Introduction

Mental and behavioural problems due to psychoactive substance use are common. The World Health Organization (WHO) in the International Classification of Diseases 10 (ICD-10)¹ identifies acute intoxication, harmful use, dependence syndrome, withdrawal state, withdrawal state with delirium, psychotic disorder, amnesic syndrome, residual and late onset psychotic disorder, other mental and behavioural disorders and unspecified mental and behavioural disorders as substance related disorders. A wide range of psychoactive substances may be problematic including alcohol, opioids, cannabinoids, sedatives, stimulants, hallucinogens, tobacco, volatile substances and so called 'legal highs'.

Substance misuse is commonly seen in people with severe mental illness (so-called dual diagnosis) and personality disorder. In many adult psychiatry settings, dual diagnosis is the norm rather than the exception. In contrast, substance misuse services are often commissioned and provided separately from psychiatric services. The model of care in most addiction services means that patients who are not motivated to engage will not be assertively treated and followed up. Dual diagnosis teams are not universally available resulting in sub-optimal treatment for substance misuse related problems for many patients with mental illness.

According to ICD-10, dependence syndrome is'a cluster of physiological, behavioural, and cognitive phenomena in which the use of a substance or a class of substances takes on a much higher priority for a given individual than other behaviours that once had greater value'. A definite diagnosis of dependence should only be made if at least three of the following have been present togther in the last year:

• compulsion to take substance
• difficulties controlling substance-taking behaviour
• physiological withdrawal state
• evidence of tolerance
• neglect of alternative interests
• persistant use despite harm.

Substance use disorders should generally be treated with a combination of psychosocial and pharmacological interventions. This chapter will concentrate on pharmacological interventions for alcohol, opioids and nicotine use. Cocaine, other stimulants and benzodiazepine use will be discussed briefly. Note that various National Institute for Health and Care Excellence (NICE) Guidelines and Technology Appraisals (see relevant sections in this chapter), Department of Health Substance Misuse Guidelines,² and National Treatment Agency for Substance Misuse guidance³ also provide a comprehensive overview of treatment approaches, as does the most recent British Association for Psychopharmacology consensus guideline.⁴

References

1. World Health Organisation. International Statistical Classification of Diseases and Related Health Problems. 10th revision version for 2007. Geneva: WHO; 2007. http://www.who.int/
2. Department of Health. Drug misuse and dependence. UK guidelines on clinical management. London: DH; 2007.
3. Day E. National Treatment Agency for Substance Misuse. Opiate detoxification in an inpatient setting. London: NTA, 2005. http://www.nta. nhs.uk/
4. Lingford-Hughes AR et al. Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012; 26:899–952.

Alcohol dependence

What is a unit of alcohol?

One unit = 10 mL of ethanol or 1L of 1% alcohol. For example, 250 mL of wine that is 10% alcohol contains 2.5 units.

How much alcohol is too much?

NICE public health guideline on preventing harmful drinking cites the following weekly limits (in units):²

The NICE guideline on the diagnosis, assessment and management of harmful drinking and alcohol dependence recommends that staff working in services providing care for problem drinkers should be competent in identifying and assessing harmful drinking and alcohol dependence.¹ The NICE public health guideline on reducing harmful drinking² recommends a session of brief structured advice based on FRAMES principles (Feedback, Responsibility, Advice, Menu, Empathy, Self-efficacy) as a useful intervention for everyone at increasing or high-risk of alcohol related problems.

Assessing alcohol use

Where consumption above recommended levels has been identified, a more detailed clinical assessment is required. This should include the following:

• history of alcohol use, including daily consumption and recent patterns of drinking
• history of previous episodes of alcohol withdrawal
• time of most recent drink
• history from family member or carer
• other drug (illicit and prescribed) use
• severity of dependence and of withdrawal symptoms
• co-existing medical and psychiatric problems
• physical examination including cognitive function
• breathalyser: absolute breath alcohol level and whether rising or falling (take at least 20 minutes after last drink to avoid falsely high readings from the mouth and 1 hour later)
• laboratory investigations: FBC, U&E, LFTs, INR, PT and urinary drug screen.

The following structured assessment tools are recommended.¹

• The Alcohol Use Disorders Identification Test (AUDIT)³ questionnaire, a 10-item questionnaire which is useful as a screening tool in those identified as being at increasing risk. Questions 1–3 address the quantity of alcohol consumed, 4–6 the signs and symptoms of dependence and 7–10 the behaviours and symptoms associated with harmful alcohol use. Each question is scored 0–4, giving a maximum total score of 40. A score of 8 or more is suggestive of hazardous or harmful alcohol use. Hazardous drinking = consumption of alcohol likely to cause harm. Harmful drinking = consumption already causing mental or physical health problems.
• The Severity of Alcohol Dependence Questionnaire (SADQ)⁴ is a more detailed 20-item questionnaire with the score on each item ranging from 0–3, giving a maximum total score of 60.

Alcohol withdrawal

In alcohol-dependent drinkers, the central nervous system has adjusted to the constant presence of alcohol in the body (neuro-adaptation). When the blood alcohol concentration (BAC) is suddenly lowered, the brain remains in a hyper-excited state, resulting in the withdrawal syndrome.

Self-limiting symptoms of withdrawal include tremor, sweating, nausea, retching, vomiting, tachycardia, agitation, headache, insomnia and malaise (essentially, a very bad hangover). Where large quantities of alcohol have been regularly consumed over a period of time (moderate-to-severe dependence), withdrawal can be associated with the development of seizures, Wernicke's encephalopathy and delirium tremens (DT), all of which are potentially life-threatening. See Table 6.1.

Table 6.1 Features of alcohol withdrawal

Pharmacologically assisted withdrawal (alcohol detoxification)

Alcohol withdrawal is associated with significant morbidity and mortality when improperly managed. Therefore all patients need general support and a proportion will need pharmacotherapy to modify the course of reversal of alcohol-induced neuro-adaptation.

Pharmacologically assisted withdrawal is likely to be needed when:

• regular consumption of > 15 units/day
• AUDIT score > 20.

Symptom scales can be helpful in determining whether the regimen prescribed is adequate, but not excessive with respect to managing symptoms. The Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar; see Figure 6.1)⁵ and Short Alcohol Withdrawal Scale (SAWS; see Figure 6.2)⁶ are both 10-item scales that can be completed in around 5 minutes. The CIWA-Ar is an objective scale and the SAWS is a self-complete tool. A CIWA-Ar score > 15 or a SAWS score > 12 should prompt assisted withdrawal.

Where assisted withdrawal is undertaken in the community, there should be someone at home (ideally 24 hours) who is able to monitor and supervise the withdrawal process. The treatment plan, including contingency plans, should be discussed with the patient and person who will be supporting them and shared with the GP. It is usually appropriate to arrange for medication to be picked up on a daily/alternate day basis and for the patient to be seen regularly during the assisted withdrawal process. Assisted withdrawal should stop if the patient resumes drinking. Outpatient-based programmes should include psychosocial support, such as motivational interviewing.

Most patients can be safely treated at home, however, inpatient treatment is likely to be required in the following circumstances.

• Regular consumption of > 30 units/day.
• SADQ > 30 (severe dependence).
• There is a history of seizures or DT.
• The patient is very young or elderly.
• There is current benzodiazepine use in combination with alcohol.
• Substances other than alcohol are also being misused/abused.
• There is co-morbid mental or physical illness, learning disability or cognitive impairment.
• The patient is pregnant.
• The patient is homeless or has no social support.
• There is a history of failed community detoxification(s).

Benzodiazepines are the treatment of choice for alcohol withdrawal. They exhibit cross-tolerance with alcohol and have anticonvulsant properties. Use is supported by NICE guidelines;^1,7 a Cochrane systematic review;⁸ and the British Association for Psychopharmacology (BAP) guidelines.⁹ Parenteral thiamine, and other vitamin replacement is an important adjunctive treatment for the prophylaxis and/or treatment of Wernicke–Korsakoff syndrome and other vitamin-related neuropsychiatric conditions.

Chlordiazepoxide is the benzodiazepine used for most patients in most centres as it is considered to have a relatively low dependence-forming potential. Some centres use diazepam. Where hepatic impairment is clinically significant (that is, the patient is in liver failure), a short-acting benzodiazepine such as oxazepam or lorazepam is the treatment of choice.

Figure 6.1 Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised.⁵ The CIWA-Ar is not copyrighted and may be reproduced freely.

Figure 6.2 Short Alcohol Withdrawal Scale (SAWS).⁶ The SAWS is a self-completion questionnaire. SAWS is not copyrighted and may be reproduced freely. Symptoms cover the previous 24-hour period.

There are three types of assisted withdrawal regimens; fixed dose reduction (the most common in non-specialist settings), variable dose reduction (usually results in less benzodiazepine being administered but best reserved for settings where staff have specialist skills in managing alcohol withdrawal), and finally front-loading (infrequently used).^1,9 Assisted withdrawal regimens should never be started if the blood alcohol concentration is very high or is still rising.

Fixed dose reduction regimen

Fixed dose regimens are recommended for use in community or non-specialist inpatient/ residential settings. Patients should be started on a dose of benzodiazepine, selected after an assessment of the severity of alcohol dependence (clinical history, number of units per drinking day and score on the SADQ). With respect to chlordiazepoxide, a general rule of thumb is that the starting dose can be estimated from current alcohol consumption. For example, if 20 units/day are being consumed, the starting dose should be 20 mg four times a day. The dose is then tapered to zero over 5–10 days. Alcohol withdrawal symptoms should be monitored using a validated instrument such as the CIWA-Ar⁵ or SAWS.⁶

Table 6.2 Moderate alcohol dependence: example of a fixed dose chlordiazepoxide treatment regimen

Mild alcohol dependence usually requires very small doses of chlordiazepoxide or else may be managed without medication.

For moderate alcohol dependence, a typical regime might be 10–20 mg chlordiazepoxide four times a day, reducing gradually over 5–7 days (see Table 6.2). Note that 5–7 days' treatment is adequate and longer treatment is rarely helpful or necessary. It is advisable to monitor withdrawal and BAC daily prior to providing the days medication. This may mean that community pharmacologically assisted alcohol withdrawals should start on a Monday to last 5 days.

Severe alcohol dependence will often require specialist/inpatient treatment. Intensive daily monitoring is advised for the first 2–3 days. This may require special arrangements over a weekend. Prescribing should not start if the patient is heavily intoxicated, and in such circumstances they should be advised to return when not intoxicated, at an early opportunity. The dose of benzodiazepine may need to be reduced over a 7–10 day period in this group (occasionally longer if dependence is very severe or there is a history of complications during previous detoxifications) (see Table 6.3).

Symptom-triggered regimen

This should be reserved for managing assisted withdrawal in specialist alcohol inpatient or residential settings. Regular monitoring (pulse, blood pressure [BP], temperature, level of consciousness, severity of withdrawal symptoms as determined using CIWA-Ar, SAWS or alternative validated measure) is required and medication is given only when withdrawal symptoms are observed. Symptom-triggered therapy is generally used in patients without a history of complications. A typical symptom-triggered regimen would be chlordiazepoxide 20–30 mg hourly as needed. Note that the total dose given each day would be expected to decrease from day 2 onwards. It is common for symptom-triggered treatment to last only 24–48 hours before switching to an individualised fixed dose reducing schedule. Occasionally (e.g. in DT) the flexible regime may need to be prolonged beyond the first 24 hours.

Table 6.3 Severe alcohol dependence: example of a fixed dose chlordiazepoxide regimen

Front-loading regimens

Front loading regimens involve giving an initial loading dose of medication, e.g. chlordiazepoxide 100 mg, followed by further doses of between 50 and 100 mg approximately every 4–6 hours until light sedation is achieved. The patient is monitored every 2 hours (or more frequently) with basic observations and a withdrawal scale. The long half-life of chlordiazepoxide ensures that withdrawal symptoms are alleviated. Front loading is contraindicated in advanced liver disease, chronic obstructive pulmonary disease or following a head injury. It should be reserved for use in wellmonitored inpatient settings.

Whichever regimen is used, a CIWA-Ar score > 15 or a SAWS score > 12 during assisted withdrawal suggest that the regimen prescribed is inadequate and further intervention is required. If a patient suffers hallucinations or agitation, an increased dose of benzodiazepine should be administered, according to clinical judgement.

Those with liver cirrhosis and/or functional liver impairment (see section on 'Hepatic impairment' in Chapter 7) should receive a shorter acting benzodiazepine such as oxazepam.⁷ Some patients may need, and be able to tolerate, relatively high starting doses, e.g. 40 mg qds whereas others may only be able to tolerate lower doses. A withdrawal scale should be used as a marker of optimal dosing. It is important to note that the risk of alcohol withdrawal seizures may be higher with oxazepam although this is more of a clinical impression than proven fact. Oxazepam is also a useful option in patients with chronic respiratory disease (note that the majority of dependent drinkers are smokers). Chlordiazepoxide and oxazepam have broadly similar potencies (10 mg ≈ 10 mg).

Complications associated with alcohol withdrawal

Seizures

Alcohol withdrawal can precipitate seizures, but note that those who have a seizure for the first time during assisted withdrawal should be investigated to rule out organic disease or idiopathic epilepsy. A meta-analysis of trials assessing the efficacy of drugs preventing alcohol withdrawal seizures demonstrated that benzodiazepines, particularly long-acting preparations such as diazepam, significantly reduced seizures de novo;¹⁰ longer-acting benzodiazepines are therefore recommended for medically assisted withdrawal in those with a previous history of seizures.¹¹ Some anticonvulsants are as effective as benzodiazepines in preventing seizures¹⁰ and some units recommend carbamazepine loading in patients with untreated epilepsy, those with a history of more than two seizures during previous withdrawal episodes, or those who have experienced previous seizures despite adequate benzodiazepine loading. Note that phenytoin does not prevent alcohol-withdrawal seizures.⁹ There is no need to continue an anticonvulsant long-term if it has been used to treat an alcohol-withdrawal related seizure.⁹

Hallucinations

Mild perceptual disturbances usually respond to chlordiazepoxide. However, those that do not can be treated with oral haloperidol.¹² Haloperidol may also be given intramuscularly or (very rarely) intravenously if necessary (but BP should be monitored for hypotension and electrocardiogram [ECG] for QT prolongation). Caution is needed because haloperidol can reduce the seizure threshold. It is also associated with acute dystonic reactions.

Delirium tremens

Delirium tremens is a toxic confusional state that occurs when alcohol withdrawal symptoms are severe. Risk factors include a long history of dependence or severe dependence, multiple previous admissions/assisted withdrawals, older age and a history of DT or alcohol-related seizures. DT is often associated with medical illness and are life-threatening. The classic triad of symptoms includes clouding of consciousness/ confusion, vivid hallucinations affecting every sensory modality, and marked tremor. Clinical features also include paranoid delusions, agitation, sleeplessness and autonomic hyperactivity (tachycardia, hypertension, sweating and fever). Symptoms of DT typically peak between 72–96 hours after the last drink. Prodromal symptoms usually include night-time insomnia, restlessness, fear and confusion. Treatment of DT requires early diagnosis and prompt transfer to a general medical setting where intravenous diazepam can be given, medical disorders treated, fluids and electrolytes replaced, and thiamine and other vitamins administered intravenously.

Wernicke's encephalopathy

Wernicke's encephalopathy is a progressive neurological condition caused by thiamine deficiency. It can occur in any condition associated with poor nutrition; those who consume large quantities of alcohol tend to be malnourished secondary to a restricted diet and alcohol-related reduced absorption of thiamine.

