SECTION 10: MANAGEMENT OF ALCOHOL, OPIOID AND BENZODIAZEPINE DEPENDENCE

Transcription

1 Formulary and Prescribing Guidelines SECTION 10: MANAGEMENT OF ALCOHOL, OPIOID AND BENZODIAZEPINE DEPENDENCE

2 10.1 Introduction One unit of alcohol (ethanol) is equivalent to 8 grams of ethanol. Calculating units of alcohol follows the formula; Number of units = Volume (in litres) x Strength ABV (Alcohol By Volume) and invaluable when estimating levels of dependence and planning treatment for medically assisted alcohol detoxification. Following alcohol consumption, it takes between 10 and 100 minutes for alcohol to reach peak levels. One unit of alcohol increases the Blood Alcohol Concentration by mg/dl. Alcohol s rate of elimination follows zero-order kinetics (around one unit per hour) Management of acute alcohol withdrawal and Wernicke s encephalopathy The management of acute alcohol withdrawal and Wernicke s encephalopathy (WE) should be considered together. Only 10% of patients with WE experience the classic tetrad of symptoms (i.e. confusion, ophthalmoplegia, nystagmus and ataxia) and therefore all patients being treated for acute alcohol withdrawal should also be treated for WE Acute alcohol withdrawal syndrome Following periods of excessive alcohol consumption, a drop in blood-alcohol concentration may precipitate withdrawal syndrome. The first symptoms of alcohol withdrawal usually appear within hours (5-8) of the last intake of alcohol and peak over hours. The alcohol withdrawal syndrome may be a continuum from simple tremor with relatively mild signs/symptoms through to hallucinations, seizures or the life threatening delirium tremens. It is important to remember that all antipsychotics have the additional risk of lowering the seizure threshold, which is a particular concern in alcohol withdrawal 1. Signs and symptoms of alcohol withdrawal Symptoms may be seen within hours of the last drink and may develop before the blood alcohol level has fallen to zero. Symptoms outlined below may vary in severity, commonly peaking at 10 to 30 hours and usually subsiding by 40 to 50 hours. Common features of alcohol withdrawal include: Tremor of hands, tongue, eyelids Nausea, vomiting, diarrhoea Fever, sweating, flushing Anxiety, agitation, irritability Tachycardia Fleeting hallucinations Insomnia Convulsions Less common features include: Hypertension Arrhythmias Paraesthesia Suicidal ideation 2

3 Delirium Tremens (DTs) DTs occur in about 5% of individuals during alcohol withdrawal but account for the highest level of morbidity and mortality 1. Onset of symptoms usually occur 2 3 days following cessation or reduction in alcohol consumption and this represents a medical emergency. Prevention and treatment is through prompt diagnosis, admission and the administration of high dose benzodiazepines (chlordiazepoxide). DTs are fatal in 15-20% of inappropriately managed cases, usually due to respiratory and cardiovascular collapse or cardiac arrhythmias. Patients most at risk are those with tachycardia, a high fever (> 39.9C/ 104F), dehydration with an associated illness (pneumonia/pancreatitis), general debility or where the diagnosis is delayed. Appropriate management reduces mortality to about 1%. Patients suspected of having Delirium Tremens or Wernicke s syndrome should be transferred to an acute medical hospital. Mental Health wards do not have the facilities for administering IV fluids and these conditions are also often associated with inter-current illnesses such as electrolyte imbalances and chest infections. Common features of delirium tremens include: Severe tremor Systolic hypertension Tachycardia: > 100/min Fever, with or without infection: temp > 38.3C/ 101F Sometimes convulsions Severe hallucinations which often evoke extreme fear (usually visual but may be tactile or auditory) Clouding of consciousness Confusion, disorientation Agitation, violent behaviour Delusions Delirium Insomnia Place of Detoxification Community Detoxification There should be suitable support and monitoring at home, preferably by a close relative. Treatment should be discussed with both the patient and supporting individual. If the patient resumes drinking during the detoxification, the process should be stopped and inpatient detoxification should be considered as the next option. If features of DTs/seizures present, emergency medical treatment should be sought. When conducting community-based assisted withdrawal programmes, a fixeddose medication regimen should be used. A fixed-dose regimen involves starting treatment with a standard dose, not defined by the level of alcohol withdrawal, and reducing the dose to zero over 7 10 days according to a standard protocol. 3

