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CHAPTER 4 CENTRAL NERVOUS SYSTEM Approved by East Sussex Health Economy Medicines Committee First line drugs –drugs which are recommended in both primary and secondary care Second line drugs – alternatives (often in specific conditions) in both primary and secondary care Specialist drugs – Drugs where a specialist input is needed (see introduction for definition) Controlled drugs are highlighted with the symbol Specialist only drugs – prescribing within specialist service only . Full details of the regulations appear in the BNF. Page: 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 Date 1/13 1/13 5/13 6/13 8/13 10/13 01/14 04/14 06/14 07/14 11/14 01/15 03/15 04/15 07/15 12/15 03/16 08/16 09/16 10/16 01/17 04/17 Hypnotics and anxiolytics Drugs used in psychoses and related disorders Antidepressant drugs Central nervous system stimulants and drugs used for ADHD Drugs used in the treatment of obesity Drugs used in nausea and vertigo Analgesics Antiepileptics Drugs used in parkinsonism and related disorders Drugs used in substance dependence Drugs for dementia Revision 4.7.4 (NICE guidance) 4.3 (NICE guidance), 4.3.4(MHRA safety update), 4.4 (MHRA drug safety update), 4.8.1 (NICE guidance) 4.11 (Minor amendment) 4.7.1 (Minor amendment) 4.1 (drug addition), 4.4 (drug addition) 4.1 (minor amendment) 4.2 (NICE guidance) 4.6 (EMA safety update) 4.7(NICE guidance) 4.8 (MHRA update) 4.2.2 (Drug addition) 4.6 (MHRA safety update) 4.7 (Minor amendment) 4.8( drug addition) 4.2 (Drug addition) 4.10 (NICE guidance) 4.11 (Minor amendment) 4.0 (NICE guidance), 4.7.3 (section update) 4.2.3, 4.8 (MHRA safety update), 4.10 (NICE guidance) 4.3 (NICE guidance) 4.2.1 (minor amendment), 4.2.2 (Drug deletion) 4.4 (minor amendment) 4.3 (NICE guidance) 4.4(formulation replacement) 4.6 (drug addition) 4.4, 4.6 (NICE Guidance) 4.11 (NICE guidance) 4.4 (Drug addition); 4.2.2 (drug addition) 4.7 (Drug addition), NICE guidance 4.2, 4.8 (MHRA safety update) First line drugs Second line drugs Contributors G Ells A Luck G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells G Ells Specialist drugs 1 2 4 10 16 18 19 22 30 34 35 37 Specialist only drugs Considerations for women of childbearing potential: see NICE CG 192 - Antenatal and postnatal mental health: clinical management and service guidance (Dec 2014) 4.1 Hypnotics and anxiolytics 4.1.1 Hypnotics Zolpidem Tablets 5mg, 10mg Zopiclone Tablets 3.75 mg, 7.5 mg Clomethiazole Capsules 192mg Elixir 250mg in 5ml (equivalent to 192mg clomethiazole base) Loprazolam Tablets 1mg Temazepam Tablets 10 mg, 20 mg Oral solutionSF 10 mg in 5 ml Sodium Oxybate Oral solution 500mg in 1 ml Notes: 1. Hypnotics should not be used regularly and should be reserved for the acutely distressed. 2. Hynpotics are only licensed and recommended for short-term use. They should not be given for more than 3 weeks (preferably 1 week only). Intermittent use is desirable with the omission of some doses. “Z–hypnotics” such as zolpidem, are recommended for short-term use only up to four weeks. 3. Hypnotics should be avoided in the elderly who are at risk of becoming ataxic and confused and so liable to fall and injure themselves. 4. Zolpidem is the first line choice of hypnotic in all patients including the elderly. 5. Loprazolam and temazepam both have short duration of action and have no active metabolites but are reserved for specialist initiation because of their high cost. 6. Oxazepam can be given as a single dose given at night for insomnia associated with anxiety 7. Temazepam is a Schedule 3 controlled drug but is exempt from prescription and handwriting requirements. Prescribers are advised to limit quantities to no more than is sufficient to meet the patient’s clinical needs for up to 30 days 8. Nitrazepam has not been included as it is not recommended due to its prolonged action. 9. Although zolpidem and zopiclone are not benzodiazepines they act on the same receptors as benzodiazepine. They are not licensed for long-term use and there is evidence of dependence in a small number of patients. 10. Chloral hydrate and its derivatives, such as chloral betaine, are considered less suitable for prescribing and therefore have not been included. They were formerly popular hypnotics for children, although the use of hypnotics in children is not usually justified. There is no convincing evidence that they are particularly useful in the elderly. 11. Promethazine is sometimes used as an alternative to benzodiazepines and other hypnotics for nighttime sedation. However, residual sedation may occur the following day and its sedative effects may diminish after a few days of continued treatment associated with headache, psychomotor impairment and antimuscarinic effects. 12. Promethazine injection may be used within the Sussex Partnership Trust (SPT) in the management of the acutely disturbed patient (unlicensed use) in accordance with Trust guidelines. 13. Sodium oxybate is licensed for use in narcolepsy with cataplexy under the supervision of a specialist in sleep disorders. The specialist will initiate and titrate the dose according to response, which may take up to 3 months. Patients who respond to treatment are suitable for shared care once their dose has been stabilised. Details of the shared care guidelines can be found here First line drugs Second line drugs Specialist drugs 2 Specialist only drugs NICE guidance: Insomnia - newer hypnotic drugs - zaleplon, zolpidem and zopiclone for the management of insomnia Technology Appraisal No. 77 (April 2004) NICE has made the following recommendations about the use of zaleplon, zolpidem and zopiclone to treat insomnia. NICE recommends that doctors should consider using non-medicine treatments, and then, if they think that a hypnotic medicine is the appropriate way to treat severe insomnia that is interfering with normal daily life, they should prescribe one for only short periods of time and strictly according to the licence for the drug. Because there is no firm evidence of differences in the effects of zaleplon, zolpidem, zopiclone and the shorter-acting benzodiazepines, NICE recommends that doctors should prescribe the cheapest drug, taking into account the daily dose required and the cost for each dose. Treatment should only be changed from one of these hypnotics to another if side effects occur that are directly related to the medicine. If treatment with one of these hypnotic medicines does not work, the doctor should not prescribe one of the others. 