Thiamine

Low-risk drinkers without neuropsychiatric complications and with an adequate diet should be offered oral thiamine: a minimum of 300 mg daily during assisted alcohol withdrawal and periods of continued alcohol intake.⁹

Thiamine is required to utilise glucose. A glucose load in a thiamine-deficient patient can precipitate Wernicke's encephalopathy.

It is advised that parenteral B-complex (Pabrinex) must be administered before glucose is administered in all patients presenting with altered mental status.

The 'classical' symptom triad of ophthalmoplegia, ataxia and confusion is rarely present in Wernicke's encephalopathy, and the syndrome is more common than is widely believed. A presumptive diagnosis of Wernicke's encephalopathy should therefore be made in any patient undergoing detoxification who experiences any of the following signs: ataxia, hypothermia, hypotension, confusion, ophthalmoplegia/nystagmus, memory disturbance and unconsciousness/coma. Any history of malnutrition, recent weight loss, vomiting or diarrhoea or peripheral neuropathy should also be noted.¹³ Individuals at high risk of developing Wernicke's encephalopathy⁷ include dependent drinkers in acute withdrawal who are malnourished or at risk of malnourishment or have decompensated liver disease and, in addition, attend the emergency department or are admitted to hospital with acute illness or injury, are homeless or are hospitalised for co-morbidity.

It is generally advised that patients undergoing inpatient detoxification should be given parenteral thiamine as prophylaxis^1,7,9,14,15 although there is insufficient evidence from randomised controlled trials (RCTs) as to the best dose, frequency or duration of use. Guidance is based on 'expert opinion'⁹ and the standard advice is one pair of Pabrinex IMHP daily (containing thiamine 250 mg/dose) for 5 days, followed by oral thiamine and/or vitamin B compound for as long as needed (where diet is inadequate or alcohol consumption is resumed).⁹ All inpatients should receive this regime as an absolute minimum.

Intramuscular (IM) thiamine preparations have a lower incidence of anaphylactic reactions than IV preparations, at 1 per 5 million pairs of ampoules of Pabrinex - far lower than many frequently used drugs that carry no special anaphylaxis warning. However, this risk has resulted in fears about using parenteral preparations and the inappropriate use of oral thiamine preparations (which do not offer adequate protection). Given the risks associated with Wernicke's encephalopathy, the benefit to risk ratio grossly favours parenteral thiamine.^9,14,16 Where parenteral thiamine is used, facilities for treating anaphylaxis should be available.^17–19

If Wernicke's encephalopathy is suspected the patient should be transferred to a medical unit where intravenous thiamine can be administered. If untreated, Wernicke's encephalopathy progresses to Korsakoff's syndrome (permanent memory impairment, confabulation, confusion and personality changes).

Treatment for patients with suspected/established Wernicke's encephalopathy (acute medical ward) is at least 2 pairs of Pabrinex IVHP (i.e. 4 ampoules) three times daily for 3–5 days, followed by one pair of ampoules once daily for a further 3–5 days or longer^1,9 (until no further response is seen).

Table 6.4 Alcohol withdrawal treatment interventions: summary

Table 6.5 Simple remedies for somatic complaints during assisted alcohol withdrawal

Alcohol withdrawal treatment interventions are summarised in Table 6.4.

Somatic complaints are common during assisted withdrawal. Some simple remedies are shown in Table 6.5.

Relapse prevention

There is no place for the continued use of benzodiazepines beyond treatment of the acute alcohol withdrawal syndrome. Acamprosate and supervised disulfiram are licensed for treatment of alcohol dependence in the UK and should be offered in combination with psychosocial treatment.¹ Treatment should be initiated by a specialist service. After 12 weeks, transfer of the prescribing to the GP may be appropriate, although specialist care may continue (shared care). Naltrexone is also recommended as an adjunct in the treatment of moderate and severe alcohol dependence.¹ As it does not have marketing authorisation for the treatment of alcohol dependence in the UK, informed consent should be sought and documented prior to commencing treatment.

Acamprosate

Acamprosate is a synthetic taurine analogue which acts as a functional glutamatergic NMDA antagonist and also increases GABA-ergic function. The 'number needed to treat' (NNT) for the maintenance of abstinence has been calculated as 9–11.⁹ The treatment effect is most pronounced at 6 months, although it remains significant for up to 12 months.¹ Acamprosate should be initiated as soon as possible after abstinence has been achieved (the BAP consensus guidelines⁹ recommend that acamprosate should be started 'during detoxification' because of its potential neuroprotective effect). NICE recommends that acamprosate should be continued for up to 6 months, with regular (monthly) supervision. The summary of product characteristics (SPC) recommends that it is given for one year.

Acamprosate is relatively well tolerated; side-effects include diarrhoea, abdominal pain, nausea, vomiting and pruritis.¹ It is contraindicated in severe renal or hepatic impairment, thus baseline liver and kidney function tests should be performed before commencing treatment. Acamprosate should be avoided in individuals who are pregnant or breast feeding. See Box 6.1.

Naltrexone

Opioid receptor blockade prevents increased dopaminergic activity after the consumption of alcohol, thus reducing its rewarding effects. Naltrexone, a non-selective opioid receptor antagonist significantly reduces relapse to heavy drinking but does not necessarily improve continuous abstinence rates.¹ Although early trials used a dose of 50 mg/day, more recent US studies have used 100 mg/day. In the UK the usual dose is 50 mg/day.

Naltrexone is well tolerated but side-effects include nausea (especially in the early stages of treatment), headache, abdominal pain, reduced appetite and tiredness. A comprehensive medical assessment should be carried out prior to commencing naltrexone, together with baseline renal and liver function tests. Naltrexone can be started when patients are still drinking or during medically-assisted withdrawal. There is no clear evidence as to the optimal duration of treatment but 6 months appears to be an appropriate period.⁹ See Box 6.2.

Patients on naltrexone should not be given opioid agonist drugs for analgesia: nonopioid analgesics should be used instead. In the event that opioid analgesia is necessary, it can be instituted 48–72 hours after cessation of naltrexone. Hepatotoxicity has been described with high doses, so use should be avoided in acute liver failure.

Injectable naltrexone has been developed to improve poor compliance and sideeffects are similar to those seen with the oral preparation.²⁰ NICE concluded that the initial evidence was encouraging but not enough to support routine use.

Nalmefene

Nalmefene is also an opioid antagonist. It effectively reduces heavy drinking days but does not promote abstinence.^21–23 There is limited and inconclusive evidence that it has a role in relapse prevention.

Disulfiram (Antabuse)

The evidence for disulfiram is weaker than for acamprosate and naltrexone.¹ NICE recommends its use 'as a second-line option for moderate-to-severe alcohol dependence for patients who are not suitable for acamprosate or naltrexone or have a specified preference for disulfiram and who aim to stay abstinent from alcohol'.¹ See Box 6.3. As with acamprosate and naltrexone it should be prescribed as part of a comprehensive treatment programme. 'Witnessing' (supervision) optimises compliance and contributes to effectiveness. Disulfiram inhibits aldehyde dehydrogenase, thus leading to acetaldehyde accumulation after drinking alcohol, which can cause extremely unpleasant physical effects. Continued drinking can lead to arrhythmias, hypotension and collapse. Despite being available for many years, the number of controlled clinical trials is limited.

Because of the known adverse effects of disulfiram the clinician must ensure that no alcohol has been consumed for at least 24 hours before commencing treatment. Contraindications to use include cardiac failure, coronary artery disease, hypertension, history of cerebrovascular disease, pregnancy and breast feeding, liver disease, peripheral neuropathy and severe mental illness. Urea and electrolytes and liver function tests should be carried out before starting disulfiram to rule out renal and liver impairment.

Doses as stated in the BNF are 800 mg for the first dose, reducing to 100–200mg daily for maintenance. It is sometimes given in higher doses. In co-morbid alcohol and cocaine dependence doses of 500 mg daily have been given. Halitosis is a common side effect. If there is a sudden onset of jaundice (the rare complication of hepatotoxicity), the patient should stop the drug and seek urgent medical attention.

Baclofen

Baclofen is a GABA-β agonist that does not have a licence for use in alcohol dependence but is nevertheless used by some clinicians. It may have a role in reducing anxiety in severely dependent patients. It is well tolerated and can be given to alcohol dependent patients with liver cirrhosis. Studies have used a 10 mg tds dose, but a 20 mg tds dose may have superior outcomes.²⁴

Anticonvulsants

Topiramate is not licensed for use in alcohol dependence, but has been show in RCTs to reduce the percentage of heavy drinking days and improve the harmful consequences of drinking, physical health and quality of life.²⁵ The dose is 25 mg daily, increasing to 300 mg daily. Its use is likely to be limited by its troublesome side-effect profile (parasthesiae, dizziness, taste perversion, anorexia and weight loss, difficulties with memory and concentration).

Gabapentin²⁶ and pregabalin²⁷ have been shown to have some efficacy in alcohol withdrawal and in reducing drinking, but the evidence is limited (although promising).

Pregnancy and alcohol use

Evidence indicates that alcohol consumption during pregnancy may cause harm to the foetus. NICE advises that women should not drink any alcohol at all during pregnancy.²⁸ If abstinence is not tolerable, NICE advises that alcohol should be avoided in the first 3 months of pregnancy, and consumption limited to '1–2 units once or twice a week' for the rest of the pregnancy.

For alcohol-dependent pregnant women who have withdrawal symptoms, pharmacological cover for detoxification should be offered, ideally in an inpatient setting. The timing of detoxification in relation to the trimester of pregnancy should be risk-assessed against continued alcohol consumption and risks to the foetus.⁹ Chlordiazepoxide has been suggested as being unlikely to pose a substantial risk, however dose-dependent malformations have been observed.⁹ The Regional Drugs and Therapeutics Centre Teratology Service²⁹ provides national advice for healthcare professionals and like to follow up on pregnancies that require alcohol detoxification. Please refer to the references below. Specialist advice should always be sought. (see also section on 'Pregnancy' in Chapter 7). No relapse prevention medication has been evaluated in pregnancy.⁹

Children and adolescents

Children and young people (10–17 years) should be assessed as outlined in the NICE Clinical Guideline 115, 2011.

The number of young people who are dependent and needing pharmacotherapy is likely to be small, but for those who are dependent there should be a lower threshold for admission to hospital. Doses of chlordiazepoxide for medically assisted withdrawal may need to be adjusted to lower levels, but the general principles of withdrawal management are the same as for adults. All young people should have a full health screen carried out routinely to allow identification of physical and mental health problems. The evidence base for acamprosate, naltrexone and disulfiram in 16–19 year olds is evolving.⁹

Older adults

There should be a lower threshold for inpatient medically-assisted alcohol withdrawal for older adults.¹ While benzodiazepines remain the treatment of choice, they may need to be prescribed in lower doses and in some situations shorter acting drugs may be preferred.⁹ Older adults with alcohol use disorders should all have full routine health screens to identify physical and mental health problems. The evidence base for pharmacotherapy of alcohol use disorders in older people is limited.

Concurrent alcohol and drug use disorders

Where alcohol and drug use disorders are co-morbid, treat both conditions actively.¹

Co-existing alcohol and benzodiazepine dependence

This is best managed with one benzodiazepine, either chlordiazepoxide or diazepam. The starting dose should take into account the requirements for medically-assisted alcohol withdrawal and the typical daily equivalent dose of the relevant benzodiazepine(s).¹ Inpatient treatment should be carried out over a 2–3 week period, possibly longer.¹

Co-existing alcohol dependence and cocaine use

In co-morbid cocaine/alcohol dependence, naltrexone 150 mg/day resulted in reduced cocaine and alcohol use in men but not in women.³⁰

Co-existing alcohol and opioid dependence

Both conditions should be treated, and attention paid to the increased mortality of individuals taking both drugs.

Co-morbid alcohol and nicotine dependence

Encourage individuals to stop smoking. Refer for smoking cessation in primary care and other settings. In in-patient settings offer nicotine patches/inhalator during assisted alcohol withdrawal.

Co-morbid mental health disorders

People with alcohol use disorders often present with other mental health disorders, particularly anxiety and depression. For most people these symptoms will diminish after 3–4 weeks of abstinence, so it is important to tackle the drinking problem as the first step in the treatment pathway. For some, the co-morbid disorder will have been the initial trigger to their drinking: for instance recurrent depressive disorder, bipolar affective disorder (BAD) and anxiety disorder (obsessive compulsive disorder [OCD]; social anxiety, post-traumatic stress disorder[PTSD]).

It may take time for the individual to admit to heavy drinking, so sympathetic history-taking skills and the use of questionnaires and blood tests will help to confirm any suspicions of an alcohol use disorder. Services for alcohol dependent individuals with co-morbidity are rarely integrated, so they may find themselves undergoing 'detox' on a general medical or psychiatric ward with subsequent referral to, and follow-up with, specialist addiction services for treatment of their alcohol problem and then referral to psychiatric services for treatment of their mental health problem(s). Some specialist addictions services within the NHS are able to offer psychological and pharmacological therapies for co-morbid mental health problem(s), but services contracted out to non-NHS agencies will not usually have this facility.

Depression

Depressive and anxiety symptoms occur commonly during alcohol withdrawal, but usually diminish by the third or fourth week of abstinence. Meta-analyses suggest that antidepressants with mixed pharmacology (the tricyclics imipramine or trimipramine) perform better than selective serotonin reuptake inhibitors (SSRIs; fluoxetine or sertraline) in reducing depressive symptoms in individuals with an alcohol use disorder, but the antidepressant effect is modest.^1,9 A greater antidepressant effect was seen if the diagnosis of depression was made after at least one week of abstinence, thus excluding those with affective symptoms caused by alcohol withdrawal. However, tricyclics are not recommended in clinical practice because of their potential for cardiotoxicity and toxicity in overdose. Preliminary research on newer drugs such as mirtazapine³¹ or escitalopram³² shows promise.

Relapse prevention medication should be considered in combination with antidepressants. Pettinati et al³³ have shown that the combination of sertraline (200 mg/day) with naltrexone (100 mg/day) had superior outcomes—improved drinking outcomes and better mood—than placebo and each drug alone.

Secondary analyses of acamprosate and naltrexone trials suggest that:

• acamprosate has an indirect modest beneficial effect on depression via increasing abstinence and
• in depressed alcohol dependent patients, the combination of naltrexone and an antidepressant is better than either drug alone⁹

Bipolar affective disorder

Bipolar patients tend to use alcohol to reduce symptoms of anxiety. Where there is comorbidity it is important to treat the different phases as recommended in guidelines for bipolar disorder. It may be worth adding sodium valproate to lithium as two trials have shown that the combination was associated with better drinking outcomes than with lithium alone. However, the combination did not confer any extra benefit than lithium alone in improving mood (see BAP consensus 2012).⁹ Note that, in those who continue to drink, electrolyte imbalance may precipitate lithium toxicity. Lithium is best avoided completely in binge drinkers.

Naltrexone should be offered, in the first instance, to help bipolar patients reduce their alcohol consumption.⁹ If naltrexone is not effective then acamprosate should be offered. In the event that both naltrexone and acamprosate fail to promote abstinence, then disulfiram should be considered, and the risks made known to the patient.