4 When managing alcohol withdrawal in the community, avoid giving people who misuse alcohol large quantities of medication to take home to prevent overdose or diversion. Prescribe for instalment dispensing, with no more than 2 days medication supplied at any time. Do not offer clomethiazole for communitybased assisted withdrawal because of the risk of overdose and misuse. Inpatient Detoxification An inpatient or residential assisted withdrawal should be considered if a service user meets one or more of the following criteria: drinking over 30 units of alcohol per day have a score of more than 30 on the SADQ (Appendix 1) have a history of epilepsy, or experience of withdrawal-related seizures or delirium tremens during previous assisted withdrawal programmes need concurrent withdrawal from alcohol and benzodiazepines The presence of significant psychiatric or physical comorbidities (for example, chronic severe depression, psychosis, malnutrition, congestive cardiac failure, unstable angina, chronic liver disease) or a significant learning disability or cognitive impairment should warrant inpatient detoxification even at lower levels of alcohol use (between 15 and 20 units of alcohol per day). A lower threshold for inpatient or residential assisted withdrawal should also be considered for vulnerable groups, for example; homeless and older adults. Fixed-dose or symptom-triggered medication regimens can be used in assisted withdrawal programmes in inpatient or residential settings. A symptom-triggered approach involves tailoring the drug regimen according to the severity of withdrawal and any complications. The service user is monitored on a regular basis and pharmacotherapy only continues as long as the service user is showing withdrawal symptoms. If a symptom-triggered regimen is used, all staff should be competent in monitoring symptoms effectively and the unit should have sufficient resources to allow them to do so frequently and safely (Appendix 2). In a fixeddose regimen, one should titrate the initial dose of medication to the severity of alcohol dependence and/or regular daily level of alcohol consumption. In severe alcohol dependence, higher doses will be required to adequately control withdrawal and should be prescribed according to the SPC. There should be adequate supervision if high doses are administered. A gradual reduction of the dose of the benzodiazepine over seven to ten days is advised to avoid alcohol withdrawal recurring. Benzodiazepine doses may need to be reduced for children and young people, older people and people with liver impairment Choice of Benzodiazepine Chlordiazepoxide has a lower potential of abuse than diazepam and is therefore the benzodiazepine of choice for the management of alcohol withdrawal. Intravenous diazepam or lorazepam has a more rapid onset of effect so may be preferred where urgent control is required. Oral equivalences for common benzodiazepines can be found in the most current edition of the BNF. 4

5 Algorithm for management of acute alcohol withdrawal symptoms 1 (See also, the algorithm for the Management of Wernicke s encephalopathy, if necessary) Levels of dependence can be estimated according to the daily units of alcohol used and the scores in the Severity of Alcohol Dependence Questionnaire (SADQ). 10, (Appendix 1) People with mild dependence usually do not need assisted alcohol withdrawal. People with moderate dependence (with a SADQ score of between 20 and 30) usually need assisted alcohol withdrawal, which can typically be managed in community setting unless there are other risks. People who are severely alcohol dependent (with a SADQ score of more than 30) will need assisted alcohol withdrawal, typically in an inpatient or residential setting. Readers are also referred to WHO AUDIT 11 for further guidance. Severity Number of units/day SADQ score Chlordiazepoxide (estimated starting dose) Moderate mg qds Severe mg qds Very severe >45 > 40 mg qds Mild dependence Requires small doses of chlordiazepoxide or may even be managed without medication. Moderate dependence units/day A typical regime might be 15-30mg QDS, reducing gradually over 5-7 days. Note that 5-7 days treatment is adequate and longer treatment is rarely helpful or necessary. The table below is an example of an outpatient regime. Day Dose 1 20mg QDS 2 15mg QDS 3 10mg QDS 4 10mg BD 5 10mg OD A client may be on the same dose for a day or two depending on clinical need, presentation and therapeutic response. In cases of more severe objective withdrawal up to 20mg PRN (split across the doses if needed) can be given in the first 48 hours if required. Thiamine 100mg TDS and Vitamin B Co strong tablets (2 tablets three times daily) may be prescribed for the prevention of WE. Severe dependence > 30 units/day (inpatient) Severely dependent patients should get 7-10 days treatment with the flexibility of as required medication for the first 2 days. If symptoms are controlled within the first 2 days it will be easier to implement the reducing regime. Patients who have DTs, head injury or cognitive impairment may need lengthier withdrawal regimes. Intensive daily monitoring is advised for the first 3 days. The intention of flexible dosing is to titrate dosage against symptoms. 5

6 The following are examples of a fixed-dose regimen for severe (7-10 days) and very severe dependence (9-14 days) Severe Day Dose 1 30mg QDS 2 25mg QDS 3 20mg QDS 4 15 mg QDS 5 10mg QDS 6 10mg TDS 7 10 mg BD 8 10 mg OD Very Severe Day Dose 1 40mg QDS + 40mg PRN divided 2 40mg QDS 3 35mg QDS 4 30mg QDS 5 25mg QDS 6 20mg QDS 7 15mg QDS 8 10mg QDS 9 10 mg TDS 10 10mg BD 11 10mg OD Options that may be considered in difficult to manage cases Doses of chlordiazepoxide >300mg per day may be given only after consultant review. (Monitor ECG, blood pressure, pulse oximetry (<90%), respiratory rate (<10/min) and temperature when giving high dose benzodiazepines) Many mental health units use PR diazepam for seizure control. If IV diazepam (or IV fluids) are necessary the patient needs to be in an acute medical hospital. If delirium tremens develops in a patient during treatment for acute alcohol withdrawal, review drug regimen. In people with delirium tremens, oral lorazepam should be offered as a first line treatment. If symptoms persist or oral medication is declined, give IM lorazepam, haloperidol or olanzapine and exclude comorbid acute medical conditions. In individuals with alcohol withdrawal seizures, consider offering a quickacting benzodiazepine (such as lorazepam) to reduce the likelihood of further seizures. Carbamazepine (inpatient setting only, see also SPC) may also be considered. Staff in the inpatient setting should be familiar with administration of rectal diazepam should a withdrawal seizure occur. If benzodiazepines are used for people with liver impairment, consider one requiring limited liver metabolism (for example, lorazepam); start with a reduced dose and monitor liver function carefully. Avoid using benzodiazepines for people with severe liver impairment. Oxazepam is another option. 6