4.1.2 Anxiolytics Please refer to NICE clinical guideline 113: Generalised Anxiety disorder and panic disorder (with or without agoraphobia in adults Tablets 2 mg, 5 mg, 10 mg Diazepam Oral Solution 2 mg in 5 ml Oral Solution 5 mg in 5 ml (“Blacklisted”) Inj (emulsion - Diazemuls®) 10 mg in 2 ml Propranolol Tablets 10 mg, 40 mg Lorazepam Tablets 1mg Injection 4mg in 1ml Oxazepam Tablets 10mg, 15mg Buspirone Tablets 5mg, 10mg Chlordiazepoxide Capsule 5mg, 10mg First line for acute agitation in secondary care Notes: 1. CSM advice: Benzodiazepines should only be prescribed for short-term use (2-4 weeks) and for anxiety which is severe, disabling or subjecting the individual to unacceptable distress. The use for short-term, mild anxiety is inappropriate and unsuitable. 2. Diazepam has a sustained action. Lorazepam and oxazepam are shorter-acting and may be preferred for patients with hepatic impairment, but they carry a greater risk of withdrawal symptoms. 3. Diazepam is the preferred benzodiazepine for benzodiazepine withdrawal regimes. 4. Lorazepam (oral) is the first line choice for the treatment of acute agitation in secondary care settings. 5. Propranolol is useful in situational anxiety, with prominent somatic symptoms such as tachycardia, sweating and tremor. Propranolol is unlikely to be of benefit for muscle tension or patients with predominately psychological symptoms such as worry, tension or fear. 6. Lorazepam injection is used within SPT for the management of acutely disturbed patients, for rapid tranquillisation, in accordance with Trust guidelines. 7. Response to treatment with buspirone may take up to 2 weeks. It is licensed for short-term use only. 8. Chlordiazepoxide is included as a specialist drug to be prescribed for the management of alcohol withdrawal. 9. Some SSRIs are licensed for the treatment of generalised anxiety disorder (GAD). 4.1.3 Barbiturates Note: 1. Intermediate-acting barbiturates no longer have a place in therapy, except for those already taking barbiturates for the management of severe intractable insomnia. 2. Phenobarbital is occasionally used in epilepsy; use as a sedative is unjustified. 3. Thiopental is used in anaesthesia. First line drugs Second line drugs Specialist drugs 3 Specialist only drugs 4.2 Drugs used in psychoses and related disorders 4.2.1 Antipsychotic drugs Notes: 1. Please refer to the NICE guidance on the following pages for prescribing for patients presenting with acute psychosis. 2. Prescribing should only be commenced after seeking specialist advice, except in circumstances where prescribers feel confident to prescribe e.g. an existing patient suffering a recurrent acute episode previously managed on antipsychotic treatment. 3. Where a specialist opinion has been sought, GP’s will be asked to continue prescribing, where appropriate. Further guidance is available on the following link: Prescribing Guidelines & Shared Care Prescribing Framework (September 2005) Atypical (Non-Traditional) Antipsychotics NICE guideline on the management of Schizophrenia Acute episode Approach with optimism and empathy Provide comprehensive assessment Principles of treatment Work in partnership with service users and carers Ensure confidentiality at all times Provide comprehensive information Include written material Use clear language Ensure culturally appropriate Ask for informed consent before treatment starts Consult advance directives Check with care co-ordinator, notes or GP Provide comprehensive care plan for multi-disciplinary approach Clinical, emotional and social needs Provide social, group and physical activities Discuss antipsychotics with service user and decide jointly on which to use If service user cannot make preference known, consult advance directive If no advance directive available, consider an atypical antipsychotic as first line If first episode, offer atypical antipsychotic Use lower end of standard dose range in BNF If a conventional antipsychotic is chosen: Use 300-1000mg chlorpromazine equivalents per day for ≥ 6 weeks (rather than chlorpromazine) Use minimum effective dose Clinical response Don’t use loading doses of antipsychotics Don’t prescribe antipsychotics for concurrent use except to cover short changeover periods If inadequate response Consider changing class of drug Side effects Monitor regularly If antipsychotic is tolerable Don’t change drug If unacceptable side effects emerge with conventional antipsychotic Marked behavioural disturbance First line drugs EPS/akathisia Weight gain/diabetes Sexual dysfunction Lethargy Effects on eyes Consider an atypical antipsychotic See rapid tranquillisation algorithm Second line drugs Specialist drugs 4 Specialist only drugs Towards end of acute episode Offer service user the opportunity to give his/her Service user focus account of the illness written in the case notes Enable service user to discuss his/her experiences Enable carers to discuss their experiences Plan for recovery Full needs assessment Include occupational potential and opportunity Assess and plan for psychological interventions Family interventions, or CBT Continue on antipsychotic for 1-2 years Medication advice Only withdraw gradually After withdrawal, monitor for relapse for 2 years after acute episode NICE guideline on the management of schizophrenia Management of poor response to treatment and treatment resistance Inadequate response to treatment Ensure adequate dose of antipsychotic has been tried over sufficient time to allow response Inadequate response despite adequate trial of antipsychotic Consider possible causes: Comorbid substance misuse Poor treatment adherence Physical illness Treat co-existing problem Consider further psychological intervention CBT or family interventions: For more than 6 months With more than 10 planned sessions Consider trial of olanzapine or risperidone for 6-8 weeks if not tried previously Inadequate response Consider trial of clozapine Inadequate response to full trial Full assessment and treatment review Very cautiously consider trial of additional antipsychotic combined with clozapine First line drugs Second line drugs Specialist drugs 5 Consider further psychological intervention Specialist only drugs NICE guideline on the management of schizophrenia – Management of physical care Provide routine physical health checks To be provided usually in primary care Monitor increased risk of cardiovascular disease Consider: Primary prevention (use standard scoring systems) Secondary prevention in those with established heart disease Specific monitoring in relation to certain antipsychotic drugs (see BNF) Promote healthy lifestyle For example, good diet, exercise and smoking cessation Monitor side effects EPS/akathisia Weight gain/diabetes Sexual dysfunction Focus on: Neurological Consider: Extrapyramidal side effects Tardive dyskinesia If no contact with primary care Secondary care should monitor physical health Lethargy Effects on eyes Metabolic and endocrine Weight Other side effects of medication Consider: Routine urine/blood screen for diabetes Selective screen for other endocrine disorders (high prolactin) Consider routine weight monitoring Photosensitivity and chlorpromazine Cover key areas on regular basis; agree frequency with service user and document in notes Regular monitoring Primary and secondary care services identify/allocate and document responsibilities for monitoring physical health Note: Prescribing should only be commenced after seeking specialist advice, except in circumstances where prescribers feel confident to prescribe e.g. an existing patient suffering a recurrent acute episode previously managed on antipsychotic treatment. “Typical” antipsychotics Butyrophenones:- Haloperidol Capules 500microgram Tablets 1.5mg, 5mg, 10mg, 20mg Oral liquidSF 2 mg in 1 ml, Injection 5 mg in 1 ml Tablets 25 mg, 50mg, 100 mg Oral solution 25 mg in 5 ml, 100 mg in 5 ml Tablets 1 mg, 5 mg Oral solution 5 mg in 5 ml Syrup 1 mg in 5 ml Tablets 200mg, 400 mg Oral solutionSF 200 mg in 5 ml Phenothiazines:- Chlorpromazine Trifluoperazine Substituted benzamide:- Sulpiride “Atypical” antipsychotics Tablets 50 mg, 100 mg 200 mg, 400 mg Amisulpride First line drugs Oral solution 100 mg in 1ml Second line drugs Specialist drugs 6 Specialist only drugs Aripiprazole Tablets 5mg,10 mg,15 mg,30 mg Orodispersible tablet 10 mg,15 mg Oral solution 1mg in 1 ml Clozapine Tablets 25 mg 100 mg Lurasidone▼ Latuda® Tablets 18.5mg, 37mg, 74mg Olanzapine Tablets 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15mg, 20mg Orodispersible tablet (Velotab®) 5 mg, 10 mg, 15mg, 20mg Tablets 25 mg, 100 mg, 150 mg, 200 mg, 300mg Prolonged release tablets (XL) 50mg, 200mg, 300mg, 400mg Tablets 500 micrograms, 1 mg, 2 mg, 3 mg, 4 mg, 6 mg Orodispersible tablet (Quicklets®) 0.5mg, 1mg, 2mg, 3mg, 4mg Liquid 1 mg in 1 ml Quetiapine Risperidone Daily formulation Notes: 1. Clozapine is usually prescribed in secondary care only. All patients must be registered with the appropriate clozapine monitoring service. 2. Olanzapine has been associated with an increased risk of hyperglycaemia, diabetes mellitus and exacerbations of diabetes. Therefore the CSM (Ref: Current Problems in Pharmacovigilance, Volume 28, April 2002) recommends that in diabetes and in patients with risk factors for diabetes mellitus, appropriate clinical and blood glucose monitoring is conducted. All other antipsychotics have also been implicated with development of metabolic syndromes. 3. Quetiapine is available in a both immediate release (IR) and prolonged release formulations (MR, SR, XL). Care should be taken in ensuring that the correct formulation is prescribed for the dosing frequency. 4. Lurasidone is a new antipsychotic which appears to have a favourable metabolic profile. It has been approved for use in the following situations: · Third line use after two previous antipsychotics (of which one must be aripiprazole) have been tried and at least one was effective but not tolerated AND · Second line use in patients identified as having significant metabolic risk factors, eg. diabetes, obesity provided aripiprazole has been tried first and has been found to be ineffective or not tolerated. Prescribers should be cautious when considering the use of higher doses as there is little evidence to support this approach. Atypical antipsychotic drugs and stroke. Prescribing Advice: Committee on Safety of Medicines has advised that risperidone or olanzapine should not be used for the treatment of behavioural symptoms of dementia. Use of risperidone for the management of acute psychotic conditions in elderly patients who also have dementia should be limited to short-term and should be under specialist advice (olanzapine is not licensed for management of acute psychosis). Prescribers should consider carefully the risk of cerebrovascular events before treating any patient with a previous history of stroke or transient ischaemic attack. Consideration should also be given to other risk factors for cerebrovascular disease including hypertension, diabetes, current smoking and atrial fibrillation. Patients with dementia who are currently treated with an atypical antipsychotic drug should have their treatment reviewed. Although there is presently insufficient evidence to include other antipsychotics in these recommendations, there is a weight of opinion that the risk of stroke may be applicable to all antipsychotics and therefore prescribers should bear in mind that a risk of stroke cannot be excluded. First line drugs Second line drugs Specialist drugs 7 Specialist only drugs Atypical Antipsychotics – Suggested Choices: 1st Choice Consideration Alternatives First episode psychosis or acute relapse, where drug choice is free of contraindications & other considerations Predominantly negative symptoms Symptomatic, acute extrapyramidal side-effects or dystonic reaction1 Symptomatic hyperprolactinaemia1 Significant weight gain1 Cheapest atypical, excluding clozapine Traditional antipsychotic Amisulpride or olanzapine Quetiapine or olanzapine Risperidone Aripiprazole or risperidone (<6mg/day) Aripiprazole or quetiapine Amisulpride or aripiprazole Impaired glucose tolerance1 Significant sedation1 Significant (postural) hypotension1 QT prolongation1 Treatment refractory condition (unresponsive to two adequate trials of antipsychotic therapy) Amisulpride or risperidone Aripiprazole or amisulpride Amisulpride or aripiprazole Amisulpride Clozapine Olanzapine Lurasidone. There is considerable patient variability to this risk. Weight management and lifestyle advice should be made available. In some cases metformin may be recommended to manage weight gain which has not responded to conventional management. Aripiprazole, lurasidone Risperidone Olanzapine Olanzapine or aripiprazole The relative risks of blood dyscrasias, other side effects, and the need for blood tests must be fully discussed with the patient (and carer). 1 History of this event and/or specific need to avoid it. Note: This table provides only a rough guide to treatment choice. Relative incidence and/or severity of side effects must always be balanced against predicted efficacy of the medication, suitability and predicted concordance etc. Informed patient choice must also be taken into consideration. NICE – Guidance on the use of newer (atypical) antipsychotic drugs for the treatment of schizophrenia. Number 43, June 2002 1.1 The individual and the clinician should make the choice of antipsychotic drug jointly responsible for treatment based on an informed discussion of the relative benefits of the drugs and their side-effect profiles. The individual's advocate or carer should be consulted where appropriate. 1.2 It is recommended that the oral atypical antipsychotic drugs amisulpride, olanzapine, quetiapine, risperidone and zotepine be considered in the choice of first-line treatments for individuals with newly diagnosed schizophrenia. 1.3 The oral atypical antipsychotic drugs listed in Section 3.3 (NICE No. 43) should be considered as treatment options for individuals currently receiving typical antipsychotic drugs who, despite adequate symptom control, are experiencing unacceptable side effects, and for those in relapse who have previously experienced unsatisfactory management or unacceptable side effects with typical antipsychotic drugs. The decision as to what are unacceptable side effects should be taken following discussion between the patient and the clinician responsible for treatment. 1.4 It is not recommended that, in routine clinical practice, individuals’ change to one of the oral atypical antipsychotic drugs if they are currently achieving good control of their condition without unacceptable side effects with typical antipsychotic drugs. 1.5 In individuals with evidence of treatment-resistant schizophrenia (TRS), clozapine should be introduced at the earliest opportunity. TRS is suggested by a lack of satisfactory clinical improvement despite the sequential use of the recommended doses for 6 to 8 weeks of at least two antipsychotics, at least one of which should be an atypical. 1.6 The clinician responsible for treatment and the multidisciplinary team regarding concordance with medication should perform a risk assessment, and depot preparations should be prescribed when appropriate. 1.7 Where more than one atypical antipsychotic drug is considered appropriate, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed. 1.8 When full discussion between the clinician responsible for treatment and the individual concerned is not possible, in particular in the management of an acute schizophrenic episode, the oral atypical drugs should be considered as the treatment options of choice because of the lower potential risk of extrapyramidal symptoms (EPS). In these circumstances, the individual's carer or advocate should be consulted where possible and First line drugs Second line drugs Specialist drugs 8 Specialist only drugs appropriate. Although there are limitations with advanced directives regarding the choice of treatment for individuals with schizophrenia, it is recommended that they are developed and documented in individuals' care programmes whenever possible. 1.9 Antipsychotic therapy should be initiated as part of a comprehensive package of care that addresses the individual's clinical, emotional and social needs. The clinician responsible for treatment and key worker should monitor both therapeutic progress and tolerability of the drug on an ongoing basis. Monitoring is particularly important when individuals have just changed from one antipsychotic to another. 1.10 Atypical and typical antipsychotic drugs should not be prescribed concurrently except for short periods to cover change over of medication. 1.11 NICE guidelines (TA 213: Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years (January 2011) recommends that aripiprazole is a treatment option for schizophrenia in people aged 15 to 17 years who have contraindications to or are intolerant of risperidone, or who are not adequately controlled on risperidone. 1.12 NICE TA 292 (July 2013) recommends the use of aripirazole within its marketing authorisation to treat severe manic episodes in bipolar 1 disorder in adolescents (13 years and over). 4.2.2 Antipsychotic depot injections Notes: 1. Nodules, muscle granulomas, abscesses or fibrosis occur in 20% of patients. These reactions can be minimised by: Using the smallest volume possible Using concentrates where available (ideally no more than 2 ml / site) Administering at the lowest frequency. Avoid weekly injections if possible. Use a good technique: z-track advisable Rotate injection sites 2. Risperidone injection should be initiated in accordance with Sussex Partnership Foundation Trust protocol 3. It is important to establish whether the patient has an allergy to sesame oil or coconut oil before selecting appropriate treatment, although the incidence of such allergy is extremely low. 4. Paliperidone palmitate is available as a monthly and a 3 monthly depot injection. The 3 monthly preparation is only available to patients who have been stable on the monthly preparation for at least 6 months. Injection 400mg powder for reconstitution Aripiprazole (Abilify maintena®) Flupentixol decanoate (Depixol®) Injection 20 mg / ml - 20mg in 1ml, 40mg in 2ml, Injection 100 mg /ml (“Concentrate”) - 50mg in 0.5ml, 100mg in 1ml, Injection 200 mg / ml (“Low-volume”) - 200mg in 1ml Diluent = Coconut oil Fluphenazine decanoate (Modecate®) Injection 25 mg / ml – 12.5 mg in 0.5 ml, 25 mg in 1 ml, 50 mg in 2 ml Injection 100 mg / ml (“Concentrate”) – 50 mg in 0.5 ml, 100 mg in 1 ml Diluent = Sesame oil Haloperidol (Haldol®) Injection 50 mg in 1 ml Injection 100 mg in 1 ml Diluent = Sesame oil Risperidone Prolonged release injection 25mg, 37.5mg, 50mg Prolonged release suspension for injection 25mg, 50mg, 75mg, 100mg, 150mg Prolonged release suspension for injection 175mg, 263mg, 350mg, 525mg Injection 200 mg in 1 ml Injection 500 mg in 1 ml (“Concentrate”) (Risperdal® Consta) Paliperidone palmitate Xepilon® (monthly injection) Paliperidone palmitate Trevicta® (3 monthly injection) Zuclopenthixol decanoate (Clopixol®) First line drugs Diluent = Coconut oil Second line drugs Specialist drugs 9 Specialist only drugs 4.2.3 Carbamazepine Antimanic drugs Refer to Section 4.8.1 Lithium carbonate (Priadel®) M/R tablet 200mg, M/R tablet 400mg Lithium citrate (Priadel®) Valproic acid as semisodium valproate SF syrup 520mg (equiv to 5.4 mmol Li+) in 5ml (5ml ≡ 200mg lithium carbonate MR tablets) Tablets E/C 250mg, 500mg (Depakote®) Notes: For guidance on the treatment of Bipolar disorder see NICE CG 185: Bipolar disorder: the assessment and management of bipolar disorder in adults, children and young people in primary and secondary care 1. Different brands of lithium and carbamazepine are not equivalent. Please specify the brand when prescribing lithium and carbamazepine to ensure that the patient receives the same preparation. 2. It is not intended that patients stabilised on Camcolit® should be changed to Priadel®. Priadel® should be preferred for all new patients. 3. Valproic acid (as semisodium valproate Depakote®) should be prescribed by brand to avoid potential confusion with sodium valproate. 4. MHRA drug safety update (April 2017): Children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and/or congenital malformations (in approximately 10% of cases) o do not prescribe valproate medicines for epilepsy or bipolar disorder in women and girls unless other treatments are ineffective or not tolerated; migraine is not a licensed indication o ensure women and girls taking valproate medicines understand the 30–40% risk of neurodevelopmental disorders and 10% risk of birth defects and are using effective contraception o valproate use in women and girls of childbearing potential must be initiated and supervised by specialists in the treatment of epilepsy or bipolar disorder 5. Carbamazepine may be used for the prophylaxis of bipolar disorder in patients unresponsive to lithium; it seems to be particularly more effective in patients with rapid cycling manic-depressive illness (4 or more episodes per year). 6. Olanzapine, quetiapine and risperidone are all licensed for the treatment of episodes of mania. Olanzapine is licensed for maintenance therapy. 7. In an acute attack of mania, treatment with a benzodiazepine or an antipsychotic drug (see above), is usually required because it may take a few days for lithium to exert it’s antimanic effect. 8. Sodium valproate is used for the treatment of manic episodes associated with bipolar disorder or psychoses and continuation therapy, but is unlicensed for this indication. Lamotrigine is used for the long-term management of bipolar affective disorder but is unlicensed for this indication. Antidepressant drugs 4.3 Refer to NICE Clinical Guideline 90 – Depression in adults (update) (December 2004) NICE Clinical Guideline 28 – Depression in children and young adults: Identification and management in primary, community and secondary care (update March 2015) Antidepressants – prescribing advice Summary 1. When an antidepressant is to be prescribed in routine care, it should be a selective serotonin reuptake inhibitor (SSRI), because SSRIs are as effective as tricyclic antidepressant (TCAs) but are less likely to be discontinued because of side effects. 2. All patients prescribed antidepressants should be informed that although the drugs are not associated with tolerance and craving, discontinuation and withdrawal symptoms may occur on stopping, missing doses or, occasionally on reducing the dose of the drug. These symptoms are usually mild and self-limiting but can occasionally be severe, particularly if the drug is stopped abruptly. All patients should be informed about the delay in onset of effect of antidepressants, the anticipated time course of treatment, and the need to take medication as prescribed. Written information should be made First line drugs Second line drugs Specialist drugs 10 Specialist only drugs available appropriate to the patient’s needs. Key Treatment Considerations in Depression Patients presenting in Primary Care with mild depression who do not want an intervention or who in the opinion of the GP, may recover with no intervention, should be encouraged to re-attend for a further assessment within the next two weeks. This is “watchful waiting”. Healthcare professionals should consider recommending a guided selfhelp programme based on cognitive behavioural therapy (CBT), if this is available. 1. Antidepressants are not recommended for the initial treatment of mild depression, (normally assessed and treated in Primary Care), because the risk-benefit ratio is poor. However, in moderate depression antidepressants should be offered to all patients routinely, before psychological intervention. 2. When patients present initially with severe depression, a combination of antidepressant and individual CBT should be considered as the combination is more cost effective than either treatment on its own. 3. For patients with a moderate or severe depressive episode, antidepressants should be continued for at least 6 months after remission. The need for continued therapy should then be reassessed, taking into consideration the number of previous episodes, the presence of residual symptoms, and any concurrent psychosocial difficulties. 4. Patients who have had two or more depressive episodes in the recent past and who have experienced significant functional impairment during the episodes, should be advised to continue antidepressants for two years after remission. 5. For patients whose depression is treatment resistant the combination of antidepressants with CBT should be considered. 6. CBT should be considered for patients with recurrent depression who have relapsed despite antidepressant treatment or if a preference for psychological therapies is expressed. 7. If a patient fails to respond to the first antidepressant prescribed, consideration must be given to whether the drug has been taken correctly at the prescribed dose. 8. If response to a standard dose is inadequate and there are no significant side effects, the dose should be gradually increased within the schedule suggested by the Summary of Product Characteristics (SPC / data sheet). 9. If there is no response after one month, consideration should be given to switching to another antidepressant. If there has been a partial response, the decision to switch should be delayed for a further two-week assessment period. (The switch may be to another antidepressant of the same class or to one of a different class). 10. For older patients with depression, give antidepressant treatment at an age appropriate dose for a period of at least six weeks before considering that it may be ineffective. If there is partial response within this period, continue treatment for a further six week assessment period. 11. When prescribing for older patients consider the significantly increased risk of drug interactions, adverse effects and intolerance. 12. In the treatment of patients in secondary care, consideration may be given to the re-introduction of any previous treatments that were inadequately delivered or adhered to in primary care. 13. The management of treatment resistant depression should normally only be undertaken by mental health specialists. When considering specialist therapies such as antidepressants in high dose or in combination, augmentation with lithium, anticonvulsants or antipsychotics, or thyroid supplementation etc, full regard must be given to the risks associated with such options and the level of evidence to support their use. 14. The dose of antidepressant used for prevention of relapse should be the same as that at which acute treatment was effective. 15. Patients who have had multiple episodes of depression and who have had good response to treatment with an antidepressant plus lithium should remain on this combination for at least six months. If one drug is then to be discontinued it should be the lithium rather than the antidepressant. 16. Patients with psychotic depression will normally need to be treated with a combination of antidepressant and antipsychotic medication. Choice of Antidepressant in Depression In moderate to severe depression, for routine care use an SSRI. These are as effective as TCAs but are less likely to be discontinued due to side effects. 1. Consider using a generic form of SSRI (eg fluoxetine or citalopram) as first line, but note the higher propensity for drug interactions with fluoxetine. 2. First choices for a second antidepressant should normally be a different SSRI or mirtazapine, or possibly a TCA, (but usually not dosulepin). 3. When switching from one antidepressant to another, consideration must be given to the potential need for a washout period or for cross-tapering, and to the need for gradual and modest incremental dose increases. Also, to the risk of drug interactions and the risk of serotonin syndrome. 4. Whenever possible, treatment with antidepressant medication should be with a single agent. 5. St John’s Wort may be of benefit in mild to moderate depression but normally should not be prescribed or advised because of uncertainties about appropriate doses, the quality of the preparation and the potential for serious interactions with other drugs. First line drugs Second line drugs Specialist drugs 11 Specialist only drugs 6. In chronic depression, antidepressant medication should be considered with CBT whenever possible. 7. In chronic depression, patients who have not responded to a SSRI should be considered for treatment with a TCA. Particularly men, as they are usually more tolerant of the side effects attributable to these drugs (imipramine should normally be avoided in female patients). 8. In treatment resistant depression, consideration may be given to the use of venlafaxine at doses in line with the recommendations of the BNF and the SPC. (Although consideration must also be given to the risk of cardiotoxicity). 9. The monoamine oxidase inhibitor phenelzine can be considered for patients who have failed to respond to alternative antidepressants and who are prepared to tolerate the side effects and dietary restrictions associated with its use. 10. Tranylcypromine should be avoided, due to its significant stimulant action and the general opinion that it is more hazardous in use. (MAOIs are not normally used in primary care). 11. All patients receiving phenelzine (or other MAOIs) require careful monitoring (including blood pressure) and prescribers must ensure that patients receive clear and full advice regarding interaction with other medication and with foodstuffs. Specific considerations 1. Paroxetine and venlafaxine are most likely to cause withdrawal symptoms due to their short half-lives. 2. Fluvoxamine may be less well tolerated than other SSRIs. 3. Escitalopram, an isomer of citalopram is not included in the formulary but is sometimes used by secondary care. However, it is licensed and has a role in the management of generalised anxiety disorder. 4. Mirtazapine can cause significant sedation and weight gain, and may also cause agranulocytosis. 5. Reboxetine may cause hypokalaemia and is not licensed for use in the elderly. 6. Mianserin can cause agranulocytosis, particularly in older patients and is rarely used. 7. If switching to or from an MAOI antidepressant, a washout period of up to two weeks will be required. 8. Treatments such as dosulepin, MAOIs, combinations of antidepressants and augmentation therapies should only be initiated and managed by specialists, or by GPs with a special interest in mental health. 9. TCAs are cardiotoxic and consideration should be given to their potential risk, particularly in patients assessed as being at risk of self-harm. Of the TCAs and related drugs, dosulepin is the most toxic and lofepramine is the least. 10. Duloxetine (Cymbalta®) belongs to the same class as venlafaxine (SNRI) but appears to produce less cardiotoxicity and was not found to prolong QTc intervals in clinical trials. However, due to the limited clinical data available, it should not be considered for first line use, (nor second-line in routine practice). 17. Trazodone is a particularly sedating antidepressant and may be a useful choice in those patients with associated sleep disturbance. Information the patient should know: The risk of recurrence of depression is high and increases with each episode. The risk of relapse is greatly reduced by taking antidepressants. Antidepressants are effective, not addictive, do not lose their efficacy over time, are not known to cause long-term side effects. Medication needs to be continued at the treatment dose for at least 6 months after you are completely better. If you stop medication suddenly it can lead to unpleasant discontinuation symptoms. If patient drives: advise about possible drowsiness & impaired driving ability. Reaction times may be reduced even if patient doesn’t feel drowsy. Antidepressants – prescribing in special situations Special Situation Breast feeding Low risk Moderate risk High Risk Amitriptyline Tricyclics (most) Venlafaxine Cardiovascular disease Fluoxetine Mirtazepine Trazodone Fluoxetine Citalopram Trazodone Venlafaxine Fluoxetine Fluoxetine Citalopram Mirtazepine Trazodone Venlafaxine Citalopram Diabetes Epilepsy First line drugs Tricyclics Fluoxetine Tricyclics Mirtazepine Tricyclics (most) Second line drugs Specialist drugs 12 Specialist only drugs Citalopram Narrow angle glaucoma Mirtazepine Trazodone Venlafaxine Liver disease Old age Lofepramine Mirtazepine Citalopram Venlafaxine Pregnancy Renal disease Tricyclics Trazodone Mirtazepine Trazodone Venlafaxine Fluoxetine Citalopram Tricyclics Fluoxetine Tricyclics Citalopram Mirtazepine Trazodone Venlafaxine Lofepramine Trazodone Tricyclics (most) Fluoxetine Tricyclics Citalopram Mirtazepine Trazodone Venlafaxine Fluoxetine Citalopram Mirtazepine Fluoxetine Venlafaxine It is not intended to change patients stabilised on non-formulary antidepressants to formulary choice. The following choices are recommended for new patients and when considering an alternative treatment. 4.3.1 Tricyclic and related antidepressant drugs Tricyclic and related antidepressants Amitriptyline Imipramine Lofepramine Clomipramine Trazodone First line drugs Tablets 10 mg, 25 mg, 50 mg Oral solution 25 mg in 5 ml, 50 mg in 5 ml Tablets 10 mg, 25 mg Tablets 70 mg Oral suspension 70 mg in 5 ml Capsule 10mg, 25mg, 50mg Capsules 50 mg, 100 mg Tablets 150 mg LiquidSF 50 mg in 5 ml Second line drugs Specialist drugs 13 For Obsessive Compulsive Disorder only Specialist only drugs Notes: 1. Due to the risk of toxicity in overdose, consider limiting the quantity prescribed on each prescription. 2. Lofepramine is associated with fewer anticholinergic side effects, is less sedating and is considered to be safer in overdose. 3. Amitriptyline, imipramine and clomipramine should be avoided where there is a suicide risk. 4. Dosulepin has been excluded from this formulary. It is more toxic than other tricyclic antidepressants particularly due to its pro-convulsive and cardiac arrhythmic effects and it is very dangerous in overdose. It is associated with an increased risk of ischaemic heart disease even when adjusted for other risk factors. The NICE guidance on the management of depression recommends that dosulepin should only be routinely initiated by specialist mental health professionals (including GPs with a Special Interest in Mental Health). 5. When initiating therapy, start low and increase to a therapeutic dose over 1 – 3 weeks. 6. Weight gain can be significant with tricyclic antidepressants. 7. If the patient drives, always counsel the patient about sedation and slower reaction times. (The latter may occur even if patient doesn’t feel drowsy.) 8. Arrhythmias and heart block occasionally follow the use of tricyclic antidepressants, particularly amitriptyline, and may be a factor in the sudden death of patients with cardiac disease. 9. Renal impairment – Tricyclic antidepressants are excreted by kidneys, therefore, start with low doses and increase slowly. Accumulation may occur causing adverse drug reactions. Dividing total daily dose into 2-3 doses may be helpful. 10. Myocardial infarction – Avoid tricyclic antidepressants if previous MI. Trazodone (see below) may be used but try to avoid any antidepressant therapy for first two months post MI if possible. 11. Elderly and dementia – AVOID tricyclic antidepressants in dementia or where significant cognitive impairment is present. 12. Clomipramine is included for the management of Obsessive Compulsive Disorder only 4.3.2 Monoamine-oxidase inhibitors Notes: 1. No MAOIs have been included as these should only be used on the recommendation of a specialist 2. The BNF classifies phenelzine, isocarboxazid and tranylcypromine as preparations less suitable for prescribing. 3. Hypertensive crisis can occur following ingestion of tyramine or other pressor amines in foods or medication. Patients should avoid consuming large amounts of tyramine-rich food (such as mature cheddar, yeast extracts, red wine and fermented soya bean products) and sympathomimetics (such as ephedrine, pseudoephedrine and phenylpropanolamine). 4. Patients should be advised to take last dose before 3 pm in order to minimise sleep disturbance / insomnia. 4.3.3 Selective serotonin re-uptake inhibitors (SSRIs) Fluoxetine Capsules 20 mg Liquid 20mg in 5ml Citalopram Tablets 10 mg, 20 mg, 40 mg Oral dropsSF (as hydrochloride) 40 mg in 1 ml 8 mg (4 drops) may be considered equivalent to 10 mg tablet Although 60mg capsules are available, it is more cost effective to supply 3 X 20mg First choice for the elderly but see MHRA dose restrictions below Notes: 1. SSRIs are usually the first choice for the management of depression rather than tricyclic antidepressants. 2. Fluoxetine is the SSRI of choice except in the elderly, when citalopram is the product of first choice. 3. Sertraline may be used for Obsessive Compulsive Disorder. 4. Escitalopram may be used for Generalised Anxiety Disorder (GAD). 5. If no / poor response achieved with an SSRI, for optimal effect, switch between classes rather than within a class. This should provide a better therapeutic effect. 6. SSRIs may exacerbate sleep disturbance and cause symptoms such as anxiety, restlessness and agitation initially. If sedation is required or in agitated depression, or panic disorder consider prescribing a benzodiazepine concurrently for the first 1 – 2 weeks (max 4 weeks). Alternatively, a sedating antidepressant can be considered. 7. Advise patients to take their SSRI in the morning as nocte administration may increase sleep disturbance. 8. If there is no response to fluoxetine at lower doses, increasing the dose is unlikely to produce any additional benefit but side effects would be expected to increase. 9. SSRIs have fewer anticholinergic and cardiotoxic effects than tricyclic antidepressants. 10. Sexual dysfunction is more likely to be a complication of treatment with SSRIs, than with TCAs 11. CVA - SSRIs are the treatment of choice in depression post CVA or depression following acquired brain injury (NB Check interactions with warfarin, if appropriate). 12. Parkinson’s disease - SSRIs should be used with caution as there are no controlled trials available and there have been case reports of fluoxetine and paroxetine exacerbating motor symptoms. 13. Arrhythmias or previous MI - SSRIs are preferred over tricyclic antidepressants if post MI. SSRIs are antidepressants of choice if history of arrhythmias 14. Hepatic impairment – restrict doses to lower end of dose range. Avoid in severe liver disease First line drugs Second line drugs Specialist drugs 14 Specialist only drugs 15. MHRA Update December 2011: Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those: With congenital long QT syndrome; With known pre-existing QT interval prolongation; or taking other medicines that prolong the QT interval. ECG measurements should be considered for patients with cardiac disease, and electrolyte disturbances should be corrected before starting treatment. For citalopram, new restrictions on the maximum daily doses now apply: 40 mg for adults; 20 mg for patients older than 65 years; 20 mg for those with hepatic impairment. For escitalopram, the maximum daily dose for patients older than 65 years is now reduced to 10 mg/day; other doses remain unchanged. 4.3.4 Other antidepressant drugs Mirtazapine Tablets 15mg, 30mg, 45mg Venlafaxine Vortioxetine▼ Duloxetine Tablets 37.5mg, 75mg M/R capsules 75mg, 150mg Brintellix®Tablets 5mg, 10mg, 20mg Cymbalta ® Capsules 30 mg, 60 mg Agomelatine▼ Valdoxan® Tablets 25mg In certain circumstances should be specialist initiated only – see notes below Notes: 1. Mirtazapine appears to be safe in overdose and is thought to cause less insomnia, anxiety and agitation. Sexual dysfunction is rare and the likelihood of drug interactions is low. Weight gain may be significant. 2. Duloxetine should be prescribed under the brand name Cymbalta® to avoid confusion with another formulation used to treat stress incontinence. 3. Venlafaxine: for major depressive disorder only 4. CSM warning - in severely depressed or hospitalised patients who require daily doses of 300mg or above, venlafaxine should only be initiated under specialist supervision. 5. Co-prescribing of venlafaxine with SSRIs should only be carried out under specialist supervision since the risk of serotonin syndrome and pharmacokinetic interations will be significantly increased, especially in overdose. 6. Venlafaxine is contra-indicated in patients who have been identified as being at very high risk of a serious cardiac ventricular arrhythmia. In addition, venlafaxine should be used with caution in patients with established cardiac disease that may increase the risk of ventricular arrhythmias e.g. recent myocardial infarction. 7. Venlafaxine is contra-indicated in patients with uncontrolled hypertension. In patients in whom BP is controlled, blood pressure measurement is recommended and dose reduction or discontinuation should be considered in those experiencing a sustained increase (more common with doses above 200mg). 8. In moderate renal and hepatic disorders or impairment the dose needs to be reduced by 50%. 9. Co-administration of venlafaxine with potent CYP3A4 inhibitors e.g. most SSRIs, TCAs, erythromycin, ketoconazole, should only occur if strictly indicated, due to the risk of clinically significant interactions. Similarly, co-administration with drugs that inhibit both CYP3A4 and CYP2D6 e.g. most SSRIs, TCAs, duloxetine, should be avoided. 10. Patients with increased risk factors for suicide should be carefully evaluated for the presence or worsening of suicide-related behaviour. A maximum of two weeks' supply of medication should be considered in these patients at initiation of treatment, during any dosage adjustment and until improvement occurs. In UK analyses of the rate of antidepressant overdose deaths per million prescriptions, (not adjusted for other risk factors), the rate for venlafaxine is higher that that for SSRIs, but lower than that for TCAs. 11. Doses below 150 mg of venlafaxine produce a predominantly SSRI action. If the patient had no response to an SSRI, doses of at least 150 mg venlafaxine per day may be required. The dose should be titrated gradually. 12. Agomelatine is a new type of antidepressant that is a melatonin receptor agonist and a selective serotonin receptor antagonist. It is licensed for the treatment of major depressive episodes in adults only (18+) and 3rd line after the failure/ intolerance of two SSRIs or an SSRI and mirtazapine. 13. Agomelatine can affect liver function resulting in elevated serum transaminase levels, hence LFTs must be monitored at baseline, 6,12,24 weeks thereafter when clinically indicated. 14. Agomelatine has been designated red status – hospital prescribing only. 15. MHRA Drug Safety Update October 2012 There have been several serious cases of hepatotoxicity reported with agomelatine (Valdoxan/Thymanax). These include six reports worldwide of hepatic failure. The existing recommendations to perform liver function tests in all patients receiving agomelatine at treatment initiation and during treatment have been extended to include testing when the dose is increased. Agomelatine should be immediately discontinued if patients present with symptoms or signs of potential liver injury, or if an increase in serum transaminases in liver function tests exceeds 3 times the upper limit of normal. Patients should be informed of the symptoms of potential liver injury and advised to stop taking agomelatine First line drugs Second line drugs Specialist drugs 15 Specialist only drugs immediately and seek urgent medical advice if these symptoms appear. 16. Vortioxetine is recommended by NICE as an option for treating major depressive episodes in adults whose condition has responded inadequately to 2 antidepressants in the current episode (NICE TA 367). This treatment is suitable for initiation in primary care and acute settings outside of mental health but clinicians are advised that there is no evidence that clearly demonstrates that vortioxetine is superior to other antidepressants in terms of clinical effectiveness. Switching antidepressants When no response or an inadequate response is obtained or a patient cannot tolerate an antidepressant, the following table may assist when switching to an alternative therapy From MAOIs Tricyclic antidepressants (TCA) SSRIs (except fluoxetine) From Fluoxetine Venlafaxine Mirtazapine To Advice Any other drug Withdraw and wait two weeks Other TCA SSRIs Venlafaxine Mirtazapine MAOIs TCA Venlafaxine Mirtazapine Cross taper cautiously Halve dose, add SSRI and withdraw slowly Cross taper cautiously, start with venlafaxine 37.5 mg at night Withdraw then start mirtazapine cautiously Withdraw and wait 2 weeks Cross taper cautiously with low dose TCA Withdraw and start venlafaxine 37.5 mg at night Withdraw and start mirtazapine cautiously To MAOIs TCA Venlafaxine, mirtazapine MAOIs TCAs, SSRIs Mirtazapine MAOIs TCAs, SSRIs, venlafaxine Advice Withdraw and wait 5-6 weeks Withdraw, wait 4-7 days, start TCA at very low dose, increase slowly Withdraw, wait 4-7 days, start alternative drug cautiously Withdraw and wait at least one week Cross taper cautiously with very low doses Withdraw before starting mirtazapine cautiously Withdraw and wait at least two weeks Withdraw and start alternative drug Discontinuation symptoms What are discontinuation symptoms? 1. At least one third of patients experience these symptoms after stopping antidepressants. 2. Onset varies from 12 hours to 5 days after the last dose (or missed dose) determined by the half-life of the drug. 3. Occasionally experienced after a dose reduction. 4. Usually mild and self-limiting, but can be severe and prolonged. Common: all antidepressants Anxiety, irritability, aggression, agitation, low mood, tearfulness. Excitation, hyperactivity, impulsive behaviour, impairment of concentration Insomnia, excessive/vivid dreaming, nightmares Lethargy, malaise, fatigue, weakness, myalgia Nausea, anorexia, abdominal discomfort, diarrhoea, vomiting Common: particularly SSRIs Dizziness, giddiness, lightheadedness, vertigo Uncoordination, unsteadiness Paraesthesia, numbness, ‘shock-like’ sensations Rhinorrhoea, salivation, tremor, sweating, tension, restlessness Uncommon / rare: Cardiovascular changes e.g. arrythmia Withdrawal related delirium or mania Movement disorders; akathesia, bradykinesia, dyskinesia, dystonia, tremor. Risk factors? Antidepressants with a short half life (e.g. paroxetine and venlafaxine) Taking an antidepressant for 8 weeks or longer. Those who developed anxiety symptoms at the beginning of antidepressant therapy (especially with SSRIs) Children and adolescents First line drugs Second line drugs Specialist drugs 16 Specialist only drugs How to treat: 1. If symptoms are mild: reassurance 2. If symptoms are severe: reintroduce the original antidepressant and gradually taper the dose e.g. half the dose every two weeks. Consider liquid forms to assist this. Consider switching to fluoxetine (long half-life). How to avoid: Wherever possible antidepressants should be discontinued over at least 4 weeks. The shorter the half-life the more important this is. Serotonin Syndrome 1. Serotonin Syndrome results from serotonin hyperstimulation. 2. Symptoms are usually mild and can be managed by drug withdrawal. 3. Severe cases can lead to multiple organ failure and death. 4. Symptoms include: restlessness diaphoresis tremor, shivering myoclonus confusion convulsions 5. Onset is usually soon after starting / changing dose. 4.4 Central nervous system stimulants and drugs used for ADHD Atomoxetine Dexamfetamine Sulphate Guanfacine ