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WORCESTERSHIRE MENTAL HEALTH PARTNERSHIP NHS TRUST OPIOD DETOXIFICATION GUIDELINES This policy should be read in conjunction with This policy should be read in conjunction with the Prescribing Guidelines for Substance Misuse Worcestershire Mental Health Partnership NHS Trust Policy Data Unique Identifier: CP0088 Ratified by: Governance Committee Ratification Date: 22nd September 2008 Review Interval: Three Years Version Update: Review Date: September 2011 Owner: Chief Operating Officer Reviewer: SMS Consultant Psychiatrist et al Responsible Forum: Clinical Effectiveness Group Document Type: Clinical Policy Superseded Policy: Search Criteria If printed, copied or otherwise transferred from its originating electronic file, this document must be considered to be an uncontrolled copy. When documents are updated, notification will be circulated throughout the organisation. Policy amendments may occur at any time and you should always consult the PDF file held on the Trust’s Intranet. CONTENTS 1 Background 2 Detoxification period 3 Preparation 4 Families & Carers 5 Assessment 6 Cautions 7 Risk Assessment 8 Setting 9 Method of detoxification 10 Simple of symptomatic relief 11 Detoxification Procedure 12 Lofexidine Detoxification 13 Buprenorphine Detoxification 14 Methadone Detoxification 15 Relapse Prevention (Naltrexone) 16 Naloxone Challenge test 17 Appendix 1 18 Appendix 2 19 Appendix 3 20 Appendix 4 21 Flow chart 22 Useful References 1 1 Background This guideline outlines the care and treatment of service users who are wishing to undergo detoxification for opioid dependence arising from the misuse of illicit substances. It covers the opioid detoxification in community and in-patient settings, and will refer to misuse of other drugs such as alcohol, stimulants and benzodiazepines only in context of opioid detoxification. Detoxification is part of the treatment process in the service users’ journey of addiction. Opioid misuse and dependence is a chronic relapsing and remitting condition, and detoxification underpins the long term goal of abstinence which is not always achieved. Opioid detoxification is a clearly defined process supporting safe and effective discontinuation of opiates while minimising withdrawal symptoms. Pharmacological approaches are primary option for detoxification, with psychosocial interventions it could lead to an effective outcome with longer abstinence periods. Review and support for physical and mental health is essential during this process. Detoxification should be routinely available as one of the treatment options for service users who identify it as a feature of their long term care plan. Service users’ needs and preferences should be a key feature of the planning of treatment and care. Service users should be allowed to make informed decisions and staff should work in partnership with them to enhance their insight into the treatment process, advantages, disadvantages and adverse effects. Keyworking is paramount in this process and also essential to communicate and co-ordinate the care plan with staff providing psycho-social interventions like Turning Point and Community Rehabilitation. For a detoxification to be successful it is crucial to involve the patient in its planning and implementation. It is also important for the patient to have clear ideas and plans in place to occupy their time after detoxification (once abstinence is achieved) –i.e. getting into training/employment, identifying structured and constructive activities, developing a ‘non-using’ support network, etc. Research has identified the following predictors of successful detoxification: Good engagement in treatment High levels of motivation Actual attempts rather than mere ideas to address related problems This guideline should be read in conjunction with the references listed at the end of this document. 2 2 Detoxification period There are different opinions from various literatures available. Some evidence that detoxification should be a process of achieving a rapid drug free state, and normally takes 10 to 28 days depending on each case. It is different to a slow reduction programme and detoxification requires good preparatory and after care work. But NICE guidelines and NTA Orange Guideline 2007 have suggested for in-patient detoxification up to 4 weeks and up to 12 weeks in a community setting. Again it should be service user led and the duration should be decided on case by case basis. 3 Preparation When a service user expresses an interest in detoxification, it should be discussed in referrals/team meeting. Service users could be from prescribing service or from Turning Point. If referral considered the keyworker within prescribing service (Secondary/Primary/DIP) with service user’s agreement and informed choice will need to liaise with care co-ordinator/staff from Turning point and Community Rehab to co-ordinate a series of discussions/contact with the service user to enable them to make an informed choice to become abstinent and also to look at after care arrangements following the detoxification period. The detail of these discussions will need to be outlined in a care plan and in care co-ordination arrangements. To obtain informed consent following information on detoxification should be discussed: physical and psychological symptoms of opiate withdrawal duration and severity of symptoms and its management use of pharmacological and non-pharmacological approaches in the management loss of opioid tolerance and risk of following overdose and death from illicit substance use along with alcohol or benzodiazepines comorbid mental health and physical health problems importance of continued engagement with services for psychosocial and appropriate pharmacological interventions to maintain abstinence and to address the risk of adverse outcomes need for changes in certain aspects of lifestyle like balanced diet, adequate hydration, sleep hygiene, regular physical exercise and other activities 3 information about self-help groups (such as SURGE, 12-step groups, etc.) and facilitate engagement with such groups service user’s anxieties surrounding the detox should be addressed prior to the program Use Appendix 1, 2 and 4 in your discussion with service users. Following the detailed discussion with service user and working in partnership with Care Coordinator, Turning Point, Community Rehab an agreed care plan should be developed. Staff should establish and sustain a respectful and supportive relationship, help service user to identify situations or states when he or she is vulnerable to drug misuse. Alternative coping strategies should be explored with access to wide range of services for support. Importance of engagement with services following detoxification should be stressed and detailed in the care plan. It is essential to maintain an effective care co-ordination and collaboration with all care providers. Service users receiving substitute maintenance treatment in the service should receive regular reviews of their care plan and detoxification option should be considered, discussed and documented. Service users who are considering detoxification on their own without support from services should be given information as above and should be strongly advised for detoxification in a structured treatment program. Also engagement with services during self detoxification and for after care should be emphasised. Service users should be encouraged to involve families and carers during the assessment and treatment plans. Service users should be made aware of their right to confidentiality and their informed decision should be respected. During the preparation process for detoxification program, the following challenging points should be addressed: coping skills to deal with detoxification program and strategies to maintain abstinence motivation and readiness for detoxification program service users expectations and acknowledgement of positive outcomes support network during and after detoxification program care plan aiming at relapse prevention 4 risk assessment ex. Low tolerance and accidental overdose post detoxification lessons learnt from previous treatments, detoxifications and rehab programs methods of detoxification, choice of medication setting or location of detoxification (in-patient or community detox) Use Appendix 1, 2, and 4 in your discussions/keyworking sessions with service users. 