxide or diazepam) are drug of choice for managing symptoms and preventing serious complications such as seizures or DTs Aim: titrate initial dose to the extent of withdrawal symptoms and then slowly reduce the dose over 7-10 days using a standard fixed dose protocol Rating scales – e.g. CIWA-Ar - can be used to measure severity of withdrawal symptoms and more accurately adjust dose, but use of “symptom-triggered detox” is only recommended if trained staff available, e.g. inpatient setting Prescribing in community for alcohol dependent patients without adequate assessment and support is not recommended, as successful withdrawal is unlikely and there are considerable associated clinical risks This is a common scenario facing GPs, and expeditious referral to specialist services for support from a specialist alcohol nurse during medicated withdrawal is advised

13. Sample chlordiazepoxide fixed dose regime Severity of alcohol dependenceModerate (1) Moderate (2)Severe SADQ SCORE 10-2015-2520-30 (Daily units)(10-15u)(15-25u)(25-30u) Day 1 15mg qds 25mg qds 30mg qds Day 2 10mg qds 20mg qds 25mg qds Day 3 10mg tds 15mg qds 20mg qds Day 4 10-5-10mg 10mg qds 15mg qds Day 5 5mg tds 10mg tds 15-10-10-15 mg Day 6 5mg bd 5mg tds 10mg qds Day 7 5mg nocte 5mg bd 10mg tds Day 8 5mg nocte 10mg bd Day 9 5mg bd Day 10 5mg nocte Very severe dependence (SADQ score 30+ / 30+units) - Refer for in patient detoxification

14. Diazepam can be prescribed using a “blue” FP10 MDA-SS prescription for daily collection Oxazepam is a consideration in cases of history of problematic BDZ misuse (due to its’ slower onset) or when there is concern about prolonged sedation (e.g. in the elderly, in patients with significant comorbidities or liver disease) Check LFTs in these cases Note risk of seizures may be higher with oxazepam

15. When managing withdrawal from co-existing BDZ and alcohol dependence increase the dose of BDZ used Calculate the initial daily dose based on the requirements for alcohol withdrawal plus the equivalent regularly used daily dose of BDZ This is best managed with one BDZ (chlordiazepoxide or diazepam) rather than multiple BDZs The prescribing regimen should last for longer than three weeks, tailored to symptoms and discomfort

16. Mutual aid Detoxification is a technical step Research consistently shows people with alcohol dependence who have stopped drinking are vulnerable to relapse and that they may have unresolved problems that predispose them to it Mutual aid groups (Alcoholics Anonymous, SMART Recovery) are a source of ongoing support for people seeking recovery from alcohol dependence, and for partners, friends, children, and other family members. Long term cohort studies show that people who actively participate in mutual aid are more likely to sustain their recovery We should routinely provide information about mutual aid groups and facilitate access for those who want to attend Evidence from RCTs suggests that proactive efforts to engage patients with mutual aid groups increase attendance, particularly introducing the patient to a group member in advance of a meeting A simple three stage process to guide this is available (www.nta.nhs.uk/uploads/mutualaid-fama.pdf).

17. If patient becomes confused consider: Have they been drinking? Assess by breath alcohol level Excessive taking of medication Severe alcohol withdrawal syndrome; associated marked disorientation, agitation and restlessness, tremor and ataxia Physical or mental illness, including infection, electrolyte disturbance and dehydration (from excessive vomiting and diarrhoea) or acute liver disease If confusion is moderate to severe and patient is generally unwell, admit If patient starts vomiting, may be due to withdrawal symptoms or associated physical illness If the patient has a fit during the programme admit, even if short lived

18. If the carer leaves during detox, establish reasons & stop detox Detox can be continued under the following circumstances: Patient finds another appropriate carer willing to support them Patient is more than 4 days into programme, they are well, have not drunk or suffered any adverse effects, are willing to continue the programme and nurse believes they could safely complete the programme without a carer If patient drinks during detoxification, stop detox In such a case, patient should be advised to continue drinking though it would be preferable for them to slowly reduce their alcohol intake in a structured way

19. Maintaining abstinence After a successful withdrawal from alcohol, acamprosate (Campral), oral naltrexone or disulfiram (Antabuse) can be considered for prescribing in combination with psychosocial interventions Before starting treatment, a comprehensive medical assessment (including baseline U&E, LFT / GGT) should be conducted All pharmacological treatments should be part of a comprehensive treatment program that includes psychosocial interventions and support