7 When managing withdrawal from co-existing benzodiazepine and alcohol dependence increase the dose of benzodiazepine medication used for withdrawal. Calculate the initial daily dose based on the requirements for alcohol withdrawal plus the equivalent regularly used daily dose of benzodiazepine. This is best managed with one benzodiazepine (chlordiazepoxide or diazepam) rather than multiple benzodiazepines. Inpatient withdrawal regimens should last for 2 3 weeks or longer, depending on the severity of co-existing benzodiazepine dependence. When withdrawal is managed in the community, and/or where there is a high level of benzodiazepine dependence, the regimen should last for longer than 3 weeks, tailored to the service user s symptoms and discomfort. Consider an antipsychotic (caution required due to lowered seizure threshold) in a patient with delirium who is distressed or considered a risk to themselves or others and if verbal and non-verbal de-escalation techniques are ineffective. This should normally be for a short-term only (usually for 1 week or less). Use antipsychotic drugs with caution or not at all for people with conditions such as Parkinson s disease or dementia with Lewy bodies (DLB). Patients with DLB (more common in men) may be extremely sensitive to antipsychotics, which may result in a sudden onset of EPSEs, profound confusion and deterioration, and can lead to death. Do not use Phenytoin. Usual choice is haloperidol PO 5mg TDS or IM equivalent. Maximum 18mg IM or 30mg PO in 24 hours (consider lower doses in the elderly). The recommended starting dose for haloperidol in most liver units, (i.e. in patients with underlying liver disease) is 1.5 2mg TDS, although treatment with benzodiazepines should be the priority. Monitor closely blood pressure and heart rate. Diastolic blood pressure and/or heart rate above 100 may indicate the need to administer higher doses of benzodiazepines. Beta-blockers may be helpful where there is sympathetic over activity. Consider atenolol 50mg daily. Avoid carbohydrate loads where possible (e.g. IV Dextrose) in chronic alcohol abusers as this will deplete thiamine reserves and may precipitate Wernicke s encephalopathy. Always administer parenteral Pabrinex before administering glucose in all patients with altered mental state Always consider the risk of re-feeding syndrome and monitor appropriately (see relevant chapter in eating Disorders section) Carefully monitor for electrolyte imbalances and especially for potassium, calcium, phosphate and magnesium levels. Consider an ECG and early referral to a medical ward when significant abnormalities are detected. Carry out a medication review for people taking multiple drugs, taking into account both the type and number of medications Wernicke s Encephalopathy 4 Wernicke s encephalopathy (WE) occurs in approximately 12.5% of alcohol misusers and is fatal in approximately 17% of untreated cases. Permanent brain 7

8 damage (Korsakoff s psychosis) occurs in approximately 85% of inappropriately managed survivors, 25% of whom require long-term institutionalisation. WE and Korsakoff s psychosis can be prevented through the identification of those at risk, and the administration of parenteral B vitamins. Failure to treat WE may constitute negligence. Damages of 500,000 and more have been awarded to cover longterm care costs in patients who have developed Korsakoff s psychosis as a result of inappropriate management of WE. Patients suspected of having Delirium Tremens or Wernicke s syndrome should be transferred to an acute medical hospital. Mental Health wards do not have facilities for administering IV fluids and these conditions are also often associated with inter-current illness such as electrolyte imbalance and chest infection. Algorithm for the management of Wernicke s encephalopathy 4 Known/suspected chronic alcohol misuser Any ONE or more from: (the classic triad of symptoms only occur in 10% of patients) - ataxia - hypothermia and hypotension - confusion - ophthalmoplegia and or nystagmus - memory disturbances - coma or unconsciousness NO YES Prophylactic treatment of Wernicke s encephalopathy Presumptive diagnosis of Wernicke s encephalopathy Give Pabrinex IM or IV, ONE pair of ampoules ONCE a day for THREE to FIVE days. Give Pabrinex IV, TWO pairs of ampoules THREE times a day for TWO to THREE days, then ONE pair daily for THREE to FIVE days, or until improvement of clinical symptoms stops. Prescribe oral B vitamins (even if parenteral vitamins refused): Thiamine (100mg TDS) and Vitamin B compound strong (TWO tablets three times daily). Review oral prescription after SIX weeks. Intramuscular Administration of Pabrinex One pair of ampoules is approximately 7ml in volume and so must be administered via THREE injection sites. IM administration is therefore only suitable for prophylactic treatment. There is a small risk of anaphylaxis when Pabrinex is administered. Facilities to manage anaphylaxis must be available. The incidence of anaphylactic reactions to IM Pabrinex is estimated to be 1 in 5 million pairs 8

9 of ampoules. Given the nature of Wernicke s encephalopathy, the benefit to risk ratio favours parenteral thiamine and fears about using it should not result in inappropriate use of oral thiamine Observations Each set of observations should consist of: BP Pulse Respiratory rate Applying the CIWA-Ar alcohol withdrawal scale (if appropriate see Appendix 2) If the patient is asleep, they should not be woken for observations. However, it should be recorded that they were asleep. Nutritional support and close monitoring of fluid balance are important. Nutrition is especially important within a few hours following parenteral thiamine administration (i.e. Pabrinex). Urea and electrolytes (including magnesium) should be regularly checked. The first 24 hours Observations should be carried out at least four times daily during the first 24 hours. This is also to determine the dose of chlordiazepoxide that should be administered. In complicated patients (e.g. those with DTs), consider monitoring and dosing at this frequency beyond the first 24 hours. Contact the prescriber if tachycardia or hypertensive. Days 2 to 6 Observations should be carried out TWICE daily from days 2 to 6. This may be more frequent if any complications are seen. These observations are solely for the purpose of monitoring the patient and not for the administration of chlordiazepoxide. The patient should be on a set reducing regime from Day Drugs for maintaining Abstinence 3,4 After a successful withdrawal of people with moderate and severe alcohol dependence, consider offering acamprosate, disulfiram or oral naltrexone in combination with an individual psychological intervention (cognitive behavioural therapies, behavioural therapies or social network and environment-based therapies) focused specifically on alcohol misuse Behavioural couples therapy should be offered to service users who have a regular partner and whose partner is willing to participate in treatment. Before starting treatment with acamprosate, oral naltrexone or disulfiram, conduct a comprehensive medical assessment (baseline urea and electrolytes and liver function tests including gamma glutamyl transferase [GGT]). In particular, consider any contraindications or cautions (see the SPC), and discuss these with the service user. 9