4 Support for families and carers It is equally important to discuss with families and carers about their concerns, impact of substance misuse on themselves and other family members, including children. Their personal, social and mental health needs should be discussed and guidance given about services available locally such as SURGE, Pressure Point and Turning Point Family Services. Information about detoxification, settings, self-help and support groups should be provided. 5 Assessment: should include: severity of opioid dependence (see Appendix 1 & 2) misuse and dependence on other substances urinalysis / oral fluid / breath testing to aid identification signs of opioid withdrawal history of treatment episodes and past detoxifications/rehabilitation programs possible complications during detox program - physical and mental health problems and their treatment risks of self harm, suicide or violence possible due to relapse of underlying mental health problems loss of tolerance and misuse of drugs or alcohol as a response to opioid withdrawal symptoms social and personal circumstances, including employment, financial situation, living arrangements, social support and criminal activity risk of relapse, support network, impact on families and carers Use Appendix 1, 2, and 4 in your discussions/keyworking sessions with service users. 5 6 Cautions a detoxification should not be routinely offered for service users in the following circumstances: suffering with physical health problems and in need of emergency treatment service users who could only engage or access services for relatively short period of time (like chaotic lifestyle, accommodation issues, police custody, refusal to engage with services, short period of sentences) not stabilised on current substitute maintenance treatment, chaotic polysubstance use presenting with emergencies at acute hospitals where primary medical condition should be managed with referral to substance misuse services not currently in structured prescribed treatment, unless there were compelling reasons for detoxification along with a good support network b If service user is suffering with alcohol problems along with opioid dependence, should be encouraged and facilitated to address it as the risk of increased use of alcohol in place of opioids. If alcohol dependent, alcohol detoxification should be completed before opioid detoxification in the community or both detoxifications could be done in an in-patient setting. c If service user is suffering with benzodiazepine problems along with opioid dependence, benzodiazepine detoxification should be completed. It should be discussed with service users their choice of completing the detoxifications together or separately and also severity of dependence for both substances 7 Risk assessment A proper understanding and interpretation of risk involves knowledge of specific withdrawal syndromes of different substances and interaction with any prescribed medications, the physical and mental health of service user. a Risks associated with withdrawal from substances History of seizures History of delirium 6 High severity of dependence and dose of substance particularly short acting drugs Poly drug use (like alcohol, benzodiazepines) Poly pharmacy (psychiatric medications, tranquilisers etc) b Risks associated with health conditions Ischemic heart conditions Hypertensive heart disease Elderly and serious physical health problems Liver, renal problems Diabetes, epilepsy, asthma Head injury, organic brain damage Pregnancy Mental health problems c Risks associated with support network Lack of people support to help cope with the detoxification program and abstinence maintenance Difficulties with child care Risks should be assessed through out the period of detoxification and there should be raised awareness of unexpected problems which may arise after all the thorough planning and delivery of the program. Service users should be made aware of the risks of worsening physical or mental health problems masked by substance misuse and importance of engaging and keeping appointments with specialist clinic. Service users should be advised to notify the services at the onset of prodromal symptoms to prevent relapse of the condition. 8 Setting a Service users should be offered routinely community based detoxification program. b In-patient detoxification could be considered for those service users who: 7 Previous failed community detoxification Significant medical or mental health problems Requiring multiple polydrug detoxification Significant social problems Service users showing sufficient insight to know that other options are unlikely to be effective 9 Methods of detoxification The choice of pharmacological intervention in opioid detoxification to help service users cope with opioid withdrawal syndrome should be an informed decision. Generally service users should be made aware that detoxification program would help them to minimise the physiological and psychological opioid withdrawal syndrome and also that some discomfort are inevitable as all signs and symptoms are rarely controlled. NICE and NTA 2007 guidelines suggests that when deciding between different pharmacological interventions, following issues should taken into consideration: Opioid detoxification should normally be started with same medication with which service user was on maintenance treatment and was stabilised Service users should be provided with all the information and it should be their preference and clinically appropriate decision Clonidine and dihydrocodeine should not be used routinely in opioid detoxification 10 Simple symptomatic relief This regime is suitable for those service users who have features of no or mild opiate dependence with current low level use of heroin (below 0.5 gram daily), preferably with short history (maximum 18 months) of use. And also service users showing good motivation to remain abstinent from opioids use. Contra-indications Pregnancy Injecting 0.2g or above of heroin daily 8 Heroin use for over 18 months (unless only has features of mild dependence, and low level of use – that is, smoking less than 0.5g daily) Poly drug use and/or alcohol misuse Severe mental and/or physical illness Detoxification Procedure Reduce current use before detoxification – ideally to 0.25g heroin daily. Before commencing symptomatic detoxification, discuss possible use of Lofexidine. If detoxification is in the Community commence programme Monday or Tuesday with frequent monitoring during the week. Zopiclone 7.5mg to 15mg nocte may be prescribed to help with insomnia. Difficulty sleeping is one of the commonest complaints and medications can only usually