Anxiety

Anxiety is commonly observed in alcohol dependent individuals during intoxication, withdrawal and in the early days of abstinence. Alcohol is typically used to selfmedicate anxiety disorders, particularly social anxiety. In alcohol dependent individuals who experience anxiety it is often difficult to determine the extent to which the anxiety is a symptom of the alcohol use disorder or whether it is an independent disorder. Medically assisted withdrawal and supported abstinence for up to 8 weeks are required before a full assessment can be made. If a medically assisted withdrawal is not possible then treatment of the anxiety disorder should still be attempted, following guidelines for the respective anxiety disorder.

The use of benzodiazepines is controversial⁹ because of the increased risk of benzodiazepine abuse and dependence. Benzodiazepines should only be considered following assessment in a specialist addiction service.

One meta-analysis suggests that buspirone is effective in reducing symptoms of anxiety, but not alcohol consumption.⁹ Studies have also shown that paroxetine (up to 60 mg/day) was superior to placebo in reducing social anxiety in co-morbid patients: alcohol consumption was not affected.⁹

Either naltrexone or disulfiram, alone or combined, improved drinking outcomes compared with placebo in patients with PTSD and alcohol dependence. Both acamprosate and baclofen have shown benefit in reducing anxiety in post hoc analyses of alcohol dependence trials (see BAP consensus for references⁹). It is therefore important to ensure that these patients are enabled to become abstinent and are prescribed relapse prevention medication. Anxiety should then be treated according to the appropriate NICE guidelines.

Schizophrenia

Patients with schizophrenia who also have an alcohol use disorder should be assessed and alcohol specific relapse prevention treatment considered, either naltrexone or acamprosate. Antipsychotic medication should be optimised⁹ and clozapine may be considered. However, there is insufficient evidence to recommend the use of any one antipsychotic medication over another.

References

1. National Institute for Health and Clinical Excellence. Alcohol use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. Clinical Guideline 115, 2011. http://guidance.nice.org.uk/CG115
2. National Institute for Health and Clinical Excellence. Alcohol-use disorders: Preventing harmful drinking. Public Health Guideline 24, 2010. http://guidance.nice.org.uk/PH24
3. Babor T, Higgins-Biddle JC, Saunders JB, Monteiro MG. AUDIT: The Alcohol Use Disorders Identification Test Guidelines for Use in Primary Care, 2nd edn. Geneva: WHO, 2001. http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6a.pdf?ua=1.
4. Stockwell T et al. The severity of alcohol dependence questionnaire: its use, reliability and validity. Br J Addict 1983; 78:145–155.
5. Sullivan JT et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989; 84:1353–1357.
6. Gossop M et al. A Short Alcohol Withdrawal Scale (SAWS): development and psychometric properties. Addict Biol 2002; 7:37–43.
7. National Institute for Health and Clinical Excellence. Alcohol-use disorders: physical complications. Clinical Guideline 100, 2010. http:// guidance.nice.org.uk/CG100
8. Amato L et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev 2010; CD005063.
9. Lingford-Hughes AR et al. Evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol 2012; 26:899–952.
10. Minozzi S et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev 2010; CD005064.
11. Brathen G et al. EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force. Eur J Neurol 2005; 12:575–581.
12. Perry EC. Inpatient management of acute alcohol withdrawal syndrome. CNS Drugs 2014; 28:401–410.
13. Thomson AD et al. Time to act on the inadequate management of Wernicke's encephalopathy in the UK. Alcohol Alcohol 2013; 48:4–8.
14. Thomson AD et al. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the accident and emergency department. Alcohol Alcohol 2002; 37:513–521.
15. Day E et al. Thiamine for prevention and treatment of Wernicke-Korsakoff Syndrome in people who abuse alcohol. Cochrane Database Syst Rev 2013; 7:CD004033.
16. Thomson AD et al. The treatment of patients at risk of developing Wernicke's encephalopathy in the community. Alcohol Alcohol 2006; 41:159–167.
17. Joint Formulary Committee. BNF 67 March-September 2014 (online). London: Pharmaceutical Press; 2014. http://www.medicinescomplete. com/mc/bnf/current/
18. Thomson AD et al. Parenteral thiamine and Wernicke's Encephalopathy: the balance of risks and perception of concern. Alcohol Alcohol 1997; 32:207–209.
19. Committee on Safety of Medicine. Parentrovite and allergic reactions. Current Problems 1989; 24.
20. Krupitsky E et al. Injectable extended-release naltrexone (XR-NTX) for opioid dependence: long-term safety and effectiveness. Addiction 2013; 108:1628–1637.
21. Karhuvaara S et al. Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study. Alcohol Clin Exp Res 2007; 31:1179–1187.
22. Mason BJ et al. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999; 56:719–724.
23. van den BW et al. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol 2013; 48:570–578.
24. Liu J et al. Baclofen for alcohol withdrawal. Cochrane Database Syst Rev 2013; 2:CD008502.
25. Johnson BA et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007; 298:1641–1651.
26. Mason BJ et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med 2014; 174:70–77.
27. Guglielmo R et al. Pregabalin for alcohol dependence: a critical review of the literature. Adv Ther 2012; 29:947–957.
28. National Institute for Health and Clinical Excellence. Antenatal care: routine care for the healthy pregnant woman. Clinical Guideline 62, 2008. http://guidance.nice.org.uk/CG62.
29. Regional Drug and Therapeutics Centre. Regional Medicines Information Service, 2014. http://www.nyrdtc.nhs.uk/Services/teratology/ teratology.html.
30. Pettinati HM et al. Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence. J Subst Abuse Treat 2008; 34:378–390.
31. Cornelius JR et al. Mirtazapine in comorbid major depression and alcohol dependence: An Open-Label Trial. J Dual Diagn 2012; 8:200–204.
32. Han DH et al. Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: clinical and neuroimaging evidence. J Psychopharmacol 2013; 27:282–291.
33. Pettinati HM et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry 2010; 167:668–675.

Opioid misuse and dependence

Prescribing for opioid dependence

Important: Treatment of opioid dependence usually requires specialist intervention—generalists who do not have specialist experience should always contact substance misuse services before attempting to treat opioid dependence. It is strongly recommended that general adult psychiatrists do not initiate opioid substitute treatment unless directly advised by specialist services. It cannot be over-emphasised that the use of methadone is readily fatal; opioid withdrawal is not.

The treatment interventions used for opioid-dependent people in the UK range from low-intensity harm minimisation, such as needle exchange, through to substitution opioid maintenance therapy and high-intensity structured programmes, such as residential abstinence-based psychosocial treatment. Pharmacological treatments can be broadly categorised as maintenance, detoxification or abstinence¹ and should always be prescribed as part of a comprehensive care package.

Treatment aims

• To reduce or prevent withdrawal symptoms.
• To reduce or eliminate non-prescribed drug use.
• To stabilise drug intake and lifestyle.
• To reduce drug-related harm (particularly injecting behaviour).
• To engage and provide an opportunity to work with the patient.

Treatment

This will depend upon:

• what pharmacotherapies and/or other interventions are available
• patient's previous history of drug use and treatment
• patient's current drug use and circumstances
• location/service where treatment is initiated.

Most opioid substitute prescribing for people with mental health problems should be initiated by specialist addiction services. Community mental health teams should work collaboratively with addiction services following local care/referral pathways and joint working protocols. However, some people with mental health problems will be admitted to psychiatric services (e.g. due to mental health relapse) and general psychiatrists will need to take over, or initiate prescribing in the immediate term. Specialist support should be sought as soon as practicable.

The guidance here is generic, but where there are special considerations for psychiatric inpatient services these have been highlighted.

Principles of prescribing²

Use licensed medications for heroin-dependence treatment (methadone and buprenorphine).

• The prescriber should ensure that the patient is dependent on opioids and that the patient is given a safe initial dose with suitable supervision and review to minimise the risk of toxicity.
• Daily dispensing advised for at least the first 3 months of prescribing.
• Supervised consumption in the first 3 months usually or until stability achieved.

Evaluating opioid dependence

Before considering prescribing any substitute pharmacotherapy, care should be taken to ensure that the patient does have a diagnosis of opioid dependence as corroborated by the following points.

• A diagnosis of opioid dependence from history and examination of patient. Assessment should include details of what substances the person is taking, quantity, frequency, route of administration, duration at current level and date and time of last use.
• At least one positive recent urine or oral fluid drug screen for opioids (note that opioid-based medication such as co-codamol and codeine phosphate can also give a positive result on screening tests so it is important to get laboratory confirmation of actual opioids or use specific drug testing kits).
• Objective signs of opioid withdrawal (nausea, stomach cramps, muscular tension, muscle spasms/twitching, aches and pains, insomnia and the objective signs listed in Table 6.6).
• Recent sites of injection may also be present (depending on route of administration of opioid) but presence alone does not indicate dependence.

Table 6.6 Objective opioid withdrawal scale

Untreated heroin withdrawal symptoms typically begin after 4–6 hours and reach their peak 32–72 hours after the last dose and symptoms will have subsided substantially after 5 days. Untreated methadone withdrawal typically reaches its peak between 4–6 days after last dose and symptoms do not substantially subside for 10–12 days.² Untreated buprenorphine withdrawal typically lasts for up to 10 days.

Specific opioid withdrawal scales are available, e.g. the Clinical Opiate Withdrawal Scale (COWS),³ Objective Opiate Withdrawal Scale (OOWS)⁴ and Short Opiate Withdrawal Scale (SOWS),⁵ which can be used to help assess levels of dependence.

Induction and stabilisation of substitute prescribing

It is usually preferable to use a longer-acting opioid agonist or partial agonist (e.g. methadone or buprenorphine respectively) in opioid dependence, as it is generally easier to maintain stability.² However, patients with a less severe opioid dependency (e.g. history of using low doses of prescribed codeine or dihydrocodeine-containing preparations only) may in some cases be better managed by maintaining/detoxifying them using that preparation or equivalent.

Buprenorphine or methadone?

NICE guidance on the management of opioid dependence recommend oral methadone or buprenorphine as the pharmacotherapeutic options in opioid dependence.¹ The decision of which to use should be based on the client's preference; their past experience of maintenance with either methadone or buprenorphine; their long-term plans, including a preference for one or other as a detoxification regimen; and in the case of buprenorphine their ability to refrain from heroin use for long enough to avoid precipitated opioid withdrawal symptoms. These considerations are highlighted in Table 6.7; in cases where methadone and buprenorphine appear equally suitable, NICE guidance advises prescribing methadone as first choice.¹

In rare cases, patients may be allergic to methadone or buprenorphine or to some of the constituents within the formulations.

Suboxone

With regards to the risk of diversion and subsequent injecting of buprenorphine, consideration may be given by the prescriber to a buprenorphine/naloxone preparation which theoretically may reduce the risk of diversion: the rationale is that as the presence of naloxone makes injecting the diverted drug less appealing due to the precipitation of opioid withdrawal symptoms. Extended treatment schedules (12 weeks) tend to be more effective than shorter detoxification regimes.¹² Suboxone is probably more effective in acute detoxification than clonidine.¹³

Dosing of this preparation is the same as for buprenorphine.

Table 6.7 Choosing between buprenorphine and methadone

Methadone

Clinical effectiveness

Methadone, a long acting opioid agonist, has been shown to be an effective maintenance therapy intervention for the treatment of heroin dependence by retaining patients in treatment and decreasing heroin use more than non-opioid based replacement therapy.¹⁴ In addition, higher doses of methadone (60 to 100 mg/day) have been shown to be more effective than lower dosages in retaining patients and in reducing illicit heroin and cocaine use during treatment.¹⁵ Methadone is also effective at reducing withdrawal severity when used for detoxification from heroin, however there is a high relapse following termination of treatment.¹⁶

Prescribing information

Methadone is a Controlled Drug with a high dependency potential and a low lethal dose. The initial two weeks of treatment with methadone are associated with a substantially increased risk of overdose mortality.^2,16–19 It is important that appropriate assessment, titration of doses and monitoring is performed during this period.

There is also an increase in mortality immediately after completing treatment—one study found that risk of death increased eight-fold to nine-fold in the month immediately after the end of opiate substitution treatment.¹⁷ There is also an increased risk of overdose immediately after leaving inpatient treatment.¹⁸ Opiate substitution treatment was found to have a greater than 85% chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months.¹⁷

Prescribing should only commence if:

• opioid drugs are being taken on a regular basis (typically daily)
• there is convincing evidence of dependence including drug testing and objective evidence of withdrawal (see above)
• consumption of methadone can be supervised initially.

Supervised daily consumption is recommended for new prescriptions, for a minimum of 3 months.² If this is not possible, instalment prescriptions for daily dispensing and collection should be used. No more than one week's supply should be dispensed at one time, except in exceptional circumstances.²

Methadone should normally be prescribed as a 1 mg in 1 mL oral solution.² Tablets can potentially be crushed and inappropriately injected and therefore should not usually be prescribed.^2,19 However, there may be occasional circumstances in which tablets are prescribed, usually by experienced prescribing doctors in specialist services.

Important: All patients starting a methadone treatment programme must be informed of the risks of toxicity and overdose, and the necessity for safe storage of any take home medication.^2,20–22 Safe storage is vital, particularly if there are children in the household, as tragic deaths have occurred when children have ingested methadone. Prescribers should consider risks to children in all assessments and treatment plans of drug using patients.

Methadone dose: continuation for patients already being prescribed methadone

For patients who are currently prescribed methadone and who require the medication to be continued by a different doctor (for example if they are admitted to hospital) and if all the criteria listed below are met, then it is safe to prescribe the claimed dose.

• Dose confirmed in writing by the previous prescriber.
• Last consumption confirmed and supervised (e.g. pharmacy contacted) and has been regularly taking this dose including within the last 3 days (to ensure that tolerance has not been reduced).
• Previous prescriber has stopped prescribing and current prescription is completed or cancelled to date (to prevent a patient receiving a double dose).
• Patient is stable or 'comfortable' on dose (no signs of intoxication/withdrawal) and the patient is not presenting as intoxicated with other drugs and/or alcohol.
• No other contraindications or cautions are present.

Note: if there is any doubt about any of these conditions do not continue the prescription at the claimed dose.

Recommendations for prescribing methadone where recent use cannot be confirmed

If the patient has missed one or more doses within the last 3 days consider starting at a lower dose and titrating up in response to withdrawal symptoms.

If the person has not been supervised taking their methadone for 3 or more days they must be re-titrated (see below).

In determining the starting dose for patients using heroin or other opioids, not already on a prescription for methadone, consideration must be given to the potential for opioid toxicity, taking into account the following.

• Tolerance to opioids can be affected by a number of factors and significantly influences an individual's risk of toxicity.²³ Of particular importance in assessing this are the client's reported current quantity, frequency and route of administration; whilst being wary of possible over-reporting. A person's tolerance to methadone can be significantly reduced within 3 to 4 days of not using opioids, so caution must be exercised after this time, with careful re-titration from a starting dose.
• Use of other depressant drugs, e.g. alcohol, benzodiazepines and psychiatric medications increase risks of toxicity.
• Long half-life of methadone, as cumulative toxicity may develop.^24,25 For this reason a patient should be reviewed regularly for signs of intoxication and the dose must be omitted if there is any sign of drowsiness or other evidence of toxicity.
• Inappropriate dosing can result in fatal overdose, particularly in the first few days.^20,21,26,27 Deaths have occurred following the commencement of a daily dose of less than 30 mg methadone.²
• It is safer to start with a low dose that can subsequently be increased at intervals if this dose later proves to be insufficient.