20. Acamprosate Acamprosate (Campral) – is a drug that can increase abstinence rates Its mechanism is not clearly defined; it appears to block the excitatory activity in the brain (via NMDA Glutamate) and enhance the inhibitory system modulated by GABA It appears to have an affect on cravings and can be an option for people struggling to maintain abstinence post-detox, particularly when anxiety is a prevalent feature In such cases, underlying anxiety disorder should be appropriately treated Acamprosate is more effective alongside psychosocial interventions In addition to increasing likelihood of abstinence, acamprosate has also been shown to reduce the number of drinks and number of drinking days in somebody who lapses to drinking, and such patients have reported that they do not need as much alcohol to gain the same level of feeling they desire (probably because acamprosate and alcohol act via similar mediators in the brain) Rarely, therefore, it may have a role in patients to reduce their consumption rather than its more typical role to assist abstinence post-detoxification – e.g. in patients who have severe physical sequelae related to alcohol and have failed in attempts to cease drinking This is an unlicensed indication

21. Acamprosate can be commenced prior to detox: there is some evidence that it has a neuroprotective effect – i.e. protecting brain cells that may undergo damage during the process of detoxification (BDZs do not protect in this way) Prescribing – 2 tablets (333mg each) tds for >60kg; - <60kg: 2mane, 1 lunchtime, 1 nocte Renal function should be checked, ideally prior to commencing – don’t prescribe if creatinine >120 Contra-indications & side effects - Acamprosate is a safe drug and side effects are minimal and transient GI problems such as diarrhoea, nausea are most common, but rarely prevent continuation with the drug The only contraindication to prescribing is in those that have severe liver damage (Childs-Pugh, grade C) Acamprosate can be prescribed by GP, ideally with a Shared Care Agreement (SCA) to assist this

22. Disulfiram Disulfiram – (Antabuse) – can help people stay abstinent from alcohol It blocks one of the key metabolising enzymes of alcohol which leads to a build-up of acetaldehyde resulting in flushing, nausea, vomiting and cardiac instability This so-called “Antabuse reaction” can be dangerous though rarely fatal Patients therefore must be alcohol free before starting disulfiram and also since the enzymes are inhibited for some time after stopping disulfiram must remain alcohol free for up to one week Generally disulfiram is given to people who are struggling to remain sober and the fear of an adverse reaction to alcohol helps to support them in their psychosocial treatment to remain sober Most effective taken in a supervised fashion – this may be undertaken by the treatment provider or carer Some patients like to have it as a safety net or for specific occasion e.g. at parties, to help them not to drink Contra-indications and cautions - Due to nature of the “Antabuse reaction”,should not be prescribed to people with CV problems, including hypertension, history of CVA, MI, evidence of psychosis, epilepsy Dangerous in OD and should not be given to people with such a risk in an un-supervised fashion Caution in those with a history of kidney or liver disease and those with diabetes

23. Prescribing - If patients are struggling to remain sober and are motivated to remain abstinent, disulfiram can be considered It is recommended to be used as an adjunct rather than as a “magic pill” A loading regimen is given and the dose is then maintained (see BNF) Before starting LFTs, U&Es and BP should be checked Patients should be warned about the interaction with alcohol including those in some products that they may not have thought about e.g. aftershaves, antiperspirants, hair dyes/rinses, mouthwashes and cough medicines. In addition, some foods contain alcohol e.g. vinegar, cakes etc. If a patient has drunk on top of disulfiram without an adverse reaction, then its effectiveness is likely to be reduced: prescribing should stop and alternatives should be reviewed Disulfiram can be prescribed by GP, ideally via a Shared Care Agreement (SCA)

24. Naltrexone Naltrexone – is an opioid antagonist that appears to be effective for attenuating craving in people who are alcohol dependent through its action at opiate receptors By blocking craving, naltrexone may enhance the ability of patients to abstain from drinking. By blocking the pleasure from alcohol, naltrexone also may reduce the amount of heavy drinking in those who do drink Adverse effects: Naltrexone has a low incidence of common adverse events. It has the capacity to cause hepatocellular injury when given in excessive doses (contraindicated in acute hepatitis or liver failure; monitor effect via LFTs). Side effects are generally mild and often diminish over time As an opioid antagonist, naltrexone competitively displaces opioid medications from their binding sites, precipitating withdrawal Care must be taken that patients have been fully withdrawn from all opioids before considering therapy with naltrexone Prescribing – It is recommended that treatment with naltrexone not begin until signs and symptoms of acute alcohol withdrawal have subsided