help to a limited extent. Time limited prescription for 2 to 4 weeks should be more than sufficient. Problems with anxiety is quite challenging and can be an important management problem during detoxification. Evidence suggests that good informed discussion during the preparation process for detoxification program can significantly help to reduce this along with reassurance techniques and psychosocial interventions are an important adjunct for successful outcome. Short duration prescriptions of small doses of long acting benzodiazepines (chlordiazepoxide or diazepam 2-5mg tds) may be useful, but should be used cautiously because of high addiction potential. Other alternative could include promazine 25mg tds (and 50mg nocte). Ibuprofen 200-400mg tds or Diclofenac 75mg bd, for muscle ache. Topical preparations may be useful in some people. Service users should be advised not to use these medication in empty stomach because of the risk of gastritis and stomach mucosal ulceration. Loperamide 4mg initially, and 2mg after each loose stool (max 16mg per day) for diarrhoea. Metoclopramide 10mg tds PRN for nausea and vomiting. Buscopan 10mg tds PRN for stomach cramps. 11 Lofexidine detoxification Lofexidine is centrally acting adrenergic agonist and indicated in management of symptoms of opioid withdrawal. 9 Pharmacology Lofexidine is an alpha-2 agonist. Agonistic activity at alpha-2 receptor provides negative feedback to descending sympathetic nerves controlling production of catecholamines and helps to control adrenergic symptoms of opioid withdrawal. It has no opioid activity, very low misuse potential and no issue of diversion. Evidence of successful outcomes for: a Heroin use up to 0.5gm b Methadone upto 30mg c Non polydrug users d Shorter drug and treatment histories e At an end stage methadone detoxification Precautions Severe coronary insufficiency, recent Myocardial Infarction, bradycardia, cerebrovascular disease, renal failure, pregnancy (teratogenicity and other effects on fetus not known), breast feeding, cardiovascular problems (evidence of QT prolongation – need for ECG investigation). Interactions Lofexidine enhances the effects of CNS depressants including alcohol. If used along with tricyclic anti-depressants may reduce the efficacy of lofexidine and may potentiate postural hypotension. Side effects Drowsiness, dryness of mucous membranes (dry mouth, throat & nose), hypotension, bradycardia, rebound hypertension on abrupt withdrawal, sedation and coma in overdosage. Lofexidine dosing regimes It could be divided into four phases The induction phase: gradually increase the dose to required level, this reduces the risk of hypotension, allows time for its detection, and to allow time for its management if it were to occur. In induction phase prescribed opioid can continue on days 1 and 2. 10 The peak dosing phase: this is intended to occur during the peak of the opioid withdrawal symptoms. The length of this phase depends on severity of withdrawal symptoms. The early reduction phase: gradual dose reduction to low dose of two tablets daily. The late reduction phase: one tablet daily for three days to prevent rebound effects and also assists avoiding a medication gap if starting naltrexone when required. The induction and reduction phases are of fixed length depending on severity of opioid withdrawal symptoms. The peak dosing phase is variable in length and depends on the expected severity of withdrawal symptoms. Lofexidine could be used in following clinical situations Mild to moderate withdrawal symptoms o during last days of buprenorphine detoxification treatment o precipitated withdrawal during buprenorphine induction from heroin/methadone o transfer from low dose methadone(≤30mls) to buprenorphine o moderate dose methadone(30-60mls) to buprenorphine transfer o naltrexone induction after low dose buprenorphine stopped opioid stabilisation to help stop illicit opioid use on top of methadone or buprenorphine prescription during titration Also, Severe withdrawal symptoms during methadone detoxification from 80mg or less, abrupt buprenorphine withdrawal from moderate or higher doses or high dose methadone (>55ml) to buprenorphine transfer 11 Phase of withdrawal Induction Mild – Moderate Opioid Withdrawal Severe Opioid Withdrawal Both Regimes Regular Lofexidine Regular Lofexidine Prn Lofexidine Day 1 – 0.2mg qds Day 1 – 0.2mg qds 0.2mg qds prn daily Day 2 – 0.4mg tds Peak dosing Day 2-5 – 0.2mg qds Day 3-8 – 0.4mg qds Early reduction Day 6 – 0.2mg tds Day 9 – 0.4mg tds Day 7 – 0.2 mg bd Day 10 – 0.2mg qds Day 11 - 0.2mg bd Late reduction Day 8-10 – 0.2mg od Day 12-14 – 0.2mg od Total prescribed tablets 56 112 [0.2mg qds for 14 days] [0.4mg days] qds for None 14 Practical management points when using Lofexidine: withdrawal symptoms should be monitored (either clinically or using rating scales – SOWS & COWS) and dosing regimen adjusted accordingly. During low dose methadone to buprenorphine transfer and during naltrexone induction, a simplified dosing regimen could be used where peak dosing (0.2mg qds) is only necessary for 1-2 days. If withdrawal symptoms are prolonged or if seen following reduction of lofexidine, peak dosing could be used for upto 2 more days. But needs caution as rapid reduction of lofexidine may result in withdrawal like symptoms. If opiates were used during lofexidine regimes, peak dosing phase needs extending by up to 2 days. It is appropriate if client uses once or twice and if opiate consumption continues then lofexidine regime needs to stopped gradually and substitute maintenance treatment should be explored. Baseline blood pressure both standing & sitting and pulse before commencing lofexidine and daily monitoring in first few days (upto 4-5 days). If diastolic BP <50mmhg, then skip the dose. If postural drop in BP >20mmhg, then again skip the next dose. If service user complaints of dizziness, light headedness, feeling unwell or tired, skip the dose and needs clinical assessment. 12 If hypotension or bradycardia is consistent with lofexidine dosing then dose increase may be delayed or skipped or stop the regime 12 Buprenorphine detoxification Buprenorphine is opioid partial agonist and indicated for opioid detoxification, substitute maintenance treatment for opioid dependence and pain management. Pharmacology Buprenorphine is a thebaine derivative, has a partial agonistic activity at opioid receptors, has high affinity for the receptors displacing other opiates. Buprenorphine binds to receptor for longer period even at low concentrations in blood and may result in prolonged withdrawal syndrome but less severe in comparison to methadone. Before initiating buprenorphine there should be evidence of withdrawal due to the risk of precipitated withdrawal and for methadone its best to leave a gap of up to 36 hours. Buprenorphine has opiate effect analgesic effect due to partial agonist activity at µ-opioid receptors. It is administered as sublingual tablet, by intramuscular injection, intravenous infusion and transdermal patches. It is not administered orally as it has very high first pass metabolism in hepatic system. Buprenorphine is metabolised by the liver via cytochrome P450 enzyme system into norbuprenorphine and other metabolites. The metabolites are further conjugated with glucuronic acid and eliminated mainly through excretion into the bile. The elimination half-life of buprenorphine is 20-73 hours (mean 37hours). As it mainly excreted by hepatic system it can be used in patients with impaired renal system and in the elderly patients. Cautions Liver function – high dose buprenorphine can cause changes in liver function in individuals with history of liver disease. Service users with history of risk factors of liver damage needs monitoring liver functioning every 6-12 weeks. Intoxication – buprenorphine should be avoided when service users are showing signs of intoxication (alcohol or other depressant drugs like benzodiazepines). Buprenorphine on its own is safer but in combination with other sedative drugs can result in respiratory depression, sedation and coma. These effects may be harder to manage. Very high doses of naloxone (10-15mg) may be needed to reverse buprenorphine effects (although lower doses such as 0.8-2mg may be sufficient), hence ventilator support is often required in cases where buprenorphine is contributing to respiratory depression (e.g., in polydrug overdose). 13 Contraindications: Avoid in respiratory depression, acute alcoholism, head injury or raised intracranial pressure, pheochromocytoma. Side effects Nausea, vomiting, constipation, drowsiness, withdrawal symptoms in patients dependent on opioids, hiccups, dyspnoea, headache, dry mouth, orthostatic hypotension, urinary retention, decreased libido, ejaculatory dysfunction, hepatic necrosis and hepatitis particularly when sublingual tablets are crushed and used intravenously. Regimes a Service users using Heroin After a short induction period of 2-3 days an individual detoxification plan can be commenced. Following are two examples of regimes that can be followed dependent on the amount of Heroin used prior to the introduction of Buprenorphine. Service users using half a gram heroin per day by smoking could commence on 30 days regime as below. Service users using half a gram by injecting route might need titration up to 12mg before reduction. Date Dose Mg Dose Mg Dose Mg Day 1 4 Date Day 2 8 14 2.8 26 0.8 3 8 15 2.8 27 0.8 4 8 16 2.8 28 0.8 5 8 17 2 29 0.4 6 6 18 2 30 0.4 7 6 19 2 8 6 20 1.6 9 6 21 1.6 10 4 22 1.6 11 4 23 1.2 12 4 24 1.2 13 4 25 1.2 14 Date Day The 2 weeks regime may be used for service users who have reduced their use of Heroin to below a half-gram per day. Service users using heroin by injecting might need titration of buprenorphine dose upto 12mg. Date b Day 1 6 2 8 3 6 4 6 5 4 6 4 7 4 8 2 9 2 10 0.8 11 0.8 12 0.4 13 0.4 Dose Mg Dose Mg Dose Mg Date Day Date Day Service users on Methadone maintenance treatment Buprenorphine can be introduced following the cessation of Methadone using the following guidelines. Methadone 30mls 20mls 10mls Buprenorphine 6-8mgs 2-4mgs 2-4mgs Service users who struggle to fully reduce their Methadone can be ‘tailed off’ by the use of Buprenorphine. Reduction to 10-20mls of Methadone should be achieved as a starting point and the following regime can be introduced. Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 4mg 4mg 2mg 2mg 0.8mg 0.4mg 0.4mg This should achieve a rapid detoxification from Methadone over a period of seven days. 15 c Service users stabilised on Buprenorphine maintenance treatment A gradual reduction in discussion with service user should be planned to minimise withdrawal symptoms. Following guidelines may be used: 13 Buprenorphine dose / day Reduction rate >16 mg 4mg per week 4 – 16 mg 2-4mg per week 2-4 mg 0.4mg - 2 mg per week Below 2 mg 0.4 – 0.8mg per week Methadone detoxification Methadone detoxification needs to be distinguished from a slow reduction of methadone. In detoxification program, preparatory work needs to be completed and a momentum of change is generated so that a drug free state is reached in around 4 weeks time. It may be extended up to 12 weeks, but efficacy may be reduced. As methadone has a longer half life, it might be difficult for service users at the final stages of detoxification. Many service users start using illicit substances to cope with detoxification program. Hence it is important for good assessment and preparatory work as explained before and also it is important for service users to engage in psychosocial interventions to develop alternative coping strategies to address psychological aspects of dependence. Weekly random drug tests could prove useful to help keep the motivation of service users and also to test for other drug use. Withdrawal symptoms should be monitored clinically or by using rating scales. It must be discussed during preparation process about testing arrangements and also that they can return back to full maintenance treatment if they struggle with the program which could help psychologically to cope with the anxieties during the program. At final stages the following ways could be tried – continue with methadone detoxification with service users agreement discussion with service users about switching to buprenorphine and then to continue with detoxification program discussion about lofexidine program 16 discussion about symptomatic relief program on its own or as an aid to continue with methadone detoxification program discussion of available option of returning to maintenance treatment if they relapse Detoxification program should be planned on case by case basis in consultation with service user. Following the detoxification program, Naltrexone can be prescribed after 10 days interval but even may precipitate withdrawal symptoms. It may be useful to use naloxone challenge test. Pharmacology Methadone is a synthetic opioid, although chemically unlike to morphine or heroin it acts on opioid receptors and thus has same effects. Methadone maintenance treatment for opioid dependence is extensively and systematically studied. It is also used in management of chronic pain due to it long duration of action. Methadone is a full mu-opioid agonist for its opioid effects; also it binds to the glutamate NMDA receptor resulting in antagonist activity against glutamate and this may be one mechanism by which it decreases craving for opioids. Methadone has a slow metabolism and very high fat solubility resulting in long duration of action. The elimination half life is 15 to 60hours with a mean around 22-24hours. Metabolism rates vary greatly between individuals due to genetic variability in the production of metabolic enzymes CYP3A4 and CYP2D6. A longer half life usually allows for once daily administration in opiate detoxification and maintenance treatments. Patients with rapid metabolisation may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations allowing for lower total doses in some such patients. The analgesic effect is shorter than the pharmacological half-life, dosing for pain control usually requires multiple doses per day. The most common route of administration is oral solution. It is also administered in oral tablets, subcutaneous, intravenous and intramuscular ampoules. Cautions Cardiovascular risk factors, prolonged QTc interval, Hypotension, hypothyroidism, asthma (avoid during an attack), decreased respiratory reserve, prostatic hypertrophy, hepatic and renal impairment, elderly, convulsive disorders. Contraindications Avoid in acute respiratory depression, acute alcoholism, excess benzodiazepine use, head injury or raised intracranial pressure, where risk of paralytic ileus, phaeochromocytoma. 17 Side effects Nausea, vomiting, constipation (decreased bowel motility), hypoventilation, miotic pupils, drowsiness, hypotension, muscle rigidity, difficulty in micutuirition, dry mouth, sweating, headache, facial flushing, vertigo, bradycardia, tachycardia, palpitaions, postural hypotension, hypothermia, mood changes, decreased libido, rashes, pruritus and urticaria. Sample methadone detoxification programs with different periods. Detoxification from 55mls of methadone Detoxification from 30mls of methadone Detoxification from 30mls of methadone Day 1 50mls 26mls 26mls Day 2 50mls 24mls 24mls Day 3 45mls 24mls 18mls Day 4 45mls 22mls 14mls Day 5 40mls 22mls 12mls Day 6 40mls 22mls 10mls Day 7 40mls 18mls 8mls Day 8 35mls 18mls 6mls Day 9 35mls 18mls 4mls Day 10 30mls 16mls 2mls Day 11 30mls 16mls Day 12 26mls 12mls Day 13 26mls 12mls Day 14 22mls 10mls Day 15 22mls 10mls Day 16 18mls 8mls Day 17 18mls 8mls Day 18 14mls 6mls Day 19 14mls 6mls Day 20 10mls 4mls Day 21 10mls 4mls Day 22 6mls 4mls Day 23 6mls 2mls Day 24 4mls 2mls Day 25 4mls Day 26 2mls Day 27 2mls Day 28 2mls 18 14 Relapse Prevention and Aftercare following detoxification Maintenance of abstinence and relapse prevention is a key stage in the journey of addiction for a successful outcome and meaningful change in the service user’s life. As a routine treatment, support and monitoring should continue to facilitate maintenance of abstinence and this should be for a period of at least 6 months. Please refer to Turning Point document about the services and support available for service users during and following the detox programme. Naltrexone Naltrexone is an opioid antagonist indicated for prevention of relapse in opioid misusers. Evidence suggests that combination treatment of Naltrexone and psychosocial interventions is more effective than either treatment alone. Available published evidence inidicates that a minority of service users wish for naltrexone treatment, naltrexone treatment program has a very high drop out rate and service users continuing treatment for 3 months or more are more likely to remain abstinent. As activation of opioid receptors produces sense of well being, Naltrexone blockade of these receptors may produce dysphoria, which might contribute towards non compliance and drop out from treatment. Naltrexone assessment should be undertaken to determine service users suitability for the treatment because of the risk issues as detailed below. Also more evidence is emerging about use of naltrexone in alcohol dependence to help with physiological craving for the substance and hence being used in north American countries and also in some centres in UK. But in UK Naltrexone is not licensed for use in alcohol dependence. Pharmacology: Naltrexone can be described as a substituted Oxymorphone (Oxymorphone is a semi-synthetic opioid analgesic and is 6-8 times more potent than morphine). Naltrexone is rapidly absorbed, with peak blood levels achieved about 1 hour after oral administration. Naltrexone is metabolised mainly to 6β-naltrexol by the liver enzyme dihydrodiol dehydrogenase. Other metabolites include 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. These are then further metabolised by conjugation with glucuronide and excreted by renal system. Naltrexone has a relatively short plasma half-life of 4 hours and its metabolite 6βnaltrexol has a half life of about 10 hours. Naltrexone has a high affinity for opioid receptor sites. Naltrexone, and its active metabolite 6βnaltrexol, are competitive antagonists at µ- and κ-opioid receptors, and to a lesser extent at δopioid receptors. They therefore competitively displaces opioid agonists if they are present, but has little intrinsic action of their own. Opioid antagonistic action could last upto 72 hours. 19 Naltrexone is marketed as its hydrochloride salt, Nalorex, scored yellow tablet containing a dose of 50mg. Contraindications: Currently physiologically dependent of opioids and they would need to undertake detoxification program; acute hepatitis or liver failure; if service users are using opioids for physical condition; currently suffering with withdrawal symptoms and would need wash-out period of 7-10 days; if they have previous history of allergy/sensitivity to naltrexone. Cautions: Hepatic or renal impairment; liver function tests before and during treatment; pregnancy and breast feeding; poly-substance dependence; major physical or mental health problems. Side effects: Nausea, vomiting, abdominal pain; anxiety, sleeping difficulty, headache, low energy; joint & muscle pain; feeling down, loss of appetite, irritability, delayed ejaculation. Service users should be made of aware of above side effects and that they tend to be transient, mild and should get better with the course of treatment. Although major adverse effects have not been reported directly related to naltrexone, again service users should be strongly advised about the risk of opioid over dose and death if they were to relapse to opioid use. Service users should be made aware that any dose of heroin which they used to use before may prove fatal. And also the risk of service users using more opioids to overcome the blockade effect of naltrexone to achieve the euphoric relaxed state. Practical issues: Naltrexone should be used along with psychosocial interventions to help the client prevent a relapse back to opioid use following detoxification. Service users should be given all the information about the treatment and that any use of heroin or other opioid drugs will have no effect. Hence Naltrexone could be viewed as a treatment helping the service user to address the issues of craving and sudden temptation to use opioids. Psychosocial interventions should be aimed to help service users to develop psychological coping strategies to stop them wanting to use heroin and maintain their motivation to remain abstinent. The Cochrane review concluded that certain circumstances may increase the probability of a positive outcome of naltrexone treatment such as stable social contacts, occupation, a confidential relationship with the therapist and clear instructions about the treatment, with participants informed consent. 20 Service users should be made aware and cautioned of the risks of adverse events such as fatal overdose in those who relapse to opioid use. Also service users should be warned of the risk of acute opioid toxicity if any attempt to overcome the blockade effect of naltrexone. Naltrexone has the potential to precipitate severe withdrawal symptoms in those who are currently using or were previously taking opioid drugs and where enough wash-out period not given. A thorough assessment should be undertaken with regards to their opioid use and also if they have used any opioid-containing preparation unknowingly (ex., over the counter analgesics). The minimum wash-out period required depends on the type of opioid use, duration of use and amount taken as a last dose. Opioids with long half lives like Methadone may require wash-out period of up to 10 days and with shorter half lives such as heroin may require up to 7 days. With Buprenorphine wash-out period of 7 days is sufficient if final dose was >2mg and duration of use was >2 weeks, and naltrexone may be started in 2-3 days if final dose was <2mg and duration of use was <2 weeks. A test dose of naloxone (0.2mg) with much shorter half life than naltrexone, may be administered as a precautionary measure as precipitated withdrawal symptoms are of much shorter duration in comparison to naltrexone. Every effort should be made to involve the carer or family member to support the service user during the treatment program which is significant for a successful outcome. Evidence shows that at the onset of treatment during first 5-7 days, supervision of Naltrexone medication by a family member or carer is associated with improved outcomes. Supervision of medication could be discussed and agreed before commencement of the program. Care plan should be discussed with the service user and/or carer, family members or friends where supervision of medication, a record of medication taken, its effect and service user’s mood state throughout the program needs to be agreed before commencement of treatment. Investigations necessary before entering naltrexone treatment program: Liver function tests should be completed before starting the treatment and it is recommended that tests are repeated every week for 6 weeks and at regular intervals of around 1 month. If test results are abnormal should be used cautiously and naltrexone is used in alcohol dependence with rare adverse outcomes. Hence the need for regular monitoring and tests. 21 Guidance to follow would be – stop using if liver functions tests reveal raise in Alanine Transaminase enzyme (serum glutamate pyruvate transaminase or alanine aminotransferase) levels more than twice the normal range. Therapeutic window - the toxic dose is around 5 times that of normal therapeutic dose. Needs good titration of dose and monitoring. Pregnancy test Urinalysis or oral mucosal fluid sampling to ensure opioid free state allowing for wash-out period time for relevant opioids, naloxone challenge test could be useful. Please refer to Appendix 3 for Naltrexone assessment details, assessment form and pathways for service users in community, local prison and non-local prisons. The naltrexone treatment program can be commenced as follows: Breakfast Lunch Day 1 12.5mg Supper Bedtime (¼ tab) Day 2 Day 3 12.5mg 12.5mg (¼ tab) (¼ tab) 25mg (½ tab) Day 4 50mg Continue the prescription Naltrexone 50mg on a daily basis. Service user should be advised to stop taking if there is any reaction. 16 Naloxone challenge test Aims to confirm physiological dependence state on opioids. Nalxone has much shorter half life and any withdrawal symptoms precipitated will be of shorter duration than if precipitated by naltrexone. 22 A test dose of Naloxone 200 microgram I. V. or I.M. is administered and observed for opioid withdrawal symptoms. After 30 min, if no withdrawal symptoms are precipitated give naloxone 600 microgram I.M. (1.5ml) and continue observing for withdrawal symptoms If withdrawal symptoms are precipitated Naltrexone treatment should not be initiated and Naloxone challenge test to be repeated 3 days later. Pharmacology of Naloxone: Naloxone is an opioid antagonist and is specifically used to reverse the life-threatening depression of central nervous system and respiratory system. Naloxone should not be confused with naltrexone which is used for relapse prevention in dependence treatment rather than for emergency overdose situation. Naloxone has very high affinity for µ-opioid receptors in central nervous system and low affinity at κ- and δ-opioid receptors. It is synthesised from thebaine also called paramorphine, an opiate alkaloid, constituent of opium. Chemical structure of naloxone resembles that of oxymorphone except that an N-methyl group is substituted with an allyl group. The naloxone derives from N-allyl and oxymorphone. It has fast onset of action and short duration of action, if used IV action starts with in 2 minutes and its effects could last up to 45 minutes. Naloxone has no bioavailability when used orally unlike naltrexone. Naloxone is available in injection ampoules, 400micrograms/ml and can be used intravenously, subcutaneous and intramuscularly. Indications: Reversal of opioid induced respiratory depression, reversal of neonatal respiratory depression resulting from opioid administration in mothers, overdosage with opioids. Cautions: Cardiovascular disease, physiological dependence on opioids Side effects: Hypotension, hypertension, ventricular tachycardia and fibrillation, cardiac arrest, hyperventilation, dyspnoea, pulmonary oedema and less commonly agitation, excitement, paraesthesia. 23 17 APPENDIX 1: Clinical Opiate Withdrawal Scale Date: ....................... Name: ................................................ FI No: ....................... For each item, circle the number that best describes the client’s signs or symptoms. Rate on just the apparent relationship to opiate withdrawal. For example, if heart rate is increased because the client was jogging just prior to assessment, the increased pulse rate would not add to the score. Score Score Resting Pulse Rate: GI Upset: over last ½ hour ______ beats/minute 0 no GI symptoms Measured after client is sitting or lying for one minute. 1 stomach cramps 2 nausea or loose stool 0 pulse rate 80 or below 3 vomiting or diarrhoea 1 pulse rate 81-100 5 multiple episodes of diarrhoea or vomiting 2 pulse rate 101-120 4 pulse rate greater than 120 Sweating: over past ½ hour not accounted for by room temperature or client activity. Tremor: observation outstretched hands of 0 no tremor 0 no report of chills or flushing 1 tremor can be felt, but not observed 1 subjective report of chills or flushing 2 flushed or observable moistness on face 2 slight tremor observable 4 gross tremor or muscle twitching 3 beads of sweat on brow or face 4 sweat streaming off face Restlessness: assessment Observation during Yawning: Observation assessment during 0 able to sit still 0 no yawning 1 reports difficulty sitting still, but is able to do so 1 yawning once or twice during assessment 3 frequent shifting or movements of legs/arms 2 yawning three or more times during assessment extraneous 5 unable to sit still for more than a few seconds 4 yawning several times/minute Pupil size: Anxiety or Irritability: 0 pupils pinned or normal size for room light 0 none 1 client reports increasing irritability or anxiousness 1 pupils possibly larger than normal for room light 2 pupils moderately dilated 2 client obviously irritable or anxious 5 pupils so dilated that only the rim of the iris is visible 4 client so irritable or anxious that participation in the assessment is 24 difficult Bone or Joint Aches: If client was having pain previously, only the additional component attributed to opiate withdrawal is scored Gooseflesh Skin: 0 skin is smooth 3 pilo-erection of skin can be felt or hairs standing up on arms 0 not present 5 prominent pilo-erection 1 mild diffuse discomfort 2 client reports severe diffuse aching of joints/muscles 4 client is rubbing joints or muscles and is unable to sit still because of discomfort Total Score: __________ Runny Nose or Tearing: Not accounted for by cold symptoms or allergies The total score is the sum of all 11 items 0 not present 1 nasal stuffiness or unusually moist eyes Initials of person completing assessment: __________ 2 nose running or tearing 4 nose constantly running or tears streaming down cheeks Score: 5-12 = mild; 13-24 = moderate; 25-36 = moderately severe; more than 36 = severe withdrawal. 25 18 APPENDIX 2: Short Opiate Withdrawal Scale NAME DATE TIME Please tick the appropriate box if you have suffered from any of the following symptoms in the last 24 hours NONE MILD MODERATE Feeling sick Stomach cramps Muscle spasms or twitching Feelings of coldness Heart pounding Muscular tension Aches and pains Yawning Runny eyes Insomnia or problems sleeping TOTAL 26 SEVERE 19 APPENDIX 3 Naltrexone assisted relapse prevention should only be initiated by specialists and specialist experienced generalists in this technique There needs to be an understanding of the crucial role of psychological interventions in achieving and maintaining abstinence. Where it is set up, shared care arrangements should be clearly delineated, between the specialist and the patient’s general practitioner. We would suggest the following approaches: 1 Client within community team: 1.1 The relevant drug worker/care coordinator will undertake a comprehensive assessment, or a detailed additional assessment where a Comprehensive assessment already exists, focussing specifically on the areas detailed in section 1.1 above (SMS Naltrexone Assessment Form) 1.2 The case will be reviewed with the relevant clinical lead for the team prior to being presented at the local CDT meeting in the normal way. 1.3 Where an agreement to naltrexone prescribing is indicated at the CDT meeting, an early appointment will be arranged with consultant and the case put forward for review of prescribing in the normal way, with Care Plan and comprehensive treatment package outlined. 1.4 The case will be reviewed with the medic at no less than 3 monthly intervals, and sooner if indicated. Liver function tests need to be undertaken, and the frequency of these will depend on past history of liver problems, obesity, alcohol use, older adults and at the request of the medical practitioner (prescribing guide lines state liver function tests should be carried out prior to, and throughout the treatment period) these results may be required at the formal reviews. 1.5 Given the risks associated with naltrexone, particularly in relation to very minimal tolerance to heroin and opiate based drugs, any suggestion of use of such drugs on top of the prescription must receive urgent attention and referral to consultant. This will require random swab testing throughout the treatment period 27 1.6 Normal period of naltrexone prescribing would not exceed 12 months, and more routinely work would be undertaken with the aim, given an appropriately targeted client, of supporting withdrawal between 3 and 6 months. 1.7 Where the client is appropriately targeted and circumstances indicate a settled and stable situation, it is not anticipated that oversight of naltrexone prescribing need remain with the Consultant beyond the first consultation, unless that is the Consultant identifies factors in the case that would require the case to remain with them. 1.8 It is anticipated that naltrexone prescribing will be suitable for a relatively small number of closely targeted and assessed clients 2 Client being released from custody: 2.1 Where the client is in a local prison the DIP In-Reach worker will undertake a full comprehensive assessment, and will specifically focus on the following areas: Previous treatment interventions and response i.e. what, when and success or otherwise. Clearly where a client’s circumstances do not indicate previous consistent engagement with treatment agencies towards establishing a stable and managed position regarding their drug use, and preferably some indication of previous attempts to withdraw from opiates, then it may be reasonable to take the view that naltrexone might not be the best option. Exceptions to this may include a long prison sentence where the client has clearly engaged consistently with treatment and support agencies in the prison and in the community, and has developed a clear perspective on naltrexone prescribing as part of a detailed treatment package upon release. Liver Function Test (LFTs) clearly indicate the suitability of the client Accommodation – must be stable and settled accommodation, with no other drug users indicated as present at the accommodation Social support networks – range of support that will reinforce a drug free lifestyle Lifestyle and associates – no indication of close and primary contact with a drug using group of friends/family Prepared to engage with Harm Reduction and Relapse Prevention work as part of a comprehensive treatment package 28 Employment/training opportunities either identified or prepared to explore as part of comprehensive treatment package If all these criteria can be met then the individual would be suitable for Naltrexone prescribing, under supervised conditions. 2.2 Where the client is not located in a local prison then the DIP Throughcare and Aftercare Care Coordinator will work with the CARAT and Healthcare staff within the relevant prison to ensure that a triage assessment, incorporating the key areas for assessment as noted above, is completed and a copy faxed to the care coordinator. 2.3 Having received the relevant information and reviewed any history of contact with treatment services that may be available, the DIP worker will review the referral for naltrexone prescribing with the clinical lead for DIP. Where the assessment indicates that all or most of the assessment criteria are met, referral for naltrexone prescribing will progress, as usual, via the CDT team meeting in the relevant area. This will include identification of drug worker, where DIP worker is unable to hold clinical responsibility for the case at that time, but where the DIP worker would continue to act as care coordinator in relation to the Care Plan. Transition to shared care should be instigated within a two week period. 2.4 Where an agreement in principle to naltrexone prescribing is indicated at the CDT meeting, the assessment and details of the case will be presented to the Consultant, in paper form, and an agreement to support naltrexone prescribing confirmed. 2.5 The prison will be informed of the decision as to whether Worcestershire CDT are able to support the prescribing of naltrexone on release a Where naltrexone can be prescribed on release – (see prescribing guidelines Department of Health) the prison will be informed in writing and this will involve them undertaking all the necessary clinical tests prior to commencing naltrexone prescribing before release. The prison would normally release with up to 7 days supply of naltrexone. An early appointment with the Consultant will be arranged within seven days post release, when the continuation script will be confirmed and Care Plan including comprehensive treatment package to support naltrexone prescribing regime confirmed. b Where naltrexone cannot be prescribed on release. – the prison will be informed in writing with reasons as to why the client does not meet the local assessment criteria, or if for clinical reasons the use of naltrexone is contra indicated. CARAT and healthcare staff will be asked to explore alternative treatment options with the 29 client prior to release. An early appointment with DIP throughcare and aftercare worker will be confirmed upon release and a detailed review of alternatives and a Care Plan completed. This may include working with partnership agencies with regards to relapse prevention. 2.6 Where naltrexone prescribing is indicated – case will be reviewed with the medic. Liver function tests need to be undertaken, and the frequency of these will depend on past history of liver problems, obesity, alcohol use, older adults and at the request of the medical practitioner (prescribing guide lines state liver function tests should be carried out prior to, and throughout the treatment period) these results may be required at the formal reviews. 