GUIDANCE ON THE TREATMENT OF DRUG AND ALCOHOL DEPENDENCE in ADULTS for INPATIENT UNITS

Transcription

1 GUIDANCE ON THE TREATMENT OF DRUG AND ALCOHOL DEPENDENCE in ADULTS for INPATIENT UNITS Incorporating GUIDANCE ON THE MANAGEMENT OF ALCOHOL WITHDRAWAL AND THE PREVENTION OF WERNICKE- KORSAKOFF SYNDROME POLICY NUMBER RATIFYING COMMITTEE Drugs and Therapeutics Group DATE RATIFIED October 2012 NEXT REVIEW DATE October 2015 AUTHORS Dr Hugh Williams - Consultant Psychiatrist, Substance Misuse Services Hon. Clinical Senior Lecturer Jed Hewitt Chief Pharmacist Jules Haste Clinical Pharmacist Helen Manuell Clinical Pharmacist (Substance Misuse Services) Summary: This guidance aims to assist inpatient staff in the safe and appropriate prescribing and administration of medicines for adults undergoing treatment for drug and alcohol problems This document is compliant with the NICE clinical guidelines 100 and 115 on alcohol dependence and alcohol-use disorders. If you require this document in another format such as large print or audio please contact the Communications Team on

2 CONTENTS Page 1. Detoxification from opioids Providing information and advice Criteria for inpatient admission for detoxification Choice of medication Dosage and duration Medical assessment all treatment regimes People who also misuse alcohol or benzodiazepines Continued treatment and support after detoxification Ultra-rapid detoxification Opioid withdrawal 6 2. Opioid detoxification using methadone Stabilisation on methadone Inpatient stabilisation Detoxification Monitoring 7 3. Opioid detoxification using buprenorphine Dosage and administration Monitoring Contraindications and cautions Buprenorphine with naloxone (Suboxone) 9 4. Lofexidine in opioid detoxification Patient selection Dosage and administration Monitoring Contraindications Adjunctive medication used with lofexidine programme Use of naltrexone Preparation Precautions Induction Ongoing treatment Restarting substitution treatment after naltrexone Benzodiazepine withdrawal Benzodiazepine stabilisation Doses of benzodiazepines equivalent to diazepam Benzodiazepine detoxification Management of Alcohol Withdrawal and the Prevention of Wernicke / 16 Korsakoff syndrome. 7.1 Criteria for inpatient detoxification Alcohol Withdrawal Syndrome Pharmacological management of alcohol detoxification Prevention of Wernicke Korsakoff syndrome General management 19 2

3 8. Pharmacological Management used in Relapse Prevention in alcohol 19 dependence 8.1 Prescribing advice for disulfiram and acamprosate Inpatient management of GHB (aka GBH) and precursor agents, GBL 22 And I,4-BD, dependence 9.1 Patients at risk Withdrawal syndrome Withdrawal management Evidence References 24 Appendices

4 1. Detoxification from opioids Detoxification from opioids can be defined as the process by which the effects of opioid drugs are eliminated from dependent opioid users in a safe and effective manner, such that withdrawal symptoms are minimised (WHO 2006). It is usually thought of as being a clear defined process lasting about 28 days as an inpatient or 12 weeks as an outpatient. Detoxification should be a readily available treatment option for people who are opioid dependent and have expressed an informed choice to become abstinent. The following factors can guide the clinician and the patient s decision about whether they are suitable for detoxification: The patient is fully committed to and informed about the process. The patient is fully aware of the high risk of relapse. The patient is either in a stable and supportive social situation or able to go into one following detoxification. Plans for continuing support and treatment are in place. A full programme of psychosocial support needs to be in place during detoxification, and access to a range of drug-free support services is vital following detoxification. 1.1 Providing information and advice In order to obtain informed consent, staff should give detailed information to service users about detoxification and the associated risks, including: The physical and psychological aspects of opioid withdrawal, including the duration and intensity of symptoms, and how these may be managed. The use of non-pharmacological approaches to manage or cope with opioid withdrawal symptoms. The loss of opioid tolerance following detoxification, and the ensuing increased risk of overdose and death from illicit drug use that may be potentiated by the use of alcohol and benzodiazepines. The importance of continued support, as well as psychosocial and appropriate pharmacological interventions, to maintain abstinence, treat comorbid mental health problems and reduce the risk of adverse outcomes (including death). Service users should be advised on aspects of lifestyle that need attention during detoxification, including diet, hydration, sleep and exercise. Service users should be provided with information about self-help groups (such as 12-step) and support groups (such as the CRI) and consideration given to facilitating engagement. Families and carers should be provided with information about detoxification and the inpatient setting. 4

5 1.2 Criteria for inpatient admission for detoxification. Inpatient detoxifications should normally only be considered for people who: Have not benefited from previous formal community-based detoxification. Need medical and/or nursing care because of significant comorbid physical or mental health problems. Require complex polydrug detoxification, for example concurrent detoxification from alcohol or benzodiazepines. Are experiencing significant social problems that will limit the benefit of community-based detoxification. Note: Pregnant women may be maintained on substitution therapy. However, if they wish to undergo detoxification, this should be done as an inpatient. In such cases the detoxification programme must be individually tailored in accordance with general principles of management of pregnant drug users. 1.3 Choice of medication Methadone or buprenorphine should be offered as the first-line treatment in opioid detoxification, normally starting with the same medication as used for any maintenance treatment. When deciding between these medications, healthcare professionals should take into account the preference of the service user. 1.4 Dosage and duration When determining starting dose, duration and regimen (for example, linear or stepped), take into account, in discussion with the service user, the: Severity of dependence. (Exercise caution if dependence is uncertain). Stability of the service user, (including polydrug and alcohol use, and comorbid mental health problems). Pharmacology of the detoxification medication and adjunctive medications. Setting of detoxification. Detoxification will usually last up to 4 weeks in an inpatient / residential letting. 1.5 Medical assessment all treatment regimes All persons for detoxification need to have completed a full medical and nursing admission procedure including: a multidisciplinary assessment, a physical examination, urinalysis and, where indicated, blood tests (FBC, U&Es, LFTs) and an ECG. 1.6 People who also misuse alcohol or benzodiazepines If a person presenting for opioid detoxification also misuses alcohol, attempt to address their alcohol misuse even if the person is not alcohol dependent. If the person is alcohol dependent, offer alcohol detoxification before starting opioid detoxification in the community or consider offering alcohol detoxification concurrently with opioid detoxification in an inpatient setting. If a person presenting for opioid detoxification is also benzodiazepine dependent, consider benzodiazepine detoxification. 5

6 Take into account the person s preference and the severity of dependence for both substances when deciding whether benzodiazepine detoxifications should be carried out concurrently with, or separately from, opioid detoxification. 1.7 Continued treatment and support after detoxification After successful opioid detoxification, and irrespective of the setting in which it was delivered, offer all service users continued treatment, support and monitoring to help maintain abstinence. This should normally last for at least 6 months. 1.8 Ultra-rapid detoxification Ultra-rapid detoxification under general anaesthesia or heavy sedation, (where the airway needs to the supported), must not be offered. This is because of the risk of serious adverse events, including death. 1.9 Opioid withdrawal The time frame of symptoms experienced is influenced by the type of opioid that has been used and whether medication is used to assist withdrawal. During un-assisted withdrawal from short acting opioids such as heroin, withdrawal symptoms appear approximately six hours after the last dose, peak at hours and then largely resolve after five days. There is a delay in the onset, peak and resolution of withdrawal symptoms during un-medicated withdrawal from longer acting opioids such as methadone and buprenorphine. Table 1 : OPIOID WITHDRAWAL SYNDROME Hours after last dose Symptoms and signs Heroin Morphine Methadone Craving for drugs, anxiety, drug-seeking behaviour Yawning, perspiration, runny nose, lachrymation (tearful eyes) Increase in above signs, plus mydriasis (dilated pupils), goose-flesh (piloerection), tremors (muscle twitches), hot and cold flushes, aching bones and muscles, anorexia, abdominal cramps, irritability Increased intensity of above, plus insomnia, increased blood pressure, increased temperature, increased respiratory rate and depth, increased pulse rate, restlessness, nausea Increased intensity of above, plus febrile facies, position (curled up on hard surface), vomiting, diarrhoea, weight loss Objective signs are those in bold. Patients undergoing withdrawal assisted by gradually reducing doses of methadone or buprenorphine experience a peak in symptoms intensity on the last day they receive opioid medication. Symptoms remain intense for the subsequent three days and then gradually wane over the following two weeks. Prolonged withdrawal symptoms lasting from weeks to months are experienced by a significant minority. The initial symptoms of opioid withdrawal are subjective in nature and typically include intense desire for further drug consumption and drug-seeking behaviour. If 6

7 no further opioids are consumed, increasing levels of anxiety and agitation are experienced together with a variety of physical symptoms namely aching, sweating, watering eyes, runny nose, feeling hot and cold, yawning, abdominal cramps, nausea, vomiting, and diarrhoea. Opioid withdrawal features can be routinely recorded on a daily basis using the Opiate Withdrawal Symptom Questionnaire (Ghodse, 1995). 2. Opioid detoxification using methadone: 2.1 Stabilisation on methadone Methadone stabilisation is carried out prior to methadone detoxification. Stabilisation involves the assessment of the patient s requirement for an appropriate daily dose of methadone that will suppress the manifestations (signs and symptoms) of opioid withdrawal over a 24-hour period, without producing intoxication. As many patients may be using illicit heroin of uncertain purity, it is not possible to establish the appropriate dose from the history alone. Even if pharmaceutical opioids are being used, it is still unwise to prescribe the equivalent dose of methadone calculated from the patient s self-report, due to the risk of overdosing if there has been inadvertent or intentional exaggeration. 2.2 Inpatient stabilisation Stabilisation as an inpatient is effected by administering 10-20mg of methadone mixture 1mg/1ml when objective signs of withdrawal are apparent. This is repeated 4-6 hrly as necessary. The total dose required in the 24-hour period from the onset of signs is the stabilising dose. It may take a number of days (3-5) for the stabilisation dose to be established. The first dose of methadone should not be higher than 10-20mg. This is to prevent accidental overdose in a patient who has minimal tolerance. Even in those with established tolerance, (i.e. confirmed to have been taking higher doses), it may be prudent to divide the dosage for the first 1-2 days. 2.3 Detoxification (Inpatient): Following stabilisation, the standard reduction regime is reduction on alternate days from 40mg methadone or less. A more rapid rate of reduction (e.g. daily dose reduction) is appropriate when starting from higher doses, as the percentage of each incremental reduction is less. The standard rate of reduction is not usually altered unless there is a specific clinical indication. 2.4 Monitoring: Patients should be under direct nursing observation throughout the day, methadone consumption supervised, withdrawal features recorded daily on ward opiate withdrawal scales, side effects monitored and any difficulties responded to. 7

8 3. Opioid detoxification using buprenorphine: Buprenorphine (Subutex) has been licensed in the United Kingdom for substitution therapy in the management (maintenance and detoxification) of opioid dependency. It is a mixed opiate agonist/antagonist. It is taken sublingually, (it is ineffective if taken orally), and may take up to five minutes for the tablet to dissolve under the tongue. Patients should avail themselves of concurrent psycho social interventions both while undergoing buprenorphine treatment on the ward and following discharge. Liver function tests should be taken prior to treatment. 3.1 Dosage and administration: Buprenorphine is available as 0.4mg, 2mg and 8mg tablets for sublingual administration. For those using heroin or other short acting opioids, (e.g. dihydrocodeine), buprenorphine can be commenced 6-8hrs after the last use. Patients should be warned that they might feel unsettled during the first few days of treatment with buprenorphine. In methadone-maintained patients it can be a little more difficult initiating buprenorphine treatment. Because of methadone s long duration of action, buprenorphine can precipitate opioid withdrawal during the crossover period. It is therefore recommended that methadone is reduced to no more than 30mg daily before introducing buprenorphine and that buprenorphine is not given until at least 24hrs after the last dose of methadone. Patients should be warned that they might feel unsettled during the first few days of treatment with buprenorphine. It should be noted that some clinicians start buprenorphine at higher doses of methadone, (e.g mg), using adjunctive lofexidine, (maximum of 2.4mg daily), in the inpatient setting. (Glasper et al, 2006). If there has been no previous treatment with buprenorphine, treatment should start on 4mg daily on day one with a further 2 4 mg six hours later if the patient experiences significant withdrawal. Thereafter the daily dose is titrated upwards in steps of 2-8 mg against withdrawal symptoms/signs, up to a maximum of 16 mg on day 2 and 32mg thereafter (e.g. day 3 onwards). However, in practice most persons requiring detoxification will be stabilised on 8-12mgs daily. A standard stabilisation and detoxification buprenorphine schedule is shown in Table 2. The duration of detoxification will depend on a number of factors including stabilisation dosage, severity of withdrawal, individual needs of the patient etc., and a degree of flexibility will sometimes be needed, (e.g. maintaining particular doses for longer, lengthening duration of detoxification etc.). Table 2 TYPICAL OPIOID WITHDRAWAL SCHEDULE FOR INPATIENTS USING BUPRENORPHINE Day Buprenorphine Day Buprenorphine Day 1 4mgs (+/- 2mg) Day mg Day mgs Day mg Day mgs Day mgs Day 4 10 mgs Day mgs Day 5 8 mgs Day Day 6 6 mgs Day Day 7 4 mgs Day 8

9 3.2 Monitoring: Patients should be under direct nursing observation throughout the day, buprenorphine consumption supervised, withdrawal features recorded daily on ward opiate withdrawal scales, side effects monitored and any difficulties responded to. Buprenorphine should be dispensed on a daily basis. 3.3 Contra-indications: Buprenorphine (Subutex) is contraindicated in cases of known hypersensitivity to buprenorphine, severe respiratory or hepatic insufficiency, breast-feeding, acute alcoholism or DTs, and in children less than 16 years of age. Caution: should be exercised if using in patients with renal impairment. Use in pregnancy: While buprenorphine should not be commenced in pregnancy, those already on buprenorphine can be given the option of remaining on it. 3.4 Buprenorphine with naloxone (Suboxone) Suboxone was marketed in 2007 and includes a dose of the opioid antagonist naloxone, (buprenorphine: naloxone 4:1), in a combined sublingual tablet. It is used at the same buprenorphine dose as the plain buprenorphine tablet. The rationale is that, when taken sublingually as intended, the naloxone is inactivated or is only absorbed at a dose which is insufficient to provoke withdrawal symptoms, but that if it is abused e.g. crushed and taken by intravenous injection, opioid withdrawal effects result. The combination tablet therefore provides the same therapeutic benefit while preventing or reducing the liability for abuse. Suboxone differs from buprenorphine (Subutex) in that it allows for an initial dose on day one of 2-4mgs that may be followed by a further dose on the same day of 2-4mg depending on the patient s requirements. The dose thereafter can be titrated upwards by 2-8mg per day to a maximum daily dose of 24mg. 4. Lofexidine in Opioid detoxification. Lofexidine is licensed for the management of opioid withdrawal symptoms and offers a non-opioid, rapid withdrawal treatment from opioids, without the risk of dependency 4.1 Patient selection: Lofexidine may be considered for those who have made an informed and clinically appropriate decision not to use opioid agonists for detoxification, to detoxify within a short period of time and who have mild or uncertain dependence, (eg young people). 4.2 Dosage and administration (Inpatients): Lofexidine is available as round, film-coated tablets containing 0.2mg lofexidine hydrochloride. If there has been no previous treatment with lofexidine, the starting regime is: Day 1: 0.2mg (1tab) twice daily. Day 2: 0.4mg (2 tabs) twice daily. Day 3: 0.6mg (3 tabs) twice daily. Day 4: 0.8mg (4 tabs) twice daily. Day 5 onwards: Continue increasing by 0.4mg (2 tabs) each day up to a maximum of 2.4 mg (12 tablets) daily according to the patient s tolerance and titrated against withdrawal symptoms. A starting dose of 0.8mg (4 tablets daily) or a more rapid increase in dosage can be used if the patient has severe early withdrawal symptoms and their blood pressure is maintained. 9

10 The total treatment period can vary between 7 to 14 days. At the end of treatment the dosage should be reduced gradually over a period of 2-4 days to avoid rebound hypertension. In an accelerated 5-day inpatient lofexidine detoxification regime, (Bearn et al, 1998), patients received 1.8 mg of lofexidine in three divided doses on the first day, then 1mg twice a day for 3 days and 0.6 mg twice a day on the final day of treatment. Patients are permitted an additional 0.4 mg lofexidine during any 24 hour period, on request. 4.3 Monitoring: Patients usually attend daily until they are stabilised on their maximum dosage. Blood pressure and pulse should be monitored prior to giving lofexidine and inquiry made about any side effects during the last 24 hrs. Lofexidine has mild hypotensive properties and a fall in BP (and pulse) are usually observed in first few days of treatment. If BP falls to below 90/60 or the person reports troublesome hypotensive symptoms, then lofexidine should be withheld until BP improves. Some patients may be able to continue detoxification on a reduced dose of lofexidine. 4.4 Contra -indications: Lofexidine is contraindicated in cases of sensitivity to other imidazoline derivatives. It should be used with caution in severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, renal impairment, marked bradycardia (55 beats per minute); QT prolongation, history of depression in long term treatment; pregnancy and breast feeding. Concurrent medications that may lower BP should be avoided, (e.g. some neuroleptics and night sedation). 4.5 Adjunctive medication used with lofexidine programme: If there is troublesome agitation or insomnia, a small dose of a benzodiazepine may be prescribed for a short period (not more than 2 weeks). Other medication such as ibuprofen (for aches and pains), metoclopramide (for nausea and vomiting) and loperamide (for diarrhoea) may also be used for symptomatic relief if necessary. Adjunctive medications Prescribing symptomatically can reduce some of the physical effects of withdrawal. There is no systematic evidence that any of these drugs work to improve outcome but they may be useful in situations where it is not possible to prescribe effective opioid substitution. Particular care is needed concerning the risks of polypharmacy and appropriate supervision and support in such cases must be ensured. Only use adjunctive medications when clinically indicated, such as when agitation, nausea, insomnia, pain and/or diarrhoea are present. Use the minimum effective dosage and smallest number of drugs needed to manage symptoms. Be alert to the risks of adjunctive medications, as well as the interactions between them and with the opioid agonist. Loperamide (for diarrhoea): 4mg immediately followed by 2mg after each loose stool for up to five days; usual dose 6-8mg daily, maximum 16mg daily. Metoclopramide (for nausea, vomiting, and may also be useful for stomach cramps): eight-hourly. Or prochlorperazine: three times a day or 12. intramuscularly 12- hourly. Mebeverine (for stomach cramps): 13 three times a day. 10

11 Diazepam (orally for agitation, anxiety, and insomnia): up to 5- four times daily when required. In severe cases of anxiety/agitation, contact the on call duty psychiatrist. Zopiclone (for insomnia): 7. at bedtime Non-steroidal anti-inflammatory drugs such as ibuprofen, diclofenac or aspirin (for muscular pains and headaches). Also paracetamol. Topical rubefacients, e.g. Deep Heat, can be helpful for relieving muscle pain associated with methadone withdrawal. 5. Use of naltrexone Naltrexone is a long acting competitive antagonist at opioid receptors and can block the effects of other opioids (e.g. heroin) for up to 72 hours. It can therefore be used as an adjunct to help maintain abstinence and to prevent relapse in opioid dependent individuals who have been detoxed. If an exogenous opioid (e.g. heroin) is used while the patient is maintained on naltrexone then no subjective effects of the heroin will be experienced. Naltrexone is recommended as a treatment option for those who are opioid dependent but who have stopped using opioids and who are highly motivated to stay drug free in an abstinence programme. It should be given as part of a support programme and with proper supervision. Patients should be informed about problems associated with this treatment. The use of naltrexone in rapid detoxification using precipitated withdrawal is not routinely recommended. (The use of naltrexone in relapse prevention in alcohol dependence is not covered in this guidance). 5.1 Preparation: Before initiating a patient on naltrexone, the nature and effects of this medication must be carefully explained to them. In addition, they should be given a specially prepared information leaflet at this stage. In particular, the patient must be warned that any attempt to overcome the blocking effect of naltrexone (e.g. with very large doses of other opioids) is extremely dangerous and can result in fatal overdose. Naltrexone should not be used in those who are currently physically dependent on opioids or those using opioid analgesia for chronic pain. Concurrent use of other opioid containing medicines must not occur while the patient is taking naltrexone. Patients should be warned that in a case of an acute trauma, e.g. when opioid analgesia may be necessary, they should inform the relevant doctor that they are on naltrexone, an opioid blocking drug. All patients taking naltrexone should carry with them a medical alert card to ensure that proper analgesia (pain relief) can be given in the case of an emergency. Naltrexone should not be used by pregnant or breast-feeding women. The common side effects of naltrexone therapy, (anxiety, insomnia, nausea, headache, abdominal pain, muscle /join pain), which are often mild and transient, should be explained to the patient and are covered in the information leaflet provided. 11

12 5.2 Precautions: Patients will need to have FBC, U&Es, and LFTs performed before being commenced on naltrexone. Naltrexone can be hepatotoxic in high doses (i.e. 5-6 times normal dosage). In the case of acute hepatitis, liver failure or significantly raised liver function tests, (i.e. 2-3 times normal), the patient will not be suitable for naltrexone. Liver function tests should repeated at monthly intervals for 4-6 months. 5.3 Induction: Patients should be 7-10 days opioid free, (3-5 days post buprenorphine detox), before being commenced on naltrexone as it can precipitate a severe and prolonged opioid withdrawal syndrome in those who are not fully detoxed and abstinent from opioids. A urine sample should be sent for toxicology a few days prior to induction. In this way the result will be to hand on the day of induction. In addition, a dipstick urine test should be carried out on the day of induction. Patients with opiate positive samples should not proceed with induction and should have their clinical management reassessed. For those with negative urines for opioids, the naloxone (Narcan) challenge test* should be carried out before the patient is commenced on naltrexone. This involves the intravenous (or i/m or s/c) administration of 0.8 mg of naloxone and observation of the patient for 30 minutes for any signs of opioid withdrawal. Opioid withdrawal usually begins within minutes and lasts 2-3hours. If withdrawal occurs, induction should not proceed further and symptomatic relief may be needed. If opioid withdrawal symptoms are not apparent at this stage, then the patient can be commenced on 2 (half a tablet) of naltrexone, observed for 1 hour and reviewed within 24 hours. Thereafter they can be maintained on 50 mg of naltrexone daily. *Note: Alternatively if urines are negative, there is little doubt about the patient s abstinence and having warned the patient, some practitioners omit the naloxone challenge test and start the patient immediately on 25 mg naltrexone. 5.4 Ongoing Treatment: In view of its extended half-life, naltrexone can thereafter be given on a thrice-weekly basis i.e. 100 mg, 100 mg, 150 mg, (Monday, Wednesday, Friday). Once initiated and maintained on naltrexone for 2-4 weeks it may be suitable thereafter to transfer prescribing to the patient s general practitioner. Compliance should be considered and, where possible, naltrexone should only be administrated under adequate supervision, (e.g. by spouse, partner etc). It should be given as a part of a programme of supportive care. As naltrexone is an adjunct to the maintenance of abstinence and prevention of relapse, it is recommended that the patient also have concurrent psychosocial interventions. In this respect they should be referred for concurrent interventions. 5.5 Restarting substitution treatment after naltrexone: Substitution therapy (e.g. with methadone or buprenorphine) can be reinstated 3 days after the last dose of naltrexone but doses should be kept low, (e.g. 20mg methadone, or 4mg buprenorphine for the first 5 days). 12

13 6. Benzodiazepine withdrawal The onset, nature and extent of withdrawal symptoms experienced are influenced by the type of benzodiazepine used and whether medication is used to assist withdrawal. During un-assisted withdrawal from short-acting benzodiazepines such as lorazepam, withdrawal symptoms may appear within hours. However, it may take several days/weeks for the benzodiazepine withdrawal syndrome to develop after stopping a long-acting drug such as diazepam. The withdrawal symptoms typically last at least four weeks after stopping medication. A significant number of patients will suffer protracted withdrawal symptoms and a return to full normal health may take several months. Many symptoms of benzodiazepine withdrawal are similar to those experienced by persons suffering from anxiety disorders. These symptoms include anxiety, insomnia, depression, tremor, poor concentration, panic attacks and palpitations. Other symptoms, namely perceptual distortions, depersonalisation, paraesthesia, muscle pain, myoclonic jerks, visual disturbances (blurring of vision, photophobia) and nasal congestion appear to be more specific of benzodiazepine withdrawal. A minority of patients will develop severe withdrawal complicated by grand-mal seizures and/or delirium. Table 3: BENZODIAZEPINE ABSTINENCE SYMPTOMS Short Term* Long Term** Psychological Anxiety Apprehension Perceptual distortion Tremor Hallucinations, delusions Insomnia Agoraphobia Nausea Depression Vomiting Unreality Convulsions Depersonalisation Paranoid thoughts and feelings of persecution Craving Somatic Paraesthesia Pain Ataxia Visual disturbances Gastrointestinal symptoms Influenza-like symptoms Metabolic and endocrine symptoms *Symptoms may occur 3 to 10 days following discontinuation of treatment with a long-acting benzodiazepine and within 24 hours after abrupt withdrawal of a benzodiazepine with a short half-life. ** These may last for months, and may appear in the first 3 to 10 days. 6.1 Benzodiazepine stabilisation (Inpatient) Benzodiazepine stabilisation may be carried out prior to benzodiazepine detoxification, to establish the baseline dose from which drug withdrawal will be commenced. Diazepam is the drug of choice to assist benzodiazepine detoxification as it has a long duration of action and therefore produces a smoother more protracted withdrawal. 13

14 The patient s reported total benzodiazepine daily intake should be converted to a diazepam equivalent dose which is set as the maximum amount of diazepam that may be dispensed within a 24-hour period. (See table below to aid conversion to diazepam equivalent dose). It should be borne in mind that most patients rarely need benzodiazepines in dosage approximating to what they report using. For example, one study found little relationship between reported use and amount if diazepam for stabilization. Furthermore, the majority of patients can be comfortably and safely stabilised on diazepam mg daily, regardless of their use prior to admission. The equivalent diazepam dose should therefore be considered to be an absolute maximum and the amount and number of doses of diazepam given should be titrated against objective and subjective symptoms of benzodiazepine withdrawal. It is wiser to give smaller divided doses and as required doses initially when trying to establish stabilisation / tolerance. 6.2 Doses of benzodiazepines that are approximate equivalent to diazepam 5 mg: Chlordiazepoxide Loprazolam Lorazepam Nitrazepam Oxazepam Temazepam 15 mg mg 500 micrograms 5 mg 15 mg 10 mg The period of benzodiazepine stabilisation should last three days. During the first day patients should be administered small doses of diazepam, (range mg), as frequently as required (e.g. qds +prn). By day four the patient can be administered their total daily requirement of diazepam in one or two doses if they wish. 6.3 Benzodiazepine detoxification (Inpatient) This involves daily reduction from an individually tailored starting dose of diazepam that has been established either before admission or following a three-day period of inpatient assessment. The length of the withdrawal schedule will depend on the dose of diazepam from which withdrawal is commenced. The withdrawal schedules detailed below should usually be followed (i.e. reduction by daily until dose of 40mg is reached, then reduction by daily). Once stabilised, the daily dose can be split, (if requested), into two approximately equal doses, the first to be taken in the morning and the second in the evening. 14

15 Table 4: TYPICAL BENZODIAZEPINE WITHDRAWAL SCHEDULE FOR INPATIENTS USING DIAZEPAM (MIXTURE) DAY 8am NOON 5pm 10pm TOTAL mg 20mg 20mg 20mg 80mg 4 20mg 20mg 20mg 70mg 5 20mg 20mg 60mg 6 20mg 50mg 7 40mg mg mg If the patient is pregnant then the withdrawal schedule should be extended to last at least 20 days, regardless of the initial diazepam dose. If the patient is struggling to tolerate their withdrawal symptoms, they may be stabilised on the previous day s diazepam dose for two days. This serves to prevent self-discharge and, in the case of pregnant women, foetal distress. Convulsions should be treated with 10 mg diazepam administered rectally. If a patient suffers a seizure they need to be reviewed by the ward doctor and further reductions in the dose of diazepam should be delayed for 48 hours. 15

16 7. Management of Alcohol Withdrawal and the Prevention of Wernicke / Korsakoff syndrome. 7.1 Criteria for inpatient detoxification The majority of patients with alcohol dependence, including those with withdrawal symptoms, can be managed in the community but in-patient detoxification is usually required if the person: is severely dependent on alcohol, is currently having (or has had ) severe withdrawal symptoms such as delirium tremens (DTs) or seizures has significant co-morbid substance dependence suffers with a serious medical or psychiatric co-morbid condition is at risk of suicide or homicide lacks social support / supervision in the community has a history of failed community detoxifications has significant cognitive impairment 7.2 Alcohol Withdrawal Syndrome Not all heavy drinkers will experience withdrawal phenomena and there is a wide range in the severity of withdrawal symptoms. In some cases withdrawal may be life threatening. It is therefore important to recognise early clinical features and treat them appropriately. Early withdrawal symptoms occur up to 12 hours after the last drink. They include tremor, sweating, anorexia, nausea, insomnia and anxiety. In moderate withdrawal the signs are more marked and transient auditory hallucinations in clear consciousness may also occur. Withdrawal fits ( rum fits ) can occur at 12 to 48 hours and are more likely if there is a previous history of withdrawal fits or epilepsy. Fits tend to be generalised tonicclonic (if focal, suspect other causes e.g.head injury) and may occur in bouts. In 30% of cases, fits are followed by delirium tremens. Severe withdrawal / delirium tremens usually develop after 72 hours but can be sooner. Clinical features include; marked tremor, confusion, disorientation, agitation, restlessness, fearfulness, visual and auditory hallucinations, delusions, autonomic disturbances, tachycardia, sweating, fever and dehydration. Persons consuming more than 16 units per day (half to one bottle of spirits per day or equivalent) are particularly at risk. Other risk factors include severe dependence, previous history of DTs, older age and coexisting medical conditions such as infection. 7.3 Pharmacological management of alcohol detoxification Which drug to use? Benzodiazepines are the treatment of choice in the management of alcohol withdrawal. Management Guidelines Alcohol dependent patients that exhibit withdrawal features or are at risk of developing withdrawal should be prescribed benzodiazepines, (i.e. diazepam or chlordiazepoxide). Dosage should be individually titrated and will depend on severity of dependence, withdrawal severity, sex, size, weight, general health and liver function. The following regime for inpatient detoxification is a guideline only: A typical inpatient regime for a severely dependent adult male would be: 16

17 Day 1: Diazepam, 20 mg qds Day 2: Diazepam, mg qds Day 3: Diazepam, 15 mg qds Day 4: Diazepam, 10 mg qds Day 5: Diazepam, 10 mg tds Day 6: Diazepam, 10 mg bd Day 7: Diazepam, 10 nocte Females, the elderly and those with milder dependence / withdrawal should be commenced on a lower starting dose, e.g. diazepam mg qds, and reduced accordingly. Alternatively, chlordiazepoxide can be used - (5 mg diazepam is approximately equivalent to mg chlordiazepoxide). A sample regime for a moderately dependent adult male would be: Day 1: Chlordiazepoxide 30 mg qds Day 2: Chlordiazepoxide, 25 mg qds Day 3: Chlordiazepoxide, 20 mg qds Day 4: Chlordiazepoxide, 15 mg qds Day 5: Chlordiazepoxide, 10 mg tds Day 6: Chlordiazepoxide, 10 mg bd Day 7: Chlordiazepoxide, 10 nocte There may be need for dose flexibility especially during the first 48hrs as dosage is titrated against withdrawal symptoms / over-sedation. Patients should therefore be regularly and closely monitored. In very severe withdrawal, (e.g. DTs), additional as required oral doses of diazepam (or IM lorazepam) may be necessary for the first few days. Similarly, dosage will need to be reduced in response to excessive drowsiness or over-sedation. Special caution is necessary in the case of severe liver impairment (eg cirrhosis) as the metabolism of benzodiazepines may be reduced and lead to over-sedation. (Lorazepam or oxazepam may be suitable alternatives to diazepam or chlordiazepoxide in these cases). For withdrawal fits or status epilepticus use rectal diazepam (Stesolid ) 10 mg (in view of risk of respiratory depression with IV route). This dose may be repeated at 15-minute intervals where necessary. In the case of severe behavioural disturbance use oral haloperidol 5-10 mg. However, be aware that use of antipsychotics may lower the seizure threshold. For severe vomiting use metoclopramide 10 mg IM or cyclizine 50 mg IM. NB. Haloperidol also has anti-emetic action and therefore if used for behavioural disturbance might also combat any nausea and vomiting. If it does not, it should not be used in combination with metoclopramide as this greatly increases the risk of extrapyramidal side effects. 17

18 What dose to start on? Scores on the Severity of Alcohol Dependence Questionnaire (SADQ) and / or units of alcohol per week can provide a rough guide to deciding the starting dose of benzodiazepines, (i.e. what point to start on the Alcohol Detoxification Prescription Chart *). However, this is no substitute for careful, regular observation and monitoring, especially in the first day or two. *Special prescription forms for prescribing benzodiazepines and vitamin supplements for alcohol detoxification are available. Table 5: Guide to starting dose of benzodiazepines for alcohol detoxification (adult male) MILD MODERATE SEVERE V SEVERE SADQ UNITS/WEEK Diazepam 5- QDS Chlordiazepoxide mg QDS 10-1 QDS 25-30mg QDS 20mg QDS mg QDS 20mg QDS 50mg QDS Severity of dependence (SADQ) (See appendix 1). The Severity of Alcohol Dependence Questionnaire is a self-administered and reliable instrument to measure the severity of alcohol dependence. This instrument can also be used to predict the degree of withdrawal symptoms and help in judging medication. The amount of alcohol consumed per week (units/week) can also give estimate of dependence and likelihood of withdrawal. (See appendices 2 and 3). Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). This scale can sometimes be used to assist in the assessment of withdrawal symptoms and their severity. A simplified version of it can be found on the reverse of the special prescription forms for inpatient alcohol detoxification. Patients should be breathalysed and the first dose of benzodiazepine given if serial readings show a falling alcohol concentration and there is no evidence of gross alcohol intoxication. Caution is needed if the patient shows a high alcometer level (e.g. 0.3/L breath alcohol, BrAC). 7.4 Prevention of Wernicke-Korsakoff syndrome Wernicke s encephalopathy is a common and potentially fatal consequence of alcoholism. Failure to prevent or successfully treat Wernicke s encephalopathy can lead to the development of Korsakoff s psychosis, which may be extremely difficult to manage and represents a huge healthcare burden. Wernicke s encephalopathy (acute confusion, ataxia, ophthalmoplegia) may be difficult to recognise /diagnose as all 3 features are only present in 10% of cases. Vitamin Supplements: It is important to note that oral thiamine is poorly absorbed in alcohol dependent patients. Therefore all patients undergoing inpatient detoxification should receive IM/IV high potency vitamin B complex preparations (Pabrinex ) for 5 days. This should be followed by oral thiamine (vitamin B1) 100mg TDS for 2 weeks if Wernicke s encephalopathy and Korsakoff s psychosis (amnesia, time disorientation and confabulation) are to be prevented. 18

19 Anaphylactic reactions are rare (1 in 5 million for IM, 1 in 250,000 for IV) but facilities for treating anaphylactic reactions must be readily available whenever IM / IV preparations of vitamin B complex preparations (Pabrinex ) are used. Note: the first dose should be given before the first meal of the day. IM is the more common and preferred route of administration. Pabrinex IM should be given in divided doses and no more than 4ml volume per injection site. If the IV route is used then drip infusion using mls of normal saline for dilution, over a period of 30 minutes is the preferred method. 7.5 General management All patients, and especially those with marked withdrawal, need close observation and monitoring of vital signs and level of consciousness, correction of dehydration or electrolyte imbalance and treatment of concurrent conditions (e.g. infection, hypoglycaemia, hepatic failure, GI bleeding etc). Patients should be orientated and reassured that any distressing symptoms will eventually settle. An explanation of the symptoms and their relationship to excessive alcohol consumption should be given. If the patient is discharged prior to completion of detoxification, clear instructions should be given regarding medication on discharge and, where necessary, arrangements made for on going supervision of detoxification (e.g. by the GP). This may also be an opportunity for discussion of follow-up psychosocial interventions, counselling, relapse prevention etc. Directive counselling during the process of detoxification can enhance a patient s motivation to continue the treatment. 8. Pharmacological Management used in Relapse Prevention in alcohol dependence Disulfiram, acamprosate and naltrexone are used for maintaining abstinence in alcohol dependent patients. Disulfiram 8.1 Disulfiram (Antabuse ) is an adjunctive treatment for alcohol dependence. It reacts with ingested alcohol (even small amounts) and produces a very unpleasant reaction. Patients taking disulfiram and exposed to alcohol-related situations are therefore discouraged from drinking and learn alternative alcoholfree coping techniques. In this way the use of disulfiram can be seen as cue exposure relapse prevention. 8.2 The disulfiram-alcohol reaction occurs within 10 minutes of ingestion of alcohol, lasts several hours and should be treated in hospital. It includes violent flushing, severe headache, palpitations, tachycardia, nausea, vomiting, hypotension and collapse. However, most patients taking disulfiram do avoid alcohol. 8.3 Before being commenced on disulfiram the patient must: o Have a physical examination and liver function tests. Disulfiram should not be 19

20 used in the presence of liver disease as indicated by AST of twice to three times the upper normal limit. LFTs should also be repeated every 2 weeks for the first 2 months of treatment and then at 3-6 monthly intervals thereafter. If the AST level rises to three times the upper normal limit then disulfiram should be discontinued. o Be totally abstinent from alcohol for 48 hrs prior to commencement. o Be informed and fully understand the potentially serious risks associated with the disulfiram-alcohol reaction. o Be advised about other substances such as aftershave or perfume, and some foods and certain medicines, which due to their alcohol content may cause a reaction. o Be given a patient treatment card stating the person is being treated with disulfiram. o Be warned that on stopping disulfiram a reaction with alcohol can still occur for up to one week. 8.4 Dosage is usually 800mg given as a single dose on day one, 600mg on day two, 400mg on day three and then maintained at 200mg daily thereafter. An alcohol challenge test should not be performed. 8.5 Where possible, agreement should be sought with the patient to have their disulfiram treatment supervised, (e.g. by a partner, friend, CPN etc), as this normally improves compliance. Patients should be reviewed initially every 3-4 weeks and thereafter at least every 3 months. 8.6 Disulfiram should not be used in patients with cardiac failure, coronary artery disease, history of CVA, hypertension, psychosis, high suicide risk, renal failure or in pregnancy or breast feeding. Caution and discussion with clinical team and consultant should be sought in cases of liver disease, moderately elevated liver function tests, epilepsy, and diabetes. In patients with obvious cognitive deficits (e.g. organic / alcoholic brain syndrome) prescribers must ensure the patient is capable of understanding / remembering instructions risks etc. 8.7 Side effects of disulfiram most commonly include drowsiness, fatigue, nausea, vomiting, halitosis and loss of libido. Less commonly psychotic reactions, dermatitis and (dose related) peripheral neuritis may occur. Disulfiram very rarely causes acute hepatitis which is a serious idiosyncratic reaction this usually presents with fever and jaundice. 8.8 Disulfiram enhances the effects of warfarin and inhibits the metabolism of phenytoin potentially leading to toxicity. Concomitant use of chlorpromazine or amitriptyline may intensify the disulfiram-alcohol reaction. Increased sedation may be seen with benzodiazepines. There are no significant interactions with methadone, other opiates or carbamazepine. See current edition BNF for more detailed information on drug interactions. Acamprosate 8.9 Acamprosate is an adjunctive treatment for alcohol dependence combined with counselling. 20

21 8.10 Before being commenced on acamprosate the patient must: Have a physical examination and liver function tests ordered Acamprosate is contraindicated in patients with known hypersensitivity, pregnancy/ breastfeeding, cases of severe hepatic failure and renal impairment (serum creatinine>120 micromol/l) 8.12 Dosage is 2 tablets three times daily with meals in subjects weighing 60 Kg or more; reducing to 2 tablets in the morning, 1 tablet at noon and 1 tablet at night in subjects weighing less than 60 kg Treatment should be initiated as soon as possible after the withdrawal period and should be maintained if the patient relapses. The recommended treatment period is 1 year, although continued alcohol abuse negates the therapeutic benefit of acamprosate Side effects of acamprosate commonly include gastrointestinal disorders and skin rashes. Very rarely hypersensitivity reactions occur Acamprosate and naltrexone combinations have led to increased acamprosate levels, causing an increase in side-effects. Other interations have not been reported. Reference: Brewer C. (1993). Recent developments in Disulfiram Treatment. Alcohol & Alcoholism, 28;

22 9. Inpatient management of GHB (aka GBH) and precursor agents, GBL and l,4-bd, dependence The misuse of gamma-hydroxybutyrate (GHB), often leading to profound unconsciousness was reported in UK in the mid-90 s (1). More recently, dependence with an associated severe withdrawal syndrome has been described (2). This syndrome also applies to withdrawal from gamma-butyrolactone (GBL) and 1,4-butanediol (l,4-bd) as these substances are converted by the body to GHB shortly after administration. 9.1 Patients at risk Patients most at risk of dependence and severe withdrawal syndrome are: Those with a high frequency (daily ) use and especially those using every 2 4 hours, around the clock. Those using greater than 30g, (usually in the region of 15 or more teaspoons), per day. Those with concurrent use / dependence of benzodiazepines and alcohol. It should be noted that withdrawal syndrome can be experienced after as little as 3 months of daily use. 9.2 Withdrawal syndrome GHB/GBL/1,4-BD withdrawal syndrome is very similar in clinical features to that of alcohol withdrawal (delirium tremens) and benzodiazepine withdrawal. (See table 1). However, the withdrawal syndrome is often more severe, often with a rapid onset (1 6 hours) after the last dose and can be longer in duration (2-3 weeks). Neuro-psychiatric symptoms are common with confusion, delirium, psychosis and agitation often being prominent features. Onset of symptoms can quick, often within hours, and delirium can evolve rapidly (3). Most dependent patients, especially those using around the clock, will need inpatient treatment, with close nursing observation. TABLE 1 TEMPORAL PATTERN OF THE SYMPTOMS OF GHB WITHDRAWAL (3) SYMPTOMS: Early (1-24 hours) Progressive (1-6 days) Episodic when waning (7-14 days) Anxiety/Restlessness Insomnia Tremor Confusion Delirium Auditory, tactile, and visual hallucinations Intermittent Tachycardia Hypertension Nausea Vomiting Diaphoresis Key: Mild = +, Moderate = ++, Severe =