25. At least 3 days (ideally up to 7) of abstinence are usually recommended prior to start Patients may experience fewer medication side effects (particularly nausea) if they are abstinent from alcohol when they begin treatment with naltrexone. However, it is safe for patients to begin taking naltrexone during medically supervised withdrawal or if they are actively drinking. LFTs should be performed before naltrexone treatment begins and at intervals thereafter (e.g. at 1,3 and 6 months, then annually) LFTs should be performed more frequently if baseline LFT results are high, there is a history of hepatic disease, a potential hepatotoxic medication is also prescribed A careful drug use history and urine toxicological screening should be used to confirm abstinence from opioids, including prescribed pain medications, and a lack of opioid dependence before initiating treatment Pain Management - As an opioid antagonist, naltrexone blocks the effect of opioid analgesics. Typical doses of opioid analgesics (e.g., codeine, morphine, oxycodone, hydrocodone) may not be effective. Non-opioid analgesic medications (e.g., aspirin, NSAIDs) and procedures (e.g., regional nerve block) can still be used for analgesia. Naltrexone is usually prescribed as a 25mg dose on day 1, and thereafter at 50mg od Naltrexone can be prescribed by GP, ideally via a SCA

26. Nalmefene Nalmefene - is an opioid receptor modulator with predominantly antagonist properties – it is pharmacologically similar to naltrexone It is thought to act by restoring the balance of a dysregulated motivational system by reducing the reinforcing effect of alcohol, and thereby reducing the urge to drink alcohol Nalmefene was launched in May 2013, and is licensed for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (>7.5 units per day for man / >5units per day for women), without physical withdrawal symptoms and who do not require immediate detoxification It should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption Prescribing - 1 tablet (18mg) as required on each day there is a risk of drinking alcohol, preferably taken 1–2 hours before the anticipated time of drinking; if a dose has not been taken before drinking alcohol, 1 tablet should be taken as soon as possible; maximum 1 tablet daily The license is restricted to patients with a continued high drinking risk level 2 weeks after assessment because patients who reduced their drinking in the initial 2 weeks, due to non-pharmacological interventions, consumed so little alcohol that there was little room for further significant improvement (floor effect)

27. One advantage of nalmefene in the treatment of alcohol dependence is that, unlike its comparators, it does not require a goal of abstinence. This may make nalmefene appealing to patients who may otherwise not seek medical treatment for their alcohol dependency Adverse effects - The most common side effects are dizziness, nausea and insomnia, though most are mild Nalmefene is contraindicated in patients with severe hepatic impairment. LFTs should be checked prior to commencement of nalmefene. Unlike naltrexone, there are no routine monitoring requirements with nalmefene. The use of nalmefene in patients with mild or moderate hepatic impairment, however, is cautioned and additional monitoring should be undertaken Pain management / toxicology – Nalmefene is – like naltrexone – an opioid antagonist, and the same principles should be applied with respect to pain management and the use of opioids including urine toxicological screening prior to its’ use Suitability for primary care - Nalmefene might be considered suitable for primary care, if the person was stable and deriving benefit, depending on the locally agreed service and the psychosocial support was available There is ongoing debate about the funding for such prescribing

28. Baclofen Baclofen - a GABA(B) agonist - may have efficacy for alcohol dependence Baclofen has been shown in some trials to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol-dependent individuals, though other studies have demonstrated no benefit There is not a clear consensus regarding the role for baclofen in alcohol dependence, nor of the appropriate dose Many of the studies have been undertaken at low dose – 30mg per day (10mg tds). There is some evidence that higher doses may be more efficacious Baclofen may be considered as a second line pharmacological intervention in those who have continuing alcohol dependence despite attempts at more conventional treatment, such as detoxification An example dosing regime would be 5mg tds on day 1, titrating to 10mg tds, with review made at 14-28 days. If there is benefit, the dose could be titrated to 20mg tds if indicated If there is no clinical benefit, baclofen should be stopped. Baclofen is unlicensed for this indication, and should be prescribed by a specialist

29. Assessment and management of alcohol use disorders BMJ, 21 February 2015 Day E, Copello A & Hull M BMJ 2015;350; 715 27-31