2.7 Normal period of naltrexone prescribing would not exceed 12 months, and more routinely work would be undertaken with the aim, given an appropriately targeted individual in the first place, of supporting withdrawal between 3 and 6 months 30 Worcestershire Mental Health Partnership NHS Trust Substance Misuse Service Assessment Form for the use of Naltrexone Name Home Address Prison and Prison No. Pregnant YES NO History of previous Treatment Interventions Successful or otherwise. Has there been previous consistent engagement. Have there attempts to opiates. been previous withdraw from Compliance to treatment Accommodation Are drug users indicated as resident at this address, is it a settled stable environment Liver Function Test Results Social Support Networks What support is there to reinforce a drug free lifestyle? Prepared to engage with harm reduction and relapse prevention work 31 Employment/Training Opportunities Please complete tick boxes if client fulfils the criteria in all area Yes then in principal they would be a suitable candidate for prescribing History of previous treatment Accommodation Liver Function Test Social Support Lifestyle and associates Prepared to engage in Harm Reduction/Relapse prevention Employment/Training opportunities Name and Signature Of assessor Assessment Date Further Action Required 32 No Proposed Care Pathway Prescribing Naltrexone within the community teams Worker will undertake a SMS Naltrexone Assessment Form Discuss with relevant clinical lead for the team an present at clinical meeting If suitable If not suitable Discuss further treatment options with the client and signpost to the appropriate services Appointment made with prescribing specialist (Consultant) Consultant Confirms Prescription Shared care arrangements should be delineated 33 Proposed Care Pathway Prescribing Naltrexone From Local Prisons Access for clients in local prisons Full assessment by DIP prison in reach Worker Discuss with DIP clinical lead If suitable If not suitable Communication with Prisons and Sign post through DIPs for appropriate treatment plans Discussed in clinical team meeting Appointment made with prescribing specialist (Consultant) Local Treatment Agencies Consultant Confirms Prescription Information sent to prison to confirm prescribing Shared care arrangements should be delineated 34 Propose Care Pathway Prescribing Naltrexone Not in Local Prison Communication with DIPs staff, Health Care and CARATs ensuring full assessment incorporating key areas. Refer back to prison for Retox scripting in preparation for release Discuss with DIP Clinical Lead If suitable If not suitable Discussed in clinical team meeting Appointment made with prescribing specialist Local treatment agencies Consultant Confirms Prescription Shared care arrangements should be delineated Communicate with Prison Sign post through DIPs for appropriate treatment plans on release Information sent to prison to confirm prescribing 35 20 Appendix 4 The following is aimed at helping the service user and keyworker/care co-ordinator to draw a comprehensive care plan during the preparatory process for detoxification program and for after care: Service User Name: Keyworker: Date: 1. Identify and please list high risk situations/triggers for craving which could lead to relapse into drug taking behaviour following the completion of detoxification program? 2. Please list the strategies you have considered and developed to avoid or limit exposure to high risk situations? 3. List below the skills you have considered and developed to manage cravings and other painful emotions without using drugs? 4. Print below the relapse prevention plan to cope with lapses into drug taking behaviour? 36 5. What is your action plan to recognise, challenge and manage unhelpful or dysfunctional thoughts about drug misuse? 6. What is your emergency plan for coping with high-risk situations when other skills are not working? 7. What is your action plan to recognise how you might ‘set yourself up’ to use illicit drugs? 8. Please list the skills you have developed and engaged in generating pleasurable sober activities and relationships, improving quality of life and attaining a lifestyle balance? 37 21 Flow chart Service user expresses the wish for opioid detoxification Case discussed at Referral / team meeting in presence of Turning Point staff Clinic appointment booked in 1-2 weeks time If considered suitable, preparation work to draw up a clear care plan Assessments completed from Community Rehab and or Turning Point Care Co-ordinator to liaise care between different agencies Clinic appointment booked and detox program decided In-patient detox community detox Assessment for Naltrexone treatment program After care to maintain abstinence and relapse prevention Joint working between Care Co-ordinator, CDT staff (Naltrexone treatment), Community Rehab, Turning Point for a period of at least 6 months 38 23 Useful References 1 Seifert J, Metzner C, Paetzold w et al. detoxification of opiate addicts with multiple drug abuse: a comparison of buprenorphine vs methadone. Pharmacopsychiatry 2002; 35:159164. 2 JHarding-Pink d. Methadone: one person’s maintenance dose is another’s poison. Lancet 1993; 341: 665-666. 3 Lingford-Hughes AR, Welch S, Nutt AJ. Evidence based guidelines for the pharmacological management of substance misuse, addiction and comorbidity: recommendations from the British Association for Psychopharmacology. J Psychopharmacology 2004; 18: 293-335. 4 Prescribing guidelines. 8th edition. The south London and Maudsley, Oxleasturst. 5 NTA guidelines. Drug Misuse and Dependence – UK Guidelines on Clinical Management 2007. http://www.nta.nhs.uk/areas/clinical_guidance/clinical_guidelines/docs/clinical_guidelines_ 2007.pdf 6 NICE guidelines. Drug misuse: opioid detoxification. http://guidance.nice.org.uk/CG52 7 NICE guidelines. Drug misuse – naltrexone. http://guidance.nice.org.uk/TA115 8 NICE guidelines. Drug misuse: psychosocial interventions. http://guidance.nice.org.uk/CG51 9 Eissenberg TR, Johnson RE, Bigelow GE et al. Controlled opioid withdrawal evaluation during 72-hr dose omission in buprenorphine maintained patients. Drug Alcohol Depen 1997; 45: 81-91. 10 Community prescribing guidelines for substance misuse service. Birmingham and Solihull mental health trust. 11 Schmittner J, Schroeder JR, Epstein DH et al. QT interval increased after single dose of lofexidine. BMJ 2004; 329: 1075. 12 Kirchmayer U, Davoli M, Verster A. Naltrexone maintenance treatment for opioid dependence. Cochrane Database of systemic reviews, Issue 2, Oxford, 2003. 13 Tucker T, Ritter A. Naltrexone in the treatment of heroin dependence; a comprehensive review. Drug Alcohol Rev 2000; 19: 73-82. 39 14 Guidelines for substance misuse. Sandwell mental health trust. 15 Gossop M, Marsden J, Stewart D, Treacy S. Outcomes after methadone maintenance and methadone reduction treatments: two-year follow-up results from the National Treatment Outcome Research Study. Drug and Alcohol Dependence 2001;62:255-264. 16 Green L, Gossop M. Effects of information on the opiate withdrawal syndrome. British Journal of Addiction 1988;83:305-309. 17 Bell J, Kimber J, Lintzeris N, White J, Monheit B, Henry-Edwards S, et al. Clinical Guidelines and Procedures for the Use of Naltrexone in the Management of Opioid Dependence. Canberra: Australian Government, 2003. 18 Cochrane Reviews. Alpha2 adrenergic agonists for the management of opioid withdrawal. http://www.cochrane.org/reviews/en/ab002024.html 19 Cochrane Reviews. Inpatient versus other settings for detoxification for opioid dependence. http://www.cochrane.org/reviews/en/ab004580.html 20 Cochrane Reviews. Methadone at tapered doses for the management of opioid withdrawal. http://www.cochrane.org/reviews/en/ab003409.html 21 Cochrane Reviews. Oral naltrexone maintenance treatment for opioid dependence. http://www.cochrane.org/reviews/en/ab001333.html 22 Cochrane Reviews. Psychosocial and pharmacological treatments versus pharmacological treatments for opioid detoxification. http://www.cochrane.org/reviews/en/ab005031.html 40