Note: opioid withdrawal is not a life-threatening condition, opioid toxicity is.

Direct conversion tables for opioids and methadone should be viewed cautiously, as there are a number of factors influencing the values at any given time. It is much safer to titrate the dose against presenting withdrawal symptoms.

The Clinical Opioid Withdrawal Scale³ or Short Opiate Withdrawal Scale⁵ provide a systematic way of assessing withdrawals.

The initial total daily dose for most cases will be in the range of 10–30 mg methadone depending on the level of tolerance.^1,2 In an acute medical or psychiatric ward, starting doses of up to 20 mg daily are usually recommended, as patients in these settings are likely to be physically unwell in the former, or being treated with various other psychoactive drugs in the latter case. In inpatient settings it is recommended that the dose is divided, for example 10 mg twice daily, in case there is any sign of toxicity.

In specialist settings, an initial dose of up to 40 mg methadone may be prescribed by an experienced competent senior clinician for patients who are assessed as being heavily dependent and tolerant, but it is unwise to exceed this dose.^1,2 An additional dose of methadone can be given later the same day in cases where there is evidence of ongoing opioid withdrawal, but this should only be undertaken by experienced prescribers with the appropriate competencies.^1,2

Note: onset of action should be evident within half an hour, with peak plasma levels being achieved after approximately two to four hours of dosing.

Recommendations for prescribing methadone by non-specialists in non-specialist areas (e.g. general psychiatric wards)

Day one–induction.

• The person must be exhibiting objective opioid withdrawal symptoms, as assessed on an opioid withdrawal scale, before any dose is prescribed.
• Give a dose of 5–10 mg of methadone mixture 1 mg/1 mL based on the severity of withdrawal. This should be given as a once only dose. Methadone will start to have an effect after 20–30 minutes with peak levels being reached at 4 hours.
• Continue to monitor for signs of withdrawal 2–4 hourly and give further doses as required—also observe for signs of intoxication.
• The initial daily dose (over 24 hours) will not usually be more than 30 mg.
• Consider prescribing naloxone as required, in case of overdose.

Day two–calculate the total dose given in the previous 24 hours, but divide and prescribe twice daily. It can then be withheld in case of over-sedation.

• Continue to monitor using an opioid withdrawal scale 4 hourly until symptoms have stabilised.
• Up to an additional 10 mg can be given in 24 hours if indicated (i.e. maximum of 40 mg).
• Liaise with the local specialist addiction service for ongoing advice and to develop a joint plan.

Ongoing prescribing.

• Once stability has been achieved continue to prescribe the required dose.

In the acute inpatient setting it is usually advisable for the person to be maintained on a stable dose rather than commence detoxification.

Methadone stabilisation in the community

This applies to patients who have not been on a prescription in the previous 3 days or more.

This is usually undertaken in specialist services by those with appropriate competencies and after a full assessment with urine toxicology and clear evidence of opioid use and withdrawal.

• First week. Outpatients should attend daily for the first few days to enable assessment by the prescriber and any dose titration against withdrawal symptoms. Dose increases should not exceed 5–10 mg a day and not usually more than 30 mg in the first week above the initial starting dose.¹ Note that steady state plasma levels are only achieved approximately 5 days after the last dose increase. Once the patient has been stabilised on an adequate dose, methadone should be prescribed as a single regular daily dose. It should not be prescribed on a pro re nata basis or at variable dosage. It is good practice to supervise consumption for the first 3 months.
• Subsequent period. Subsequent increases of 5–10 mg methadone can continue after the first week, and there should be at least a few days between each successive increase.² It may take several weeks to reach the therapeutic daily dose of 60–120 mg.² Stabilisation is usually achieved within 6 weeks but may take longer. However, it is important to consider that some patients may require more rapid stabilisation. This would need to be balanced by a high level of supervision and observation thereby allowing the ability to increase doses more rapidly.

Methadone cautions

• Intoxication. Methadone should not be given to any patient showing signs of intoxication, especially due to alcohol or other depressant drugs (e.g. benzodiazepines).^23,28 Risk of fatal overdose is greatly enhanced when methadone is taken concomitantly with alcohol and other respiratory depressant drugs. Concurrent alcohol and illicit drug consumption must be borne in mind when considering subsequent prescribing of methadone due to the increased risk of overdose associated with polysubstance misuse.^21,26,28,29
• Severe hepatic/renal dysfunction. Metabolism and elimination of methadone may be affected in which case the dose or dosing interval should be adjusted accordingly against clinical presentation. Because of extended plasma half-life, the interval between assessments during initial dosing may need to be extended.

Methadone overdose

In the event of methadone overdose, naloxone should be administered following the BNF guidelines. Naloxone can be given by intravenous, intramuscular or subcutaneous route. The emergency services should always be called. See Box 6.5 later in this section.

Dose: 0.4–2 mg repeated at intervals of 2–3 minutes to a maximum of 10 mg if respiratory function does not improve. If no response consider alternative causes for overdose.

Although the onset of action will be slower with the intramuscular route, this is the preferred route within the psychiatric setting or addiction service where the intravenous route may be difficult and actually take longer to administer.

In the medical setting a continuous intravenous infusion (2 mg/500 mL) at a rate adjusted according to response may be used.

Naloxone is short-acting and therefore the effect may reverse within 20 minutes to 1 hour, meaning that a patient can revert back into an overdose state. Therefore ongoing medical monitoring should be provided after naloxone administration and patients should be kept under observation in a suitable medical facility.

Analgesia for methadone-prescribed patients

Non-opioid analgesics should be used in preference (e.g. paracetamol, non-steroidal anti-inflammatory drugs [NSAIDs]) initially where appropriate. If opioid analgesia (e.g. codeine, dihydrocodeine, morphine) is indicated due to the type and severity of the pain, then this should be titrated accordingly for pain relief in line with usual analgesic protocols. There are specific considerations for patients receiving methadone, buprenorphine or naltrexone. In the case of patients prescribed methadone, if an opioid analgesic is appropriate, a non-methadone opioid may be co-prescribed, i.e. it is not necessary to 'rationalise' the patient's entire opioid requirements to one drug.³⁰ Titrating the methadone dose to provide analgesia may be used in certain circumstances but this should only be carried out by experienced specialists.

As outlined elsewhere in this chapter, patients taking buprenorphine or naltrexone may be relatively refractory to opioids prescribed for analgesia, although in practice if a patient on buprenorphine requires treatment for acute pain, an additional opioid may be added titrated against response.¹¹

If naltrexone is stopped to allow for the prescribing of opioid analgesia, careful monitoring will be required because of the increased risk of both relapse and overdose.^17,30

Patients with a history of substance misuse may also need acute pain management in hospital following surgery, trauma or other illness. The primary objectives during the period of acute pain are to manage the pain and avoid the consequences of withdrawal, so it is important to maintain sufficient background medication to achieve both. Liaison with both the inpatient pain team and the local addictions services, as well as collaborative discussion with the patient, are important. The patient may be known to the addictions services, who will be able to inform the treatment plan, assist in a reliable conversion from street drugs (if these are also being taken) to prescribed analgesics and help plan a smooth transition from acute pain intervention to ongoing management of the patient's substance misuse.¹⁷ Further details can be found in a consensus document by the British Pain Society, Royal College of Psychiatrists, Royal College of GPs and The Advisory Council on the Misuse of Drugs.³⁰

As advised in the consensus document, in palliative care, the principles of providing analgesia 'in substance misusers are fundamentally no different from those for other adult patients needing palliative care', although increased liaison with substance misuse services is essential. Those who are opioid dependent may receive maintenance therapy from a substance misuse service 'and this should be regarded as a separate prescription from that for analgesia when attending as a [pain clinic] outpatient', as also described in the context of chronic non-cancer pain above. During admission all medication would usually be received from the inpatient unit, but with 'a clear plan for separate follow-ups for substance misuse and symptom palliation ... in place on discharge except during the terminal phase of an illness'.³⁰ Again, further details can be found in the consensus advice document.³⁰

Methadone and risk of Torsades de Pointes/QT interval prolongation

It is possible that methadone either alone or combined with other QT prolonging agents may increase the likelihood of QT interval prolongation on the ECG, which is associated with Torsades de Pointes and can be fatal.^31–33

Recommended ECG monitoring

In 2006, the Medicines and Healthcare product and Regulatory Authority (MHRA) recommended that patients with the following risk factors for QT interval prolongation are carefully monitored whilst taking methadone: heart or liver disease, electrolyte abnormalities, concomitant treatment with CYP3A4 inhibitors, or medicines with the potential to cause QT interval prolongation (e.g. some antipsychotics, erythromycin, amongst others). See Table 6.8. In addition, any patient requiring more than 100 mg of methadone per day should be closely monitored,³⁴ because of possible increased risk of QTc prolongation.³¹ Thus, in individuals with such risk factors, e.g. those with known heart disease, and those being titrated up to doses of methadone exceeding 100 mg, should have a baseline ECG and subsequent ECG monitoring. The timeframe for the latter is not yet subject to a rigorous evidence base; annual checks in the absence of cardiac symptomatology would be a reasonable minimum frequency where there are risk factors as listed. It is also important to check the actions of any medications being prescribed with methadone for CYP3A4 inhibitory activity, to inform the risk-benefit analysis when commencing methadone.³⁵

Table 6.8 Recommended ECG monitoring

Buprenorphine appears to be associated with less QTc prolongation and therefore may be a safer alternative in this respect,³⁶ although there are few studies in this area at present; and there are many other factors to take into account when choosing an appropriate opioid substitute, as described earlier.

Remember that QT should be corrected for heart rate to produce a corrected QT (QTc) in milliseconds (ms). This is normally documented on the ECG recording. The ECG should be read by a professional with experience in reading ECGs. Brief guidelines as to actions to take are documented below. Always seek specialist advice where there is prolongation of the QT interval.

A recent review of ECG monitoring suggests that there is insufficient evidence for the efficacy of QTc screening strategies for preventing cardiac morbidity and mortality in methadone-maintained patients and there is concern that in some settings the procedures involved may be 'too demanding and too stressful' and may 'interfere with the availability of patients to undergo methadone maintenance and may expose patients to health consequences of untreated opioid addiction including increased mortality risk'.³⁷

Patients on or about to start methadone in inpatient settings on both medical and psychiatric wards should always have an ECG, and patients on high doses or with other risk factors should if possible have ECGs when treated in the community, although consideration should be taken of the risks and benefits if a community patient refuses to attend for ECG monitoring.

Buprenorphine

Clinical effectiveness

Buprenorphine (Subutex) is a synthetic partial opioid agonist and with a low intrinsic activity and high affinity at μ opioid receptors. It is an effective treatment for use in maintenance treatment for heroin addiction, although not more effective than methadone at adequate dosages.³⁸ There is no significant difference between buprenorphine and methadone in terms of completion of detoxification treatment, but withdrawal symptoms may resolve more quickly with buprenorphine.³⁹

Prescribing information

Buprenorphine is absorbed via the sublingual route which takes approximately 5–10 minutes to complete. It is effective in treating opioid dependence because:

• it alleviates/prevents opioid withdrawal and craving
• it reduces the effects of additional opioid use because of its high receptor affinity^8–10
• it is long-acting allowing daily (or less frequent) dosing. The duration of action is related to the buprenorphine dose administered: low doses (e.g. 2 mg) exert effects for up to 12 hours; higher doses (e.g. 16–32 mg) exert effects for as long as 48–72 hours.

Buprenorphine starting dose

The same principles as for methadone apply when starting treatment with buprenorphine. However, of particular interest with buprenorphine is the phenomenon of precipitated withdrawal. Patient education is an important factor in reducing the problems during induction.

Continuing an already established buprenorphine prescription

As for continuation of methadone prescribing, the following principles apply.

• Dose confirmed in writing by the previous prescriber.
• Last consumption confirmed and supervised (e.g. pharmacy contacted) and has been regularly taking this dose including within the last 3 days (to ensure that tolerance has not been reduced).
• Previous prescriber has stopped prescribing and current prescription is completed or cancelled to date (to prevent a patient receiving a double dose).
• Patient is stable or 'comfortable' on dose (no signs of intoxication/withdrawal) and the patient is not presenting as intoxicated with other drugs and/or alcohol.
• No other contraindications or cautions are present.

Starting buprenorphine

The first dose of buprenorphine should be administered when the patient is experiencing opioid withdrawal symptoms to reduce the risk of precipitated withdrawal. As with methadone, clear evidence of daily opioid use (including drug testing) and withdrawal symptoms are mandatory before commencing a prescription for buprenorphine. The initial dose recommendations are shown in Table 6.9.

No more than 8 mg buprenorphine should be given on the first day in a non-specialist setting. In some cases 8 mg may be sufficient, but this may be increased to 12–16 mg the following day if there is continuing evidence of withdrawal and no evidence of intoxication. The doses should be given in divided doses so that it can be reviewed promptly in the event of any intoxication. If there is concern that doses higher than 16 mg may be required specialist advice should be sought and only increased under advice from addiction specialists.

If patients are on other respiratory sedatives such as benzodiazepines, the lower doses should be used and the patient monitored for intoxication and respiratory depression.

Table 6.9 Recommended starting doses of buprenorphine in opioid withdrawal

Table 6.10 Factors affecting risk of precipitated withdrawal with buprenorphine

Table 6.11 Recommended doses of buprenorphine for patients transferring from methadone (< 40 mg (ideally ≤ 30 mg))

Transferring from methadone to buprenorphine

This should usually be under the supervision of a suitably experienced specialist prescriber. Patients transferring from methadone are at risk of experiencing precipitated withdrawal symptoms that may continue at a milder level for 1–2 weeks. Factors affecting precipitated withdrawal are listed in Table 6.10.

Transferring from methadone dose < 40 mg (ideally ≤ 30 mg) to buprenorphine

Methadone should be ceased abruptly and the first dose of buprenorphine given at least 24 hours after the last methadone dose. The conversion rates shown in Table 6.11 at the start of treatment are recommended, but higher doses may be subsequently needed depending on clinical presentation.

Transferring from methadone 40–60 mg dose to buprenorphine

• The methadone dose should be reduced as far as possible without the patient becoming unstable or chaotic, and then abruptly stopped.
• The first buprenorphine dose should be delayed until the patient displays clear signs of withdrawal, generally 48–96 hours after the last dose of methadone. Symptomatic medication (lofexidine) may be useful to provide transitory relief.
• An initial dose of 2–4 mg should be given. The patient should then be reviewed 2–3 hours later.
• If withdrawal has been precipitated further symptomatic medication can be prescribed.
• If there has been no precipitation or worsening of withdrawal, an additional 2–4 mg of buprenorphine can be dispensed on the same day.
• The patient should be reviewed the following day at which point the dose should be increased to between 8–12 mg.

Transferring from methadone doses > 60 mg to buprenorphine

Such transfers should not be attempted in an outpatient setting except in exceptional circumstances by an experienced practitioner. Usually patients would be partially detoxified from methadone and transferred to buprenorphine when the methadone was at or below 30 mg daily. However, if transfer from higher dose methadone to buprenorphine is required, a referral to an inpatient unit should be considered.

Transferring from other prescribed opioids to buprenorphine

There is little experience in transferring patients from other prescribed opioids (e.g. codeine, dihydrocodeine, morphine). Basic principles suggest that transferring from opioids with short half-lives should be similar to inducting heroin users; whereas transferring from opioids with longer half-lives will be similar to transferring from methadone.