10 Acamprosate Acamprosate has been shown to increase abstinence rates in people receiving treatment for alcohol dependence by 10-20% (40% at best). Evidence suggests the intended actions of acamprosate are maintained over 1 year but not beyond. It should be initiated as soon as possible after abstinence has been achieved and should be maintained if the patient relapses. Contraindications include severe renal or hepatic failure so functions tests should be performed prior to initiation. Avoid in those who are pregnant or breastfeeding. Refer to BNF/SPC for full details Acamprosate is usually prescribed at a dose of 1998mg (666mg three times a day) unless the service user weighs less than 60 kg, and then a maximum of 1332mg should be prescribed per day. Acamprosate should usually be prescribed for up to 6 months, or longer for those benefiting from the drug who want to continue with it. It should be stopped if drinking persists 4 6 weeks after starting the drug. Service users taking acamprosate should stay under supervision, at least monthly, for 6 months, and at reduced but regular intervals if the drug is continued after 6 months. Do not use blood tests routinely, but consider them to monitor for recovery of liver function and as a motivational aid for service users to show improvement. Disulfiram Disulfiram inhibits aldehyde dehydrogenase, leading to on acetaldehyde accumulation after drinking alcohol which can cause unpleasant physical effects. Continued drinking can lead to arrhythmias, hypotension and collapse. Disulfiram appears to reduce the number of drinking days but not to increase abstinence. Supervised consumption may improve efficacy. Contra-indications for using disulfiram include cardiac failure, coronary artery disease, and history of cerebrovascular accident, hypertension, psychosis, severe personality disorder and suicide risk. Disulfiram should not be continued for more than six months without a review. Refer to BNF/SPC for full details. After a successful withdrawal for people with moderate and severe alcohol dependence, consider offering disulfiram in combination with a psychological intervention to service users who have a goal of abstinence but for whom acamprosate and oral naltrexone are not suitable, or prefer disulfiram and understand the relative risks of taking the drug If using disulfiram, start treatment at least 24 hours after the last alcoholic drink consumed. Usually prescribe at a dose of 200 mg per day. For service users who continue to drink, if a dose of 200 mg (taken regularly for at least 1 week) does not cause a sufficiently unpleasant reaction to deter drinking, consider increasing the dose in consultation with the service user. Before starting treatment with disulfiram, test liver function, urea and electrolytes to assess for liver or renal impairment. Check the SPC for warnings and contraindications in pregnancy. 10

11 Make sure that service users taking disulfiram stay under supervision, at least every 2 weeks for the first 2 months, then monthly for the following 4 months. If possible, they should have a family member or carer, who is properly informed about the use of disulfiram, oversee the administration of the drug. Service users on disulfiram should be medically monitored at least every 6 months after the initial 6 months of treatment and monitoring. Warn service users taking disulfiram, and their families and carers, about: The interaction between disulfiram and alcohol (which may also be found in food, perfume, mouthwash etc.), the symptoms of which may include flushing, nausea, palpitations and, more seriously, arrhythmias, hypotension and collapse. The rapid and unpredictable onset of the rare complication of hepatotoxicity; advise service users that if they feel unwell or develop a fever or jaundice that they should stop taking disulfiram and seek urgent medical attention. Naltrexone Naltrexone is a non-selective opioid antagonist and has UK marketing authorisation for treatment of alcohol dependence Naltrexone is thought to reduce pleasurable effects of alcohol due to its propensity to block the release of endogenous opioids and reduce dopaminergic activity. Thus naloxone reduces alcohol s rewarding effects and motivation to drink or ravings. Naltrexone is shown to reduce the number of drinking days and the amount of alcohol consumed in those who are still drinking or have just relapsed. Naltrexone should not be stopped if drinking resumes unless drinking persists for longer than 4-6 weeks. It should not be started in patients known or suspected of being dependent on opiates including heroin, methadone or buprenorphine and analgesia such as tramadol, codeine or other opiate containing agents. Naltrexone will precipitate acute opiate withdrawal in these patients. It is usually prescribed after alcohol detoxification.though patients who are less dependent or drinking harmfully also benefit. Start prescribing at a dose of 25 mg per day and aim for a maintenance dose of 50 mg per day. It can also be prescribed on an as needed basis to reduce heavy drinking in those patients who do not require immediate detoxification. LFTs should be monitored monthly with this administration. Draw the service user s attention to the information card that is issued with oral naltrexone about its impact on opioid-based analgesics. Oral naltrexone should usually be prescribed for up to 6 months or longer for those benefiting from the drug who wish to continue with it. It should be stopped if drinking persists 4 6 weeks after starting the drug. Service users taking oral naltrexone should stay under supervision, at least monthly for 6 months and at reduced but regular intervals if the drug is continued after 6 months. Do not use blood tests routinely, but consider them for older people, for people with obesity, for monitoring recovery of liver function and as a motivational aid for service users to show improvement. If the service user feels unwell advise them to stop the oral naltrexone immediately. 11

12 Nalmefene Nalmefene) is an opioid receptor antagonist with a differing pharmacological profile to naltrexone at the three opioid receptor subtypes. Nalmefene exhibits antagonist activity at the mu and delta opioid receptors, and partial agonist activity at the kappa opioid receptors.almefene has a marketing authorisation in the UK for 'the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level without physical withdrawal symptoms and who do not require immediate detoxification'. It may have a better safety profile than Naltrexone with less risk of liver toxicity. Nalmefene is recommended within its marketing authorisation, as an option for reducing alcohol consumption, for people with a milder form of alcohol dependence: who have a high drinking risk level (between 5-10 units/daily for women and 7-12units/daily for men). ( be) without physical withdrawal Symptoms and therefore do nott require alcohol detoxification. The marketing authorisation states that nalmefene should: only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption and be initiated only in patients who continue to have a high drinking risk level 2 weeks after initial assessment. It therefore should not be prescribed for inpatients. Any prescribing by trust community teams should be in consultation with CDAS. Other medications: Benzodiazepines should only be used for managing alcohol withdrawal and not as ongoing treatment for alcohol dependence. Do not use antidepressants (including selective serotonin reuptake inhibitors [SSRIs]) routinely for the treatment of alcohol misuse alone. Do not use gammahydroxybutyrate (GHB) for the treatment of alcohol misuse National Services The DVLA must be informed about all patients with any form of alcohol problems Alcoholics Anonymous (Available 10am to 10pm, 7 days a week) Tel: Drinkline (Available 24 hours a day, 7 days a week) Tel Approved drugs for the treatment of opioid dependence Methadone Buprenorphine Drug 2 Formulations 2 Buprenorphine + Naloxone (Suboxone) 1mg/ml Sugar Solution 1mg/ml Sugar Free Solution S/L tabs 0.4mg, 2mg, 8mg S/L tabs (2mg + 0.5mg), (8mg + 2mg) 10.4 NICE Clinical Guidelines 12

13 NICE TA114, January Methadone and Buprenorphine for the management of opioid dependence 5 Methadone and buprenorphine using flexible dosing regimens are recommended as options for maintenance therapy in the management of opioid dependence. Methadone should never be prescribed to a patient without first consulting the Community Drug Team for on-going care. It is not necessary to prescribe out of hours. If absolutely necessary, small doses of codeine or dihydrocodeine can be used. Titration (initiation) of methadone must only be performed in conjunction with specialists. Remember opioid withdrawal is NOT a life-threatening condition, opioid toxicity can be fatal. The decision of which drug to prescribe should be made on a case by case basis, taking into account a number of factors. These include history of opioid dependence, commitment to a particular long-term management strategy, an estimate of the risks and benefits of each treatment made by the responsible clinician in consultation with the patient, physical health status, motivation and whether the patient is pregnant or breastfeeding. If both drugs are equally suitable, methadone may be preferred if the client agrees. Methadone particulars 2,3 Methadone is a synthetic opioid receptor agonist with pharmacological activity similar to that of morphine. The British national formulary (BNF) states that methadone should be used in opioid dependence at an initial dose of 10 40mg daily, which is increased by up to 10mg daily (with a maximum weekly increase of 30mg) until no signs of withdrawal or intoxication are seen. The usual maintenance dose range is mg daily. Methadone is available as an oral solution (1mg/ml), an oral concentrate (10mg/ml), tablets or injectable ampoules. Only oral formulations of methadone are considered in this guidance. Administering methadone orally avoids the risks associated with injecting. Methadone has a long elimination half-life (usually hours), which allows for a oncedaily dosing schedule. Methadone appears to have no serious long-term side effects associated with chronic administration. In people stabilised on a methadone maintenance regimen, the drug does not have the pronounced narcotic effects seen with shorter-acting opioids. Methadone is metabolised primarily by CYP3A4, but also by CYP2D. In addition, methadone induces its own metabolism. Some drugs, including rifampicin, phenytoin, phenobarbital and some antiviral drugs used in the treatment of HIV infection, speed up the elimination of methadone from the body (enzyme inducers). Other drugs, such as fluvoxamine, fluoxetine, erythromycin, cimetidine may have the opposite effect on methadone metabolism (enzyme inhibitors). Knowledge of these interactions usually enables the appropriate adjustment of methadone dose for effective treatment. For full details of side effects, contraindications and drug interactions, see the SPC. Initiation of treatment with methadone presents a potential risk of respiratory depression and should be undertaken with care. Interactions between methadone and other respiratory depressants such as alcohol, benzodiazepines and the newer nonbenzodiazepine hypnotics (Z-drugs), other sedatives or tricyclic antidepressants may also induce serious respiratory depression. Clients should be advised as follows: 13

14 MOST DEATHS OCCUR BY MIXING METHADONE & OTHER SEDATIVES (e.g. alcohol, benzodiazepines, antidepressants). Do not mix drugs Overdoses are most common after a period of not using opiates (opiate naive), so use less than you normally would. You can always use more if not strong enough Be careful when using a drug for the first time. If you do not know how a new drug will work for you, use small amounts and do not mix with other drugs There is a risk of death early in methadone treatment as a result of excessive initial doses, failing to recognise cumulative effects, giving methadone to people with impaired liver function (due to chronic hepatitis) or failing to inform patients of the dangers of overdose if they are using other drugs at the same time. The relatively slow onset of action and long half-life means methadone overdose and toxic effects may become life threatening several hours after a dose is taken. During the initiation phase, the methadone dose should be adjusted carefully in order to eliminate drug craving and prevent withdrawal while avoiding the risk of intoxication or overdose. This process needs to be monitored by a doctor or trained nurse, and may require regular visits by the patient to a community prescribing centre. Initially patients may need to be seen at least fortnightly, but when they are stable, the frequency of assessment can be reduced. Methadone is considered to increase the QT interval. In 2006 the MHRA recommended that patients on methadone and with additional risk factors for QT prolongation (heart or liver disease, electrolyte imbalances, treatment with CYP3A4 inhibitors or other medicines causing QT prolongation) should be closely monitored. Similarly, any patient requiring more than 100 mg of methadone should be monitored for evidence of increased QTc Buprenorphine particulars 2,3 Buprenorphine is chemically distinct from methadone. Buprenorphine has a higher affinity for opioid receptors and this reduces the impact of additional illicit diamorphine (including heroin) or other opiate use by preventing these drugs from binding to the opioid receptors. The long half-life and high affinity of buprenorphine for opioid receptors means that it has a prolonged duration of action at higher doses which can allow alternate-day dosing regimens. Buprenorphine also has a relatively good safety profile. Even higher than normal therapeutic doses rarely result in clinically significant respiratory depression because of its partial agonist activity at the opioid receptor involved with respiratory function. Due to its high receptor binding affinity, it is more difficult to displace buprenorphine from receptor binding sites using opiate antagonists (e.g. naloxone) in comparison with other opiate agonists such as methadone. The safety of buprenorphine mixed with high doses of other sedative drugs such as alcohol or benzodiazepines remains unclear. Starting buprenorphine treatment in opioid-dependent clients may precipitate symptoms of withdrawal because buprenorphine displaces any residual opiate agonists from the opiate receptor sites. For full details of side effects and contraindications, see the SPC. Buprenorphine has abuse potential as tablets can be crushed before being injected. The introduction of buprenorphine and naloxone (Suboxone) may reduce this potential. Methadone and buprenorphine should ideally be administered daily under supervision, for at least the first 3months of treatment. Supervision should be relaxed only when the patient s compliance is assured and illicit substance use has stopped. Both drugs should be given as part of a programme of supportive care. 14

15 Opioid dependent patients may have co-morbid psychiatric conditions. A thorough psychiatric assessment should be carried out before starting substitution therapy. Some patients may develop psychosis, depressive or anxiety symptoms during the withdrawal phase and therefore they should be carefully monitored. NICE TA115, January Naltrexone for the management of opioid dependence 6 Naltrexone is recommended as a treatment option in detoxified formerly opioid-dependent people who are highly motivated to remain in an abstinence programme. Naltrexone should only be administered under adequate supervision to people who have been fully informed of the potential adverse effects of treatment. It should be given as part of a programme of supportive care. The effectiveness of naltrexone in preventing opioid misuse in people being treated should be reviewed regularly. Discontinuation of naltrexone treatment should be considered if there is evidence of such misuse. Naltrexone Naltrexone is an opioid antagonist with a high affinity for opioid receptors. It competitively displaces opioid agonists, blocking the euphoric and other effects of opioids minimising the positive rewards associated with their use. It is postulated that Naltrexone reduces the pleasurable effects of alcohol by blocking the effects of opioids released by alcohol that enhance dopamine release in the mesolimbic system. NICE CG52, July Drug misuse opioid detoxification 7 Methadone or buprenorphine should be offered as the first-line treatment in opioid detoxification. When deciding between these medications, healthcare professionals should take into account: Whether the service user is receiving maintenance treatment with methadone or buprenorphine; if so, opioid detoxification should normally be started with the same medication The preference of the service user. Lofexidine may be considered for people: Who have made an informed and clinically appropriate decision not to use methadone or buprenorphine for detoxification Who have made an informed and clinically appropriate decision to detoxify within a short time period With mild or uncertain dependence (including young people). Clonidine should not be used routinely in opioid detoxification. Dihydrocodeine should not be used routinely in opioid detoxification Dosage and duration of detoxification When determining the starting dose, duration and regimen (for example, linear or stepped) of opioid detoxification, healthcare professionals, in discussion with the service user should take into account the: 15

16 Severity of dependence (particular caution should be exercised where there is uncertainty about dependence) Stability of the service user (including polydrug and alcohol use, and comorbid mental health problems) Pharmacology of the chosen detoxification medication and any adjunctive medication Setting in which detoxification is conducted. The duration of opioid detoxification should normally be up to 4 weeks in an inpatient/residential setting and up to 12 weeks in a community setting. Ultra-rapid, rapid or accelerated detoxification SEPT does not undertake Ultra-rapid, rapid or accelerated detoxification Ultra-rapid and rapid detoxification using precipitated withdrawal should not be routinely offered. This is because of the complex adjunctive medication and the high level of nursing and medical supervision required. Accelerated detoxification, using opioid antagonists at lower doses to shorten detoxification, should not be routinely offered. This is because of the increased severity of withdrawal symptoms and the risks associated with the increased use of adjunctive medications. Adjunctive medications When prescribing adjunctive medications during opioid detoxification, healthcare professionals should: Only use them when clinically indicated, such as when agitation, nausea, insomnia, pain and/or diarrhoea are present Use the minimum effective dosage and number of drugs needed to manage symptoms Be alert to the risks of adjunctive medications, as well as interactions between them and with the opioid agonist. Monitoring of detoxification medication Healthcare professionals should be aware that medications used in opioid detoxification are open to risks of misuse and diversion in all settings (including prisons), and should consider: Monitoring of medication concordance Methods of limiting the risk of diversion where necessary, including supervised consumption Opioid Detoxification for General Inpatient The following opioid detoxification algorithms are for patients who present for general medical hospital treatment. Methadone should never be prescribed to a patient without first consulting the Community Drug Team. It is not necessary to prescribe out of hours. Opioid withdrawal is not a life-threatening condition, opioid toxicity is. 16

17 Patient claiming or known to be dependent on morphine, heroin or other opioids Yes Is the patient on a supervised methadone program? Call Community Drug Team to confirm dose of No Contact Community Drug Team for further advice Dose confirmed No Is patien pregnant? Yes Yes No Prescribe methadone. Ensure today s dose not already consumed in it NB: Do not supply methadone as a TTA. Patient to resume usual methadone program on discharge unless CDAS confirms hospital is to supply. Prescribe Buprenorphine s/l tabs as follows: Day 1 4 mg Day 2 8 mg Day 3 8 mg Day 4 6 mg Day 5 4 mg Day 6 2 mg Day 7 0.8mg *produced If patient is discharged prior to completing In consultation with Dr Luty, programme, buprenorphine should not be Consultant in addictions prescribed as a TTA. Refer to community i 10.6 Methadone and Buprenorphine prescribing guidelines The guidelines are primarily for use by the Community Drug and Alcohol Services and GPs working with them. Goals and Objectives of Substitute Prescribing Treatment The goals of substitute prescribing are to reduce the health, social, economic and legal consequences of illegal opiate use to the individual and the community. The objectives of substitute prescribing are: To reduce illegal use of opiates To reduce other drug use To improve the health of the client To help reduce the spread of infectious diseases associated with illegal opiate use, especially HIV, Hep B and Hep C To reduce death associated with illegal opiate use 17

18 To reduce crime associated with illegal opiate use To facilitate an improvement in social functioning To make the environment a safer place to live in Substitute Prescribing Treatment Approaches The Community Drug & Alcohol Service (CDAS) is committed to providing a range of interventions that are flexible enough to meet the needs of clients and to respond to changes during the treatment course. Short and long-term goals, which are constructed around a hierarchy of drug misuse behaviour change are the main factors which influence substitute-prescribing treatment. The ultimate aim, where possible, is to stop addiction to opiates. Substitute prescribing treatment approaches are therefore individually tailored to meet a client s severity of dependence and other related problems or difficulties (health, social, legal and economic). Although substitute prescribing is a major element of treatment, it is just one component that should be used in conjunction with other care planned approaches that include counselling, other psychotherapeutic interventions and other services linked within the care planning approach. Screening of Clients for Substitute Prescribing Treatment Screening is the initial stage where the member of the team determines whether a client is eligible and suitable for substitute prescribing treatment and allows the client to make an informed decision whether or not to accept treatment. The screening process is designed to speed up admissions into treatment and to prevent unsuitable clients being held on long waiting lists Written screening procedure should include the following areas: OPIATE DEPENDENCY It should be determined that a person is opiate dependant, taking into account the actual drug of misuse, amount and frequency. Failure to provide a urine sample automatically disqualifies the client from admission to the program. SUITABILITY FOR SUBSTITUTE PRESCRIBING TREATMENT A clinical judgment should be made that substitute-prescribing treatment is indicated. Substitute prescribing is the treatment of choice for opiate dependency and should not be given to non-opiate dependent individuals. Poly-drug users, who are misusing a range of drugs and are opiate dependent, should be considered for substitute prescribing treatment with a view to controlling the opiate dependency. DOUBLE SCRIPTING The GPs should be informed to check that the individual is not receiving substitute prescribing elsewhere. PREVIOUS TREATMENT - Any previous treatment for drug dependency should be investigated, including reason for discharge. INFORMED CONSENT Client must fully understand and agree to the treatment offered. AGE The person must be old enough to give informed consent; if under the age of 16 years, consent from Parents or Legal Guardian is required. (See Policy on Working with Young People) 18

19 COMPLICATING FACTORS such as mental illness, HIV/ AIDS, pregnancy, hepatitis are not contra-indications to substitute prescribing treatment, but will require additional and/or specific management. Prescribing agreement Initially all clients will be given a substitute prescription on a daily dispensing basis with supervision until after the first review (usually after three months). Clients will be informed that the safety and security of substitute prescribing is their sole responsibility and that under no circumstances will repeat prescription(s) be issued. A prescription sheet will only be given to the client and not a Third Party unless an agreement exists with the clients regular pharmacy where scripts may be posted or delivered. If a client does not collect his/her prescription sheet on the day it is due, the pharmacist should be informed to dispense only the remaining dosage. The Client must be informed of this. A joint working agreement should be agreed upon and all clients should be registered with a GP. Prescribing for pregnant service users If a pregnant opiate user is seeking substitute prescribing, all attempts should be made to find a prescriber as soon as practicable. The initial screening should focus on immediate needs so that clients can be admitted onto the program as quickly as possible. In the first trimester clients are at risk of spontaneous abortion and should be titrated with adequate doses as quickly as possible to prevent withdrawal. Dose changes can be made in the second trimester when the pregnancy is more stable. In the third trimester due to increase surface area, increased levels of hormones and foetal demands, doses may need to be increased to prevent withdrawal symptoms which may precipitate premature labour. If a client is already taking buprenorphine they can continue to do so following informed consent and advice that the safety of buprenorphine in pregnancy has not been demonstrated. There is more experience on the safety of methadone in pregnancy. All staff to read this in conjunction with policy on Working with Pregnant Women who Misuse Drugs. Urine/saliva screening All clients are required to undergo a urine /saliva screen for opiates prior to admission to a substitute prescribing treatment program and/or at regular intervals. Urine/saliva testing for illegal drugs is one method of monitoring client s treatment progress. Testing is useful to detect whether unsanctioned opiate use is occurring or whether the prescribed substitute prescription is being taken or diverted. Positive tests may also signal low and/or ineffective substitute prescribing dose levels. Apart from the initial urine/saliva screening for admission to treatment, tests are only useful when conducted randomly and checked to ensure that client urine has not be substituted. 19

20 Significant treatment decisions should not be based solely on urine/saliva testing and never on the basis of just one positive result. Clients should be tested randomly unless there are strong arguments for more regular testing. Absence of the substitute prescribed after random testing will also result in exclusion from the program. Clients rights and staff responsibilities All clients should receive professional and courteous care and be treated with dignity and respect. Clients have the right to leave treatment at any time and to be detoxified from substitute prescribing or other drugs within the program. Staff are obliged to advise clients of the advantages and disadvantages of withdrawing from substitute prescribing or other drug treatment. Clients have the right to have details of their treatment kept confidential in accordance with Professional Code of Conduct and Health Service arrangements. Clients have the right to be informed about the medical implications of taking substitute prescribing or other prescribed drugs. All clients have the right to participate in the process of devising their own treatment plans and setting both short and long goals. Clients should have access to the CDAS Complaints Procedure. Disqualification from the programme If a client misses three consecutive appointments arranged with his/her counsellor or the medical officer then the client will be disqualified from the programme and a rapid withdrawal will be offered unless a valid reason is provided. Physical abuse or threat/actual assault on CDAS personnel or anyone attending CDAS premises may result in disqualification from the programme. Where a client makes discriminating remarks to CDAS personnel or others attending premises on the grounds of racial origin, sexuality or gender then the client may be dismissed from treatment. Wilful damage to property belonging to the service or premises occupied by the Service may also result in dismissal from the programme. A negative urine/saliva test for substitute prescribing substance disqualifies the client from the programme. The principles underlying treatment for drug misuse and dependence in the UK can be found in the Orange Guidelines (Department of Health (England) and the devolved administrations (2007). Drug Misuse and Dependence: UK Guidelines on Clinical Management. London: Department of Health (England), the Scottish Government, Welsh Assembly Government and Northern Ireland Executive) ( Treatment of benzodiazepine dependence Confirm that benzodiazepine dependence is present patient should have at least one benzodiazepine positive urine drug screen within the last few weeks and be in receipt of long-term prescription for benzodiazepine (at least 3 months for established dependence) Prescribing should be for a short time and with a clear goal in mind Benzodiazepines need to be taken daily (rather than binge consumption). 20

21 Only prescribe one Benzodiazepine at a time. If using more than one Benzodiazepine change to one preparation. Convert all Benzodiazepines to Diazepam (because of longer ½ life, and wider range of tablet strengths for small dose increments). Benzodiazepine conversion equivalents: Diazepam 5mg = Chlordiazepoxide 15 mg = Lorazepam mg = nitrazepam 5 mg = oxazepam 15 mg = Temazepam 10 mg (BNF 61) Aim for lowest dose possible. Very rarely should dose exceed Diazepam 30 mg (or equivalent) daily The patient should not be intoxicated, stoned or drowsy during the day. If insomnia continues to be a problem, use a non-benzodiazepine hypnotic for a short period (up to 2 weeks) The Ashton manual 9 is a useful reference source Reduce the daily dose by 1/10-1/8 dose every 2 weeks or 2 mg every 2 weeks If prescriptions have been lost or the drugs have been used before the next is due they should not be repeated. Prescription from multiple sources can be problematic. There should be in place an agreement with primary care colleagues about which service will be the sole prescriber and will be monitoring progression of the reduction programme Signs and symptoms of Benzodiazepine withdrawal 8 Symptoms Signs Increased psychomotor activity, agitation, muscular weakness, tremulousness, hyperpyrexia, diaphoresis, delirium, convulsions, elevated blood pressure, pulse and temperature, tremor of eyelids, tongue and hands Anxiety, depression, euphoria, incoherent thoughts, hostility, grandiosity, disorientation, tactile, auditory and visual hallucinations, suicidal thoughts Example: Switching from clonazepam to diazepam Clonazepam (Intermediate acting) 0.5mg 1mg 8mg Diazepam (Long acting) 5mg 10mg 80mg Maudsley Guidelines 1-2 mg clonazepam = 10mg diazepam National Prescribing Services Limited ( 0.5mg clonazepam = 5mg diazepam Go for 1mg clonazepam = 10mg diazepam Switch intermediate acting clonazepam to long acting diazepam. This will provoke less severe withdrawal. Half lives of benzodiazepines vary greatly Degree of sedation induced also varies 21