Stabilisation dose of buprenorphine

Outpatients should attend regularly for the first few days to enable assessment by the prescriber and any dose titration. Dose increases should be made in increments of 2–4 mg at a time, daily if necessary, up to a maximum daily dose of 32 mg. Effective maintenance doses are usually in the range of 12–24 mg daily⁴³ and patients should generally be able to achieve maintenance levels within 1–2 weeks of starting buprenorphine.

Buphrenorphine less than daily dosing

Buprenorphine is licensed in the UK as a medication to be taken daily. International evidence and experience indicates that many clients can be comfortably maintained on one dose every 2–3 days.^81–84 This may be pertinent for patients in buprenorphine treatment who are considered unsuitable for take-away medication because of the risk of diversion.

The following conversion rate is recommended:

2-day buprenorphine dose = 2 × daily dose of buprenorphine (to a max 32 mg)

3-day buprenorphine dose = 3 × daily dose of buprenorphine (to a max 32 mg)

Note: in the event of patients being unable to stabilise comfortably on buprenorphine (often those transferring from methadone), the option of transferring to methadone should be available. Methadone can be commenced 24 hours after the last buprenorphine dose. Doses should be titrated according to clinical response, being mindful of the residual 'blockade' effect of buprenorphine which may last for several days.

Buprenorphine cautions

• Liver function. There is some evidence suggesting that high dose buprenorphine can cause changes in liver function in individuals with a history of liver disease.⁴⁸ Such patients should have liver funstion tests (LFTs) measured before commencing with follow-up investigations conducted 6–12 weeks after commencing buprenorphine. More frequent testing should be considered in patients of particular concern, e.g. severe liver disease. Elevated liver enzymes in the absence of clinically significant liver disease however does not necessarily contraindicate treatment with buprenorphine
• Intoxication. Buprenorphine should not be given to any patient showing signs of intoxication, especially due to alcohol or other depressant drugs (e.g. benzodiazepines). Buprenorphine in combination with other sedative drugs can result in respiratory depression, sedation, coma and death. Concurrent alcohol and illicit drug consumption must be borne in mind when considering subsequent prescribing of buprenorphine due to the increased risk of overdose associated with polysubstance misuse.

Overdose with buprenorphine

Buprenorphine as a single drug in overdose is generally regarded as safer than methadone and heroin because it causes less respiratory depression. However, in combination with other respiratory depressant drugs the effects may be harder to manage. Very high doses of naloxone (e.g. 10–15 mg) may be needed to reverse buprenorphine effects (although lower doses such as 0.8 to 2 mg may be sufficient), hence ventilator support is often required in cases where buprenorphine is contributing to respiratory depression (e.g. in polydrug overdose). The emergency services should always be called. See Box 6.5 later in this section.

Analgesia for buprenorphine-prescribed patients

Non-opioid analgesics should be used in preference (e.g. paracetamol, NSAIDs). Buprenorphine reduces or blocks the effect of full opioid agonists complicating their use as analgesics in patients on buprenorphine. If adequate pain control cannot be achieved then it may be necessary to transfer the patient to a stable methadone dose so that an opioid analgesic can be effectively used for pain control (see notes on analgesia for methadone-prescribed patients earlier in this chapter).

Suboxone

With regards to the risk of diversion and subsequent injecting of buprenorphine, consideration may be given by the prescriber to a buprenorphine/naloxone preparation which theoretically may reduce the risk of diversion. The different sublingual and parenteral potency profiles of buprenorphine and naloxone is key: if used sublingually the naloxone will have negligible effects. However, if the combined preparation is injected, the naloxone will have a substantial effect and can attenuate the effects of the buprenorphine in the short-term and is also likely to precipitate withdrawal in opioid dependent individuals on full opioid agonists.⁴⁹

Alternative oral preparations

Oral methadone and buprenorphine should continue to be the mainstay of treatment;² other oral options such as slow release oral morphine (SROM) preparations and dihydrocodeine are not licensed in the UK for the treatment of opiate dependence.²

However, a specialised clinician may in very exceptional circumstances prescribe oral dihydrocodeine as maintenance therapy, where clients are unable to tolerate methadone or buprenorphine, or in other exceptional circumstances; taking into account the difficulties associated with its short half-life, supervision requirements, and diversion potential.²

Slow release oral morphine preparations have been shown elsewhere in Europe to be useful as maintenance therapy in those failing to tolerate methadone; again only for prescribing by specialised clinicians.² A recent review of studies on slow release oral morphine suggested that there was insufficient evidence to assess the effectiveness of this treatment.⁵⁰

Injectable opioid maintenance prescribing

With regard to the prescribing of injectable opioids, a small number of patients in the UK continue to receive these under the former 'British system',² and a further minority are being treated in trial clinics in the UK,⁵¹ modelled on the recent Swiss and Dutch injectable opioid maintenance clinics. The trials in Europe have shown promising results, and the UK results have also shown favourable outcomes. Meanwhile, injectable opioid treatment is not currently available in all specialist services in the UK.² Notably, a Home Office licence is required to prescribe diamorphine for addictions treatment, and specialist levels of competence are required to prescribe injectable substitute opioids.²

At present, clients should only be considered for injectable opioid prescribing in combination with psychosocial interventions, as part of a wider package of care, as an option in cases where the individual has not responded adequately to oral opioid substitution treatment, and in an area where it can be supported by locally commissioned and provided mechanisms for supervised consumption.^2,51 Patients are generally seen for supervised injecting in a specialist facility twice a day.

Opioid detoxification and reduction regimes

Opioid maintenance can be continued from the short term to almost indefinitely, depending on clinical need. Some patients are keen to detoxify after short periods of stability and other patients may decide to detoxify after mediumto long-term periods of stability on maintenance prescriptions. All detoxification programmes should be part of a care programme. Given the risk of serious fatal overdose post detoxification, services providing such treatment should educate the patient about these risks and supply and train them with naloxone and overdose training for emergency use.^1,52,53

Regarding the length of detoxification, the NICE guidelines state 'dose reduction can take place over anything from a few days to several months, with a higher initial stabilisation dose taking longer to taper', and indicate that 'up to 3 months is typical for methadone reduction, while buprenorphine reductions are typically carried out over 14 days to a few weeks'.⁵⁴ In practice, detoxification in the community may extend over a longer period, if this facilitates the client's comfort during the process, compliance with the care-plan, continued abstinence from illicit use during detoxification, and subsequent abstinence following detoxification.

Detoxification in an inpatient setting, the NICE guidelines indicate, may take place over a shorter time than in the community (suggesting 14–21 days for methadone and 7–14 days for buprenorphine) 'as the supportive environment helps a service user to tolerate emerging withdrawal symptoms'.⁵⁵ As in the community, stabilisation on the dose of a substitute opioid is first achieved, followed by gradual dose reduction; with additive medications judiciously prescribed for withdrawal symptoms if and as needed.

Detoxification carries a recognised risk of relapse and indeed fatal overdose. Therefore, if a patient is being detoxified there needs to be adequate aftercare in place, such as a rehabilitation programme and community support. For patients having emergency psychiatric or medical admissions, detoxification is not usually indicated unless with the support of specialist services and aftercare arrangements are in place.

Opioid withdrawal in a community setting

Methadone

Following a period of stabilisation with methadone, or a longer period of maintenance, the patient and prescriber may agree a reduction programme as part of a care plan to reduce the daily methadone dose. The usual reduction would be by 5–10 mg weekly or fortnightly, although there can be much variation in the reduction and speed of reduction. In the community setting, patient preference is the most important variable in terms of dose reduction and rate of reduction. The detoxification programme should be reviewed regularly and remain flexible to adjustments and changes, such as relapse to illicit drug use or patient anxieties about speed of reduction. Factors such as an increase in heroin or other drug use or worsening of the patient's physical, psychological or social well-being, may warrant a temporary increase, or stabilisation of the dose or a slowing-down of the reduction rate. Towards the end of the detoxification the dose reduction may be slower 1–2 mg per week. Recent studies show that length of stability on maintenance treatment and prolonged reduction schedules (up to a year) substantially improve the chances of achieving abstinence.⁵⁶

Buprenorphine

The same principles as for methadone apply when planning a buprenorphine detoxification regime. Dose reduction should be gradual to minimise withdrawal discomfort. A suggested reduction regime is shown in Table 6.12.

Table 6.12 Recommended dose reduction schedule for buprenorphine

Opioid withdrawal in a specialist addiction inpatient setting

Methadone

Patients should have a starting dose assessment of methadone, over 48 hours by a specialist inpatient team. The dose may then be reduced following a linear regime over up to 4 weeks.⁵⁴

Buprenorphine

Buprenorphine can be used effectively for short-term inpatient detoxifications following the same principles as for methadone.

Lofexidine

Lofexidine, an α₂-adrenergic agonist, can counteract the adrenergic hyperactivity associated with opioid withdrawal⁵⁷ (demonstrated by characteristic signs and symptoms, such as tachycardia, sweating, runny nose, hair standing on end, shivering, and goose bumps). Thus, it is licensed for the management of symptoms of opioid withdrawal,⁵⁴ although additional short term adjunctive medications may be needed, such as loperamide for diarrhoea.² Detoxification using lofexidine is much faster than with methadone or buprenorphine, typically lasting 5–7 days, and up to a maximum of 10 days. The usual regimen commences at 800 μg daily, rising to 2.4 mg in split doses, which is then reduced over subsequent days.²² Side-effects may include a dry mouth, drowsiness, and clinically significant hypotension and bardycardia;² the latter two in particular must therefore be monitored during lofexidine prescribing. Lofexidine should be used with caution in patients with cardiovascular disease or being treated with medications associated with QT prolongation.

Although lofexidine is not useful for detoxification of those with substantial opioid dependence,² there are certain circumstances in which this regimen may have a role: in cases where the client has made an informed and clinically appropriate decision not to use methadone or buprenorphine for detoxification; where they have made a similarly informed and clinically appropriate decision to detoxify within a short time period; and where there is only mild or uncertain opioid dependence (including young people).⁵⁴ Treatment also enables early initiation onto naltrexone.

Relapse prevention—psychosocial interventions

Psychosocial and behavioural therapies play an important role in the treatment of drug misuse. By helping people develop skills to resist drug misuse and cope with associated problems, they form an important adjunct to pharmacological treatments.²

These include brief interventions, such as exploring ambivalence about drug use and possible treatment, with the aim of increasing motivation to change behaviour; providing information about self-help groups (e.g. Narcotics Anonymous); behavioural couples therapy; family therapy, community reinforcement approach and other psychosocial therapies.² One particular form of therapy is Contingency Management, considered by NICE⁵⁵ as having a strong evidence base from a growing body of work in the US. The principle of this therapy is to provide structured external incentives focused on changing specific behaviours. For example, low monetary value vouchers may be provided in a structured setting contingent on each presentation of a drug-negative test until stability is achieved. Vouchers of higher monetary value (e.g. £10) should be considered to encourage harm reduction on a one-off basis or over a limited duration for managing physical health problems, such as concordance with, or completion of:

• hepatitis B/C and HIV testing
• hepatitis B immunisation
• tuberculosis testing.⁵⁵

'The emphasis on reinforcing positive behaviours is consistent with current knowledge about the underlying neuropsychology of many people who misuse drugs and is more likely to be effective than penalising negative behaviours. There is good evidence that contingency management increases the likelihood of positive behaviours and is cost effective'.⁵⁵ Further details are beyond the scope of this text and the interested reader is therefore referred to the 2007 NICE guidelines on psychosocial interventions in drug misuse.

The 2011 review comments on the 2007 NICE guidelines, although not leading to a current updating of the guidelines,⁵⁸ highlighted that the 2007 guidelines did not sufficiently emphasise the importance, from world-wide experience of psychosocial interventions outside the realms of double-blind trials, such as the 12-step programme, which also has an important role to play in relapse prevention and recovery - 'the experience of the millions who have recovered through a 12-step programme'.⁵⁹

Naltrexone in relapse prevention

Evidence for the effectiveness of naltrexone as a treatment for relapse prevention in opioid misusers has been inconclusive.⁶⁰ However, for those who preferred an abstinence programme, are fully informed of the potential adverse effects and benefits of treatment, are highly motivated to remain on treatment, and have a partner supporting concordance, naltrexone treatment has been found by NICE to be a cost-effective treatment strategy in aiding abstinence from opioid misuse.⁶¹ The naltrexone implant, not currently licensed in the UK, may also have a role to play in reducing opioid use in a motivated population of patients⁶² following further research.

Close monitoring is particularly important when naltrexone treatment is initiated because of the higher risk of fatal overdose at this time. Discontinuation of naltrexone may also be associated with an increase in inadvertent overdose from illicit opioids. Thus, supervision of naltrexone administration, and careful choice of who is prescribed it (those who are abstinence-focused and motivated) is very important. Moreover, people taking naltrexone often experience adverse effects of unease (dysphoria), depression and insomnia, which can lead to relapse to illicit opioid use while on naltrexone treatment, or failure to continue on treatment. The dysphoria may be caused by either withdrawal from illicit drugs or by the naltrexone treatment itself, emphasising the importance of prescribing naltrexone as part of a care programme that includes psychosocial therapy and general support.⁶¹

Initiating naltrexone treatment

Naltrexone has the propensity to cause a severe withdrawal reaction in patients who are either currently taking opioid drugs or who were previously taking opioid drugs and there has not been a sufficient 'wash-out' period prior to administering naltrexone.

The minimum recommended interval between stopping the opioid and starting naltrexone depends on the opioid used, duration of use and the amount taken as a last dose. Opioid agonists with long half-lives such as methadone will require a wash-out period of up to 10 days, whereas shorter acting opioids such as heroin may only require up to 7 days.

Experience with buprenorphine indicates that a wash-out period of up to 7 days is sufficient (final buprenorphine dose > 2 mg; duration of use > 2 weeks) and in some cases naltrexone may be started within 2–3 days of a patient stopping (final buprenorphine dose < 2 mg; duration of use < 2 weeks).

A test dose of naloxone (0.2–0.8 mg), which has a much shorter half-life than naltrexone, may be given to the patient as an intramuscular (IM) dose prior to starting naltrexone treatment. Any withdrawal symptoms precipitated will be of shorter duration than if precipitated by naltrexone.

Patients must be advised of the risk of withdrawal prior to giving the dose. It is worth thoroughly questioning the patient as to whether they have taken any opioid containing preparation unknowingly (e.g. over-the-counter analgesic). See Box 6.4.

Dose of naltrexone

An initial dose of 25 mg naltrexone should be administered after a suitable opioid-free interval (and naloxone challenge if appropriate). The patient should be monitored for 4 hours after the first dose, for symptoms of opioid withdrawal. Symptomatic medication for withdrawal (lofexidine) should be available for use, if necessary, on the first day of naltrexone dosing (withdrawal symptoms may last up to 4–8 hours). Once the patient has tolerated this low naltrexone dose, subsequent doses can be increased to 50 mg daily as a maintenance dose.

Naltrexone is contraindicated in patients with hepatic dysfunction and liver function tests should be monitored during treatment.

Pregnancy and opioid use

Substitute prescribing can occur at any time in pregnancy and carries a lower risk than continuing illicit use.²

Women can present with opioid dependency at any stage in pregnancy and stabilisation on substitute methadone is the treatment of choice at any stage in pregnancy. Detoxification in the first trimester is contraindicated due to the risk of spontaneous abortion and in the third trimester it is associated with preterm delivery. If detoxification is requested, this is most safely achieved in the second trimester but should only be supervised by specialists with the appropriate competencies and with careful monitoring for any evidence of instability. Enforcing detoxification is contraindicated as it is likely to deter some clients from seeking help, and the majority will then return to opioid use at some point during their pregnancy;⁶³ fluctuating opioid concentrations in the maternal blood from intermittent use of illicit opioids may then lead to foetal withdrawal or overdose.^64,65 Given the value of a comprehensive care package, pregnant women attending treatment usually have better general health than those using drugs who are not in treatment, even if the former continue to also use illicit drugs.² The emphasis must therefore be on early engagement in treatment,² and, methadone maintenance treatment during pregnancy, in the context of a multidisciplinary team (including obstetricians, neonatologists, and addictions specialists) and detailed holistic package of care, (including comprehensive psychosocial input);⁶³ this is currently regarded as the gold standard.^64,65

The majority of neonates born to methadone-maintained mothers will, however, require treatment for neonatal abstinence syndrome (NAS).⁶⁴ NAS is characterised by a variety of signs and symptoms relating to the autonomic nervous system, gastrointestinal tract and respiratory system;⁶⁴ with methadone it usually commences after 48 hours.⁶⁶ In the case of any mother using drugs or in opioid substitution treatment, it is important to have access to skilled neonatal paediatric care, to monitor the neonate and treat as required.

Specialist advice should be obtained before initiating opioid substitution treatment or detoxification, particularly with regards to management and treatment plan during pregnancy. Maternal metabolism of methadone may increase towards the third trimester of pregnancy. At this time an increased methadone dose may be required or occasionally split dosing on the medication to prevent withdrawal.

Limited controlled data are available on the treatment of opioid dependence in pregnancy,^63,65,67 and particularly the use of buprenorphine in pregnancy.^63,68

A review of the evidence suggests that there were no significant differences between methadone, buprenorphine and slow release oral morphine in pregnancy.⁶⁷ However, the buprenorphine cases recorded to date suggest that buprenorphine, compared with methadone, may lead to a less severe abstinence syndrome in the neonate,⁵⁴ while methadone may be related to better treatment retention.⁶⁷

It is useful to anticipate potential problems for women prescribed opioids during pregnancy with regard to opioid pain relief: such women should be managed in specialist antenatal clinics due to the increased associated risks. Antenatal assessment by anaesthetists may be recommended with regard to anticipating any anaesthetic risks, any analgesic requirements and problems with venous access.

Pregnancy and breast feeding—methadone

Although the newborn may experience a withdrawal syndrome, as described, there is no evidence of an increase in congenital defects with methadone.

Methadone is considered compatible with breast feeding, although other risk factors such as HIV, hepatitis C, use of benzodiazepines, cocaine and other drugs need to be considered and may mean that breast feeding is contraindicated. The NICE guidelines² recommend that breast feeding should still be encouraged, but that with regards to methadone and breast feeding 'the dose is kept as low as possible while maintaining stability, and the infant monitored to avoid sedation'.

Pregnancy and breast feeding—buprenorphine

Currently buprenorphine is not licensed as an opioid substitute treatment during pregnancy or breast feeding although there is increasing experience of the use of this drug in pregnancy. More evidence is available on the safety of methadone, which for that reason makes it the preferred choice. However, women well maintained on buprenorphine prior to pregnancy may remain on buprenorphine following full informed consent and advice that safety of buprenorphine in pregnancy has not been fully established.² All such decisions should be made by experienced prescribers and fully documented.

Opioids overdose

The recommended procedure in the event of an opioids overdose is shown in Box 6.5.

'Take-home' naloxone

Research trials have assessed the impact of providing take-home naloxone and overdose-management training to opioid-using patients.^52,53 With overdose-management training, opiate users can be trained to execute appropriate actions to assist the successful reversal of potentially fatal opiate overdose.⁶⁹ Some services are providing one dose of take-home naloxone (400 μg) in combination opioid overdose-management training (as above) to opioid-using clients in treatment, and wider provision may reduce opioidrelated deaths further.⁶⁹

NICE guidelines related to substance abuse

The National Institute of Health and Care Excellence has issued various guidelines related to substance misuse. These are summarised in Boxes 6.6–6.10.

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Nicotine and smoking cessation

Smoking remains the Western world's major preventable cause of early death. Reductions in smoking behaviour have a major positive impact on numerous health outcomes.

NICE guidance on smoking cessation

Harmful effects from nicotine dependence are generally related to the harm caused by smoking cigarettes and therefore the primary goal of treatment is complete cessation of smoking. The three main treatments licensed in the UK for smoking cessation are nicotine replacement (all formulations are available over the counter), the antidepressant bupropion prolonged-release and varenicline tartrate. Nicotine replacement therapy (NRT) has been investigated in a large number of well conducted RCTs, and varenicline and bupropion in a smaller number of such trials. NICE have developed tobacco treatment guidance^1–3 relating to planned abrupt cessation of tobacco which is the optimal approach, gradual smoking reduction prior to cessation (a form of harm reduction) for those unable or unwilling to stop smoking completely, and managing temporary abstinence when smokers are unable to smoke, ie. due to smoking restrictions such as during an inpatient stay.

For smoking cessation NICE make the following recommendations.

• NRT, varenicline and bupropion are recommended for those who want to stop smoking.
• NRT, varenicline and bupropion should only be prescribed as part of an 'abstinentcontingent treatment' model in which smokers make a committment to stop smoking on a particular date and medication is only continued if the user remains abstinent from smoking at follow-ups. To increase cost-efficacy, the total treatment course is dispensed in divided prescriptions. NRT should initially be prescribed to last for 2 weeks after the stopping date and varenicline and bupropion for 3–4 weeks after the stop date. Subsequent prescriptions should be given if the smoker is making good progress at their quit attempt.
• Varenicline and bupropion should not be used in the under 18 s, pregnant and breastfeeding women.
• Explain the risks and benefits of using NRT to young people aged from 12 to 17, pregnant or breast-feeding women, and people who have unstable cardiovascular disorders. To maximise the benefits of NRT, people in these groups should also be strongly encouraged to use behavioural support in their quit attempt.
• Varenicline or bupropion may be offered to people with unstable cardiovascular disorders, subject to clinical judgement.
• NHS-funded smoking cessation treatments should not usually be offered within 6 months of an unsuccessful attempt at smoking cessation with either NRT, varenicline or bupropion, unless there are external circumstances which lead to relapse.
• Do not offer NRT, varenicline or buproprion in any combination.
• Consider offering a combination of nicotine patches and an acute form of NRT (such as gum, inhalator, lozenge or nasal/mouth spray) to people who show a high level of dependence on nicotine or who have found single forms of NRT inadequate in the past.
• Factors to consider when deciding which of the three treatments to initate include:
• motivation to stop
• availability of counselling
• previous experience with smoking cessation aids
• contraindications to use and the potential for adverse events
• personal preference of smoker.

More recently, in recognition of the fact that not all smokers are able or willing to stop smoking, or abstain from nicotine completely, NICE have recommended smokers to use one or more licensed nicotine-containing products while still smoking and for as long as needed to prevent relapse. Healthcare staff are encouraged to raise awareness of this new strategy among smokers. For those forced into temporary tobacco abstinence by smoking restrictions NICE also advises using such products to alleviate nicotine withdrawal symptoms.³

Another development has been a focus on tackling smoking cessation in people with mental health conditions. NICE, the Royal College of Physicians and the Royal College of Psychiatrists have all recently called for radical changes in the prioritisation, service provision and prevention of tobacco related deaths and disability in people with mental health disorders.^2,4 Widely held misconceptions that such smokers are not motivated to stop, are unable to do so if they try, or that their mental health might deteriorate as a result of quitting, are not supported by the data. In fact there is evidence that smoking cessation is associated with reduced depression, anxiety, stress, and improved positive mood and quality of life compared to continuing to smoke in those with and without psychiatric disorders.⁵

NICE has also made recommendations on brief interventions and referral to NHS smoking cessation services some of which are outlined below.⁶

• Everyone who smokes should be advised to stop.
• All smokers should be asked how interested they are in stopping.
• Healthcare workers (including GPs and hospital doctors) should offer referral to smoking cessation services and if the person does not want to attend these services, can initiate pharmacotherapy as per NICE guidelines if sufficiently experienced.

Nicotine replacement therapy (NRT)

Clinical effectiveness

A Cochrane review of 117 RCTs of NRT against placebo or non-NRT for smoking cessation⁷ concluded that all six commercially available forms of NRT are effective. NRT increases the odds of quitting by approximately 1.5- to 2-fold regardless of clinical setting. NRT significantly reduces the severity of nicotine withdrawal symptoms and urge to smoke and should be given as per recommended doses in the BNF and outlined below. The dosages may vary according to the degree of nicotine dependence as indicated by markers such as daily cigarette consumption, latency to first cigarette in the morning, and severity of withdrawal symptoms on previous quit attempts. There was a tendency for nicotine inhaler and nasal spray to be more effective than gums, lozenges or patches.

In order to widen access of NRT in at-risk patient groups, the MHRA state that NRT may be used by:

• Adolescents aged 12 to 18, but as there are limited data on the safety and efficacy, duration should be restricted to 12 weeks. Treatment should only be continued longer than 12 weeks on the advice of a healthcare professional.
• Pregnant women–ideally they should stop smoking without using NRT but, if this is not possible, NRT may be recommended to assist a stopping attempt as it is considered that the risk to the foetus of continued smoking by the mother outweighs any potential adverse effects of NRT. The decision to use NRT should be made following a risk-benefit assessment as early in pregnancy as possible. The aim should be to discontinue NRT use after 2–3 months. Intermittent (oral) forms of NRT are preferable during pregnancy although a patch may be appropriate if nausea and/or vomiting are a problem. If patches are used, they should be removed before going to bed at night. Generally clinicians are advised to use only 16-hour patches with pregnant women as then the onus is not on the woman to remember to remove the patch. If she forgets to take 16-hour one off there is no further nicotine delivery.
• Breast-feeding women–NRT can be used by women who are breast feeding. The amount of nicotine the infant is exposed to from breast milk is relatively small and less hazardous than the second-hand smoke they would otherwise be exposed to if the mother continued to smoke. If possible, patches should be avoided. NRT products taken intermittently (oral forms) are preferred as their use can be adjusted to allow the maximum time between their administration and feeding of the baby, to minimise the amount of nicotine in the milk.
• Patients with cardiovascular disease–dependent smokers with a myocardial infarction (MI), severe dysrhythmia or recent cerebrovascular accident (CVA) who are in hospital, should be encouraged to stop smoking with non-pharmacological interventions. If this fails NRT may be considered, but as data on safety in these patient groups are limited, initiation of NRT should only be done under medical supervision. For patients with stable cardiovascular disease, NRT is a lesser risk than continuing to smoke.
• Patients with diabetes–nicotine releases catecholamines, which can affect carbohydrate metabolism. Diabetic patients should be advised to monitor their blood sugar levels more closely than usual when starting NRT.
• Patients with renal or hepatic impairment–NRT should be used with caution in patients with moderate to severe hepatic impairment and/or severe renal impairment, as the clearance of nicotine or its metabolites may be decreased, with the potential for increased adverse effects.
• Patients taking other drugs–drug interactions may occur as a result of stopping smoking rather from NRT per se. The only interaction that is possibly directly attributable to NRT is with adenosine (adverse haemodynamic effects).

Preparations and dose

All NRTs, when used to make an abrupt attempt to stop smoking, should be used for about 8–12 weeks but may be continued beyond this time if needed to prevent relapse. They can also be used in combination if required, usually the patch plus a faster-acting oral or nasal NRT for relief of situational urges to smoke. Cochrane report an odds ratio of 1.34 for combination NRT versus patch alone for long term abstinence.⁷ Unless given adequate behavioural support in combination with NRT, and enough information about how these products work, smokers tend not to use sufficient NRT for relief of withdrawal and do not use it for long enough to prevent relapse. Even the fastest acting NRTs (nasal and mouth spray) deliver nicotine much more slowly than inhaled tobacco smoke and so do not give the same subjective satisfaction.

• Sublingual tablet (2 mg): recommended dose of one tablet per hour or, for heavy smokers (smoking more than 20 cigarettes per day), two tablets per hour maximum 40 × 2 mg daily.
• Gum (2 mg or 4 mg, variety of flavours, chewed slowly when urge to smoke occurs) up to maximum of 15 pieces daily. Gum needs to be rested against the gums or buccal mucosa for absorption to occur. There is some evidence of reduced efficacy for the 2 mg preparation.⁷
• Patch: two different types are available (24 hour or 16 hour). There is no difference in efficacy. Both types come in three strengths to allow gradual weaning.
• 16 hour patches deliver nicotine over a 16 hour period and are removed at bedtime (dose 25 mg,15 mg, 10 mg)
• 24 hour patches are worn throughout the night and taken off and replaced in the morning (21 mg, 14 mg, 7 mg).
• Nasal spray (each metered spray delivers 0.5 mg nicotine. A dose = 1 spray to each nostril, up to maximum of 2 doses per hour or 32 doses per day). Most suitable for highly dependent smokers.
• Inhalator (15 mg/cartridge) used with a plastic mouthpiece. Dose initially up to 6 cartridges per day—puffed for 20 minutes every hour.
• Lozenge (1 mg, 2 mg and 4 mg) up to maximum of 15 per day. Again, as with gum, needs to be used correctly. Patients should be advised not to suck the lozenge, rest between gum and cheek or put under the tongue.
• Nicotine oromucal spray (1 mg): Apply 1–2 sprays into the mouth every 30 minutes, for 8 weeks, then reduce use by 50% over 2–4 weeks and down to 0 within another 2 weeks.
• Orodispersable nicotine mouth strips (2.5 mg): One strip every 1–2 hours for 6 weeks, then one every 2–4 hours for 3 weeks reducing to one every 4–8 hours for 3 weeks. Minimum of 9 to maximum of 15 strips a day. Suitable for less nicotine dependent smokers.

E-cigarettes

In the past two or three years the number of people switching partly or wholly to e-cigarettes has massively increased. Smoking e-cigarettes ('vaping') is essentially unsupervised NRT. The advantage is a fast delivery of nicotine which mimics tobacco smoking. Disadvantages include the normalisation of smoking in a different form and the possibility that carcinogens may still be present in the tobacco-derived nicotine solutions. Many smokers find delivery from some e-cigarettes to be unsatisfactory, and so equipment which allows the user to alter the nicotine delivery may be preferred.

Side-effects

Mainly mild local irritant effects such as skin irritation, hiccups, stinging in the mouth/ throat/nose depending on formulation. These usually disappear with continued use as tolerance develops rapidly.

Bupropion (amfebutamone)

Clinical effectiveness

Bupropion (Zyban) is an atypical antidepressant with dopaminergic and noradrenergic actions, and has been advocated by NICE for smoking cessation. A systematic review of 65 RCTs of bupropion revealed a near doubling of smoking cessation as compared to the placebo control (where NRT is not used).⁸ Trials show it significantly reduces the severity of nicotine withdrawal symptoms and urges to smoke and in some patients will make smoking less pleasurable and rewarding.

There is a risk of about 1 in 1000 of seizures associated with bupropion use and therefore this must be considered before initiation of treatment.

Bupropion is contraindicated in patients with a history of seizures, eating disorders, a CNS tumour, bipolar disorder, pregnancy, breast feeding or those experiencing acute benzodiazepine or alcohol withdrawal. As many drugs reduce seizure threshold, including other antidepressants, a risk-benefit assessment must be made in such cases and if bupropion is prescribed it should be at half dose.

Side-effects

Insomnia, dry mouth, headache (common ~30%). Seizure, hypersensitivity reaction or rash (rare ~0.1%).

Start 1–2 weeks before the planned 'quit date' at 150 mg daily for 6 days, then 150 mg twice daily for a maximum of 7–9 weeks. The dose will need to be reduced in the elderly or in those experiencing side-effects. Not recommended for those < 18 years old.

Varenicline (Champix)

Varenicline tartrate is a partial agonist binding with high affinity to the α₄β₂ nicotinic acetylcholine receptor. Two large scale randomised placebo-controlled trials comparing it directly with bupropion suggest it is nearly 80% more effective.^9,10 The Cochrane review gives a number needed to treat (NNT) of 10 for varenicline to achieve an additional successful 6–12 month quitter compared with placebo, compared with an NNT of 20 for bupropion and 10 for single NRT.¹¹ Varenicline is also more effective than 24 hour NRT.¹² Like NRT and bupropion, varenicline significantly reduces nicotine withdrawal symptoms, but there is also evidence it makes smoking less rewarding so may help prevent 'slips' develop into full relapse.

Dose

Days 1–3: 0.5 mg once daily

Days 4–7: 0.5 mg twice daily

Day 8–end of week 12: 1.0 mg twice daily

Smokers should be advised to set a 'quit date' between days 8–14 but can delay quitting for up to 35 days. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks treatment at 1 mg twice daily may be considered. The only contraindication is hypersensitivity to the drug or excipients. There are no known drug interactions.

Warnings and precautions

Smoking cessation, with or without pharmacotherapy, has been associated with exacerbation of underlying psychiatric illness (e.g. depression). It should not be used in the under 18s, pregnant or breast-feeding women, or in those with end stage renal disease. Those with severe renal impairment may require a dosage reduction.

Side-effects

The main side effect is nausea (30%). Depression and suicidality have also been reported¹³ during post-marketing surveillance and care should be taken to monitor patients for any signs of agitation, mood changes or suicidal thoughts.¹⁴

Extra considerations for those with a psychiatric diagnosis

People with mental health problems who smoke tend to be more highly nicotine-dependent than the general population of smokers and may find withdrawal intolerable,¹⁵ a factor which predicts lower success rates with smoking cessation interventions. The relationship between tobacco use and different psychiatric disorders has been extensively reviewed.^4,15 Clinicians should also be aware of the possible emergence of depression in patients who attempt to stop smoking. Switching to e-cigarettes (wholly or partly) might be considered desirable in many patients.

Bupropion has been shown to be effective in people with schizophrenia particularly when combined with NRT.¹⁶ Benefits of bupropion treatment must be weighed against the risk of seizures—see section on 'Bupropion' on the previous page. Noradrenergic antidepressants such as nortriptyline^8,17 and venlafaxine¹⁸ may also be effective smoking cessation treatments in those with schizophrenia, but SSRIs are not.

Varenicline is the most effective smoking cessation treatment but may also be associated with higher risks than NRT. There is MHRA advice about suicidal behaviour and varenicline which can be found in the BNF; 'Patients should be advised to discontinue treatment and seek prompt medical advice if they develop agitation, depressed mood or suicidal thoughts. Patients with a history of psychiatric illness should be monitored closely while taking varenicline. If you have a history of depression, you may be more likely to experience common side-effects of varenicline and/or the symptoms of nicotine withdrawal, i.e. tension/agitation, irritability/anger, confusion and depression'.¹⁹ Recent published research has provided some reassuring findings and to date no causal association between varenicline and neuropsychiatric adverse effects has been found.^20–22

Effects of stopping smoking on other drugs

Stopping smoking may alter the pharmacokinetics or pharmacodynamics of other drugs, including several used in psychiatry, for which dosage adjustment may be necessary irrespective of which or whether any stop smoking medication is being used (examples include alprazolam, theophylline, chlorpromazine, diazepam, warfarin, insulin, clomipramine, clozapine, desipramine, doxepin, fluphenazine, haloperidol, imipramine and oxazepam). Stopping smoking is not thought to alter blood levels of chlordiazepoxide, ethanol, lorazepam or midazolam. These interactions are caused by the components in the smoke (polycyclic aromatic hydrocarbons) and not the nicotine. It is unclear if quitting affects blood levels of amitriptyline and nortriptyline. Smoking cessation usually results in an increase of plasma levels of CYP1A2 substrates (smoking induces CYP1A2). See section 'Smoking and psychotropic drugs' in Chapter 8.

References

1. National Institute for Health and Clinical Excellence. Smoking cessation services in primary care, pharmacies, local authorities and workplaces, particularly for manual working groups, pregnant women and hard to reach communities. Public Health Guidance 10, 2008. http://www.nice.org.uk/PH010
2. National Institute for Health and Care Excellence. Smoking cessation - acute, maternity and mental health services. Public Health Guidance 48, 2013. http://guidance.nice.org.uk/PH48
3. National Institute for Health and Care Excellence. Tobacco harm reduction. Public Health Guidance 45, 2013. http://guidance.nice.org.uk/PH45
4. Royal College of Physicians, Royal College of Psychiatrists. Smoking and mental health: A joint report by the Royal College of Physicians and the Royal College of Psychiatrists. London: RCP; 2013. http://www.rcplondon.ac.uk/publications/smoking-and-mental-health.
5. Taylor G et al. Change in mental health after smoking cessation: systematic review and meta-analysis. BMJ 2014; 348:g1151.
6. National Institute for Health and Clinical Excellence. Brief interventions and referral for smoking cessation in primary care and other settings. Public Health Intervention Guidance 1, 2006. http://www.nice.org.uk/
7. Stead LF et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2012; 11:CD000146.
8. Hughes JR et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev 2014; 1:CD000031.
9. Gonzales D et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006; 296:47–55.
10. Jorenby DE et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006; 296:56–63.
11. Cahill K et al. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2012; 4:CD006103.
12. Aubin HJ et al. Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 2008; 63:717–724.
13. McIntyre RS. Varenicline and suicidality: a new era in medication safety surveillance. Expert Opin Drug Saf 2008; 7:511–514.
14. Medicines and Healthcare Products Regulatory Agency. Varenicline: adverse psychiatric reactions including depression. Drug Safety Update 2008; 2:2–3.
15. Ziedonis D et al. Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine Tob Res 2008; 10:1691–1715.
16. Tsoi DT et al. Interventions for smoking cessation and reduction in individuals with schizophrenia. Cochrane Database Syst Rev 2013; 2:CD007253.
17. Wagena EJ et al. Should nortriptyline be used as a first-line aid to help smokers quit? Results from a systematic review and meta-analysis. Addiction 2005; 100:317–326.
18. Cinciripini PM et al. Combined effects of venlafaxine, nicotine replacement, and brief counseling on smoking cessation. Exp Clin Psychopharmacol 2005; 13:282–292.
19. McClure JB et al. Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline. J Gen Intern Med 2009; 24:563–569.
20. Anthenelli RM et al. Effects of varenicline on smoking cessation in adults with stably treated current or past major depression: a randomized trial. Ann Intern Med 2013; 159:390–400.
21. Thomas KH et al. Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort study. BMJ 2013; 347:f5704.
22. Gibbons RD et al. Varenicline, smoking cessation, and neuropsychiatric adverse events. Am J Psychiatry 2013; 170:1460–1467.

Pharmacological treatment of dependence on stimulants

The most commonly misused stimulants are cocaine (as hydrochloride or free base), amfetamine sulfate and methamfetamine hydrochloride. These drugs are usually insufflated (snorted) (e.g. cocaine HCL; amfetamine SO₄), smoked (cocaine base) or injected. There are no effective pharmacotherapies for the treatment of stimulant dependence. A wide variety of pharmacological agents have been assessed and found lacking,¹ although research is ongoing.² Effective medications are available for some psychiatric complications of stimulant use. For example, antidepressants have a role in treating major depressive disorder associated with stimulant use³ as do antipsychotics for amfetamine psychosis.⁴ However, neither class of drug is efficacious in treating stimulant dependence itself.^5–7

The recommended treatment for dependence on stimulants is psychosocial; in particular contingency management,⁸ although benefit has also been shown for cognitive behavioural and relapse prevention approaches.⁹

Cocaine

Detoxification

There are no currently used evidence-based pharmacological treatments for the management of cocaine withdrawal. Symptoms of withdrawal include depressed mood, agitation and insomnia.¹⁰ These are usually self limiting. It should be noted that given cocaine's short half-life and the binge nature of cocaine use, many patients essentially detoxify themselves regularly with no pharmacological therapy. Symptomatic relief such as the short-term use of hypnotics may be helpful in some but these agents may be diverted for illicit use or become agents of dependence themselves.³

Substitution treatment

There is little evidence for substitution therapy for the treatment of cocaine misuse and it should not be prescribed.³

Ongoing research

There is inconclusive evidence that some agents may increase rates of abstinence. These include drugs that increase extracellular dopamine by stimulating dopamine release (dexamfetamine),^11,12 inhibiting dopamine reuptake (bupropion and modafinil),^11–14 or inhibiting dopamine metabolism (disulfiram).¹⁵ The anticonvulsant vigabatrin has shown some efficacy in both increasing abstinence and retention in treatment.¹⁶ Most of these medications have substantial side-effects and all have uncertain long-term outcomes. Hence they remain subjects for further research rather than clinical treatment options.

Vaccination

Anti-addiction vaccines may offer an alternative pharmacological approach. Vaccinated individuals produce antibodies which bind to drug molecules inhibiting their passage across the blood–brain barrier and reducing their subjective effects.¹⁷ The first placebo-controlled RCT of a cocaine vaccine (administered as 5 injections over 12 weeks) in opioid and cocaine dependent patients showed a significant decrease in cocaine use in patients who attained effective serum anticocaine antibody levels.¹⁸ However, only 38% of vaccinated patients attained such levels and this occurred slowly such that the decrease in cocaine use only became significant between weeks 9 and 16 and then rapidly dropped off. It remains to be seen how far these issues can be addressed and whether anti-addiction vaccines will have a role in the treatment of cocaine and other drug dependence in the future.

Amfetamines

A wide variety of amfetamines are misused including 'street' amfetamine, methamfetamine and pharmaceutical dexamfetamine. Any drug in this class is likely to have misuse potential. As with cocaine there is no evidence base for pharmacological treatment of withdrawal,^3,4,7 although the number of agents that have been investigated is limited.^4,7 A recent systematic review of dexamfetamine, bupropion, methylphenidate and modafinil as replacement therapies found no reduction in amfetamine use or craving and no increase in sustained abstinence.¹⁹ Future research may change this outcome in view of the small sample sizes and paucity of studies available for review. Naltrexone has shown promise in initial trials by attenuating the subjective effects of dexamfetamine²⁰ and reducing amfetamine use in dependent individuals.²¹

Detoxification

Treatment should focus on symptomatic relief, although many symptoms of amfetamine withdrawal (low mood, listlessness, fatigue, etc.) are short-lived and may not be amenable to pharmacological treatment. Insomnia can be treated with short courses of hypnotics.

Maintenance

Dexamfetamine maintenance should not be initiated. There is no good evidence for this practice.³ There are, however, patients that have been prescribed dexamfetamine as a maintenance treatment for drug dependence for many years. Ideally, such patients should be gradually detoxified over several months. For some, though, the consequences of enforced detoxification may be worse than continuing to prescribe dexamfetamine. In these cases the best decision may be to continue to prescribe. A decision to continue prescribing dexamfetamine should only be made by an addiction specialist.³

Polysubstance abuse

In those that are dependent on opioids and cocaine, the provision of effective substitution therapy for treatment of the opioid dependence with either methadone or buprenorphine can lead to a reduction in cocaine use.³

References

1. de Lima MS et al. Pharmacological treatment of cocaine dependence: a systematic review. Addiction 2002; 97:931–949.
2. Haile CN et al. Pharmacotherapy for stimulant-related disorders. Curr Psychiatry Rep 2013; 15:415.
3. Department of Health. Drug misuse and dependence. UK guidelines on clinical management. London: DH; 2007.
4. Shoptaw SJ et al. Treatment for amphetamine withdrawal. Cochrane Database Syst Rev 2009;CD003021.
5. Amato L et al. Antipsychotic medications for cocaine dependence. Cochrane Database Syst Rev 2007;CD006306.
6. Pani PP et al. Antidepressants for cocaine dependence and problematic cocaine use. Cochrane Database Syst Rev 2011;CD002950.
7. Srisurapanont M et al. Treatment for amphetamine dependence and abuse. Cochrane Database Syst Rev 2001;CD003022.
8. National Institute for Health and Clinical Excellence. Drug misuse: psychosocial interventions. Clinical Guideline 51, 2007. http://www.nice. org.uk/.
9. Dutra L et al. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry 2008; 165:179–187.
10. Rounsaville BJ. Treatment of cocaine dependence and depression. Biol Psychiatry 2004; 56:803–809.
11. Castells X et al. Efficacy of psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev 2010;CD007380.
12. Perez-Mana C et al. Efficacy of indirect dopamine agonists for psychostimulant dependence: a systematic review and meta-analysis of randomized controlled trials. J Subst Abuse Treat 2011; 40:109–122.
13. Anderson AL et al. Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend 2009; 104:133–139.
14. Martinez-Raga J et al. Modafinil: a useful medication for cocaine addiction? Review of the evidence from neuropharmacological, experimental and clinical studies. Curr Drug Abuse Rev 2008; 1:213–221.
15. Pani PP et al. Disulfiram for the treatment of cocaine dependence. Cochrane Database Syst Rev 2010;CD007024.
16. Brodie JD et al. Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry 2009; 166:1269–1277.
17. Shen XY et al. Vaccines against drug abuse. Clin Pharmacol Ther 2012; 91:60–70.
18. Martell BA et al. Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Arch Gen Psychiatry 2009; 66:1116–1123.
19. Perez-Mana C et al. Efficacy of psychostimulant drugs for amphetamine abuse or dependence. Cochrane Database Syst Rev 2013; 9:CD009695.
20. Jayaram-Lindstrom N et al. Naltrexone attenuates the subjective effects of amphetamine in patients with amphetamine dependence. Neuropsychopharmacology 2008; 33:1856–1863.
21. Jayaram-Lindstrom N et al. Naltrexone for the treatment of amphetamine dependence: a randomized, placebo-controlled trial. Am J Psychiatry 2008; 165:1442–1448.

Benzodiazepine misuse (see section in Chapter 4)

Benzodiazepine prescribing increased during the 1970s, mainly because of their improved safety profile relative to barbiturates. However, it was soon noted that benzodiazepines have a high potential for causing dependence. Prescriptions originally started for other disorders may be continued long-term and develop into dependence. This is particularly common in elderly patients and those with anxiety spectrum disorders or depression.

A Cochrane review evaluated the evidence for pharmacological interventions for benzodiazepine mono-dependence and concluded that a gradual reduction of benzodiazepine dose (by about an eighth of the dose per fortnight) was preferable to an abrupt discontinuation¹ (see section on 'Benzodiazepines' in Chapter 4 for suggested regimens). A more recent review confirmed that withdrawal over a period of less than 6 months is appropriate for most patients.² A meta-analysis supports the effectiveness of multi-faceted prescribing interventions (usually including psychological interventions/support) in reducing benzodiazepine use in older patients³ and a recent RCT has demonstrated that a simple educational approach based on self-efficacy theory resulted in almost a quarter of long-term elderly benzodiazepine users engaging voluntarily in reducing and discontinuing use.⁴

A large number of patients presenting to addictions services may be using illicit benzodiazepines on top of their primary substance of abuse. Although some services provide prescriptions for benzodiazepines, there is no evidence that substitute prescribing of benzodiazepines reduces benzodiazepine misuse. If benzodiazepines are prescribed, this should ideally be for a short-term, time-limited (2–3 weeks) prescription and with a view to detoxification.

If patients have been prescribed benzodiazepines for a substantial period of time, it may be preferable to convert to equivalents of diazepam as this is longer acting and so less likely to be associated with withdrawal symptoms between doses. Benzodiazepine dependence as part of polysubstance dependence should also be treated by a gradual withdrawal of the medication. Benzodiazepines prescribed at greater than 30 mg diazepam equivalent per day may cause harm⁵ and so this should be avoided if at all possible. Psychosocial interventions including contingency management have had some success at reducing benzodiazepine use.

Pregnancy and benzodiazepine misuse

Benzodiazepines are not major human teratogens but should ideally be gradually discontinued before a planned pregnancy. If a woman is prescribed benzodiazepines and found to be pregnant, the prescription should be gradually withdrawn over as short a time as possible, being mindful of the risk of withdrawal seizures and the potential consequences for the pregnant woman and foetus. A risk benefit analysis should be undertaken and specialist advice sought (see section on 'Pregnancy' in Chapter 7).

References

1. Denis C et al. Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings. Cochrane Database Syst Rev 2006;CD005194.
2. Lader M et al. Withdrawing benzodiazepines in primary care. CNS Drugs 2009; 23:19–34.
3. Gould RL et al. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. Br J Psychiatry 2014; 204:98–107.
4. Tannenbaum C et al. Reduction of Inappropriate Benzodiazepine Prescriptions Among Older Adults Through Direct Patient Education: The EMPOWER Cluster Randomized Trial. JAMA Intern Med 2014.
5. Department of Health. Drug misuse and dependence. UK guidelines on clinical management. London: DH; 2007.

GBL and GHB dependence

GBL (γ-butaryl-lactone, a pro-drug of GHB) and GHB (γ-hydroxybutyrate) use is uncommon, but medically important because in dependent users withdrawal can proceed rapidly to agitated delirium with paranoia and muscle rigidity so severe that it can occasionally cause rhabdomyolysis and acute renal failure. Doctors in emergency departments and psychiatric admission wards need to be able to recognise and manage acute withdrawal.

GBL and GHB reduce anxiety and produce disinhibition and sedation, primarily through actions at the gamma-aminobutyric acid (GABA)-β receptor. These drugs are used for socialising and facilitating sex, and sometimes for sleep. The drugs have a narrow therapeutic index and overdose is not uncommon. Dependence on these drugs is quite rare, but in dependent users withdrawal has a rapid onset and can produce severe delirium and muscle rigidity.^1,2 Fatalities associated with withdrawal have been reported.³

The GBL withdrawal syndrome^1,2,4

Dependent users take GBL 'round the clock' (every 3–4 hours or more frequently). Onset of withdrawal is usually 3–4 hours after the last dose of GBL and is characterised by anxiety, sweating, fine tremor and resting tachycardia. Untreated, this can proceed to delirium, often with psychotic features (visual and tactile hallucinations, paranoia), followed by severe tremors and muscle rigidity. Muscle rigidity may be so severe as to produce fever, and rhabdomyolysis and acute renal failure have been observed. The requirement for medication eases over 4–6 days, although there are case reports of more prolonged withdrawal.

The principle of managing withdrawal is to treat early and prevent the development of delirium and other complications, as once established, delirium can be difficult to control. Early treatment with high doses of benzodiazepines are required, and baclofen (a GABA-β agonist) has been included in management to reduce the risk of muscle rigidity.⁵ See Box 6.11. Existing withdrawal scales are unlikely to be helpful.

Management of elective GBL withdrawal

In such patients, withdrawal should be medically supervised. After withdrawal, persisting anxiety and insomnia are common, and there is a high risk of relapse. Before initiating elective withdrawal management, a plan should be in place to monitor and support patients for 4 weeks to minimise risk of relapse. Patients with good social support who live in proximity to where treatment is to be delivered can be managed on an ambulatory basis, other patients should be managed in an inpatient setting.

Community detoxification

• Ambulatory detoxification should only be attempted if there is someone at home who is able to monitor and supervise the withdrawal process and there is the option available of transferring the patient to an inpatient unit if symptoms are not well-controlled.
• Discuss treatment plan with the patient and person who will be supporting them. It is helpful to write this out and keep a copy in notes.
• On day one of planned ambulatory detoxification, the patient is asked to attend having used no GBL for 2 hours and advised to dispose of their remaining supplies of GBL. They will need to stay at the clinic for 4 hours on day one. They must be advised that they cannot drive motor vehicles during withdrawal and should be advised not to drink alcohol during withdrawal.
• Initiate treatment once signs and symptoms develop—pulse > 90, sweaty palms, fine tremor, and/or anxiety—administer diazepam 20 mg, repeat after 2 hours, at which time also administer baclofen 10 mg. Monitor hourly for anxiety/sedation.
• Once 6 hours have passed since last GBL usage and the patient has had at least 40 mg diazepam and 10 mg baclofen, they may be dispensed a further 40 mg diazepam and 30 mg baclofen and then seen on the following two days.
• At each daily review, adjust medication. Diazepam is seldom needed beyond 5 days.

Inpatient treatment

Patients lacking social support are more safely managed in inpatient settings. Pharmacological management is as for ambulatory withdrawal—early initiation of high dose benzodiazepines, titrated against response. In both situations, it is advisable to have flumazenil available.

References

1. Bell J et al. Gamma-butyrolactone (GBL) dependence and withdrawal. Addiction 2011; 106:442–447.
2. McDonough M et al. Clinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review. Drug Alcohol Depend 2004; 75:3–9.
3. Zvosec DL et al. Case series of 226 gamma-hydroxybutyrate-associated deaths: lethal toxicity and trauma. Am J Emerg Med 2011; 29:319–332.
4. Wojtowicz JM et al. Withdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review. CJEM 2008; 10:69–74.
5. LeTourneau JL et al. Baclofen and gamma-hydroxybutyrate withdrawal. Neurocrit Care 2008; 8:430–433.

Drugs of misuse: a summary

One in twelve adults use illicit drugs in any one year,¹ and at least a third of those with mental illness can be classified as having a 'dual diagnosis'.^2,3 There is now compelling evidence that cannabis use increases the risk of psychosis.^4,5 It is therefore important to be aware of the main mental state changes associated with drugs of abuse. Note also that substance misuse in fully compliant patients with schizophrenia increases relapse rate to the levels seen in those who are non-compliant⁶ (that is, substance misuse negates the benefits of antipsychotic treatment). Urine-testing for illicit drugs is routine on many psychiatric wards. It is important to be aware of the duration of detection of drugs in urine and of other commonly used substances and drugs that can give a falsepositive result. Some false positives are unexpected and so not readily predictable, for example amisulpride can give a false positive for buprenorphine.⁷ False positive results are most likely with point of care testing kits. If a positive result has implications for a patient's liberty, and the patient denies use of substances, a second sample should be sent to the laboratory. Table 6.13 summarises the physical and mental changes associated with various drugs, withdrawal from those drugs and general results for urine testing.

Table 6.13 Drugs of misuse: effects, withdrawal and testing

References

1. UK National Statistics. Drug Misuse: Findings from the 2012 to 2013 Crime Survey for England and Wales. https://www.gov.uk/government/ uploads/system/uploads/attachment_data/file/225122/Drugs_Misuse201213.pdf.
2. Menezes PR et al. Drug and alcohol problems among individuals with severe mental illness in south London. Br J Psychiatry 1996; 168:612–619.
3. Phillips P. et al. Drug and alcohol misuse among in-patients with psychotic illnesses in three inner-London psychiatric units. Psychiatr Bull 2003; 27:217–220.
4. Sara GE et al. The impact of cannabis and stimulant disorders on diagnostic stability in psychosis. J Clin Psychiatry 2014; 75:349–356.
5. Di FM et al. High-potency cannabis and the risk of psychosis. Br J Psychiatry 2009; 195:488–491.
6. Hunt GE et al. Medication compliance and comorbid substance abuse in schizophrenia: impact on community survival 4 years after a relapse. Schizophr Res 2002; 54:253–264.
7. Couchman L et al. Amisulpride and sulpiride interfere in the C&DIA DAU buprenorphine test. Ann Clin Psychiatry 2008; 45 Suppl 1.
8. Truven Health Analytics. Micromedex 2.0. http://www.micromedex.com/ . 2013.
9. Substance Abuse and Mental Health Services Administration (US). Substance abuse: clinical issues in intensive outpatient treatment. Treatment Improvement Protocol (TIP) Series, No. 47. http://store.samhsa.gov/product/TIP-47-Substance-Abuse-Clinical-Issues-in-IntensiveOutpatient-Treatment/SMA13-4182. 2006.
10. Brahm NC et al. Commonly prescribed medications and potential false-positive urine drug screens. Am J Health Syst Pharm 2010; 67:1344–1350.
11. Shoptaw SJ et al. Treatment for amphetamine psychosis. Cochrane Database Syst Rev 2009;CD003026.
12. Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001; 178:116–122.
13. Hall W et al. Long-term cannabis use and mental health. Br J Psychiatry 1997; 171:107–108.
14. Arseneault L et al. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry 2004; 184:110–117.
15. Budney AJ et al. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 2004; 161:1967–1977.

Interactions between 'street drugs' and prescribed psychotropic drugs

There are some significant interactions between 'street drugs' and drugs that are prescribed for the treatment of mental illness. Information comes from case reports or theoretical assumptions, rarely from systematic investigation. A summary can be found in Table 6.14, but remember that the evidence base is poor. Always be cautious.

In all patients who misuse street drugs:

• Infection with hepatitis B and C is common. The associated liver damage may lead to a reduced ability to metabolise other drugs and increased sensitivity to adverse effects.
• Infection with HIV is common.^1,2 Antiretroviral drugs are involved in pharmacokinetic interactions with a number of prescribed drugs. For example, ritonavir can decrease the metabolism of Ecstasy and precipitate toxicity, and a number of antiretrovirals can increase or decrease methadone metabolism;³ see section on 'HIV' in Chapter 7 for a summary.
• Prescribed drugs may be used in the same way as illicit drugs (i.e. erratically and not as intended). Large quantities of prescribed drugs should not be given to outpatients.
• Additive or synergistic effects of respiratory depressants may play a contributory role in deaths from overdose with methadone or other opioid agonists.⁴ Caution is needed in prescribing sedative medicines such as benzodiazepines.

Acute behavioural disturbance

Acute intoxication with street drugs may result in behavioural disturbance. Non-drug management is preferable. If at all possible a urine drug screen should be performed to determine the drugs that have been taken before prescribing any psychotropic. A physical examination should be done if possible (BP, TPR and ECG).

If intervention with a psychotropic is unavoidable, promethazine 50 mg or olanzapine 10 mg po/IM are probably the safest options. Temperature, pulse, respiration and blood pressure must be monitored afterwards. Benzodiazepines are commonly misused with other street drugs and so standard doses may be ineffective in tolerant users. Interactions are also possible (see Table 6.14). Try to avoid the use of benzodiazepines: they are unlikely to be effective at standard clinical doses.

Table 6.14 Interactions between 'street drugs' and psychotropics

References

1. Vocci FJ et al. Medication development for addictive disorders: the state of the science. Am J Psychiatry 2005; 162:1432–1440.
2. Tsuang J et al. Pharmacological treatment of patients with schizophrenia and substance abuse disorders. Addict Disord Treat 2005; 4:127–137.
3. Gruber VA et al. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV /AIDS Rep 2010; 7:152–160.
4. National Institute for Health and Clinical Excellence. Drug misuse: opioid detoxification. Clinical Guideline 52, 2007.
5. Department of Health. Drug misuse and dependence. UK guidelines on clinical management. London: DH; 2007.
6. Gowing LR et al. The health effects of ecstasy: a literature review. Drug Alcohol Rev 2002; 21:53–63.
7. Zullino DF et al. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol 2002; 17:141–143.
8. Green AI et al. Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Schizophr Res 2003; 60:81–85.
9. Wines JD, Jr. et al. Opioid withdrawal during risperidone treatment. J Clin Psychopharmacol 1999; 19:265–267.
10. Uehlinger C et al. Increased (R)-methadone plasma concentrations by quetiapine in cytochrome P450s and ABCB1 genotyped patients. J Clin Psychopharmacol 2007; 27:273–278.
11. Poling J et al. Risperidone for substance dependent psychotic patients. Addict Disord Treat 2005; 4:1–3.
12. Albanese MJ et al. Risperidone in cocaine-dependent patients with comorbid psychiatric disorders. J Psychiatr Pract 2006; 12:306–311.
13. Sattar SP et al. Potential benefits of quetiapine in the treatment of substance dependence disorders. J Psychiatry Neurosci 2004; 29:452–457.
14. Grabowski J et al. Risperidone for the treatment of cocaine dependence: randomized, double-blind trial. J Clin Psychopharmacol 2000; 20:305–310.
15. Kishi T et al. Antipsychotics for cocaine or psychostimulant dependence: systematic review and meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry 2013; 74:e1169–e1180.
16. Kampman KM et al. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend 2003; 70:265–273.
17. Farren CK et al. Significant interaction between clozapine and cocaine in cocaine addicts. Drug Alcohol Depend 2000; 59:153–163.
18. Benowitz NL et al. Effects of delta-9-tetrahydrocannabinol on drug distribution and metabolism. Antipyrine, pentobarbital, and ethanol. Clin Pharmacol Ther 1977; 22:259–268.
19. Hemeryck A et al. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab 2002; 3:13–37.
20. Bush E et al. A case of serotonin syndrome and mutism associated with methadone. J Palliat Med 2006; 9:1257-1259.
21. Pani PP et al. Antidepressants for cocaine dependence and problematic cocaine use. Cochrane Database Syst Rev 2011;CD002950.
22. Fletcher PJ et al. Fluoxetine, but not sertraline or citalopram, potentiates the locomotor stimulant effect of cocaine: possible pharmacokinetic effects. Psychopharmacology (Berl) 2004; 174:406–413.
23. Silins E et al. Qualitative review of serotonin syndrome, ecstasy (MDMA) and the use of other serotonergic substances: hierarchy of risk. Aust N Z J Psychiatry 2007; 41:649–655.
24. Soto PL et al. Citalopram enhances cocaine's subjective effects in rats. Behav Pharmacol 2009; 20:759–762.
25. Miller BL et al. Neuropsychiatric Effects of Cocaine: SPECT Measurements. In: Paredes A, Gorelick DA, eds. Cocaine: Physiological and Physiopathological Effects. 1 ed. New York: Haworth Press; 1993. 47–58.
26. Roldan CJ, Habal R. Toxicity, cocaine. http://www.emedicine.com/ . 2004.

Further reading

Hunt GE et al. Psychosocial interventions for people with both severe mental illness and substance misuse. Cochrane Database Syst Rev 2013; 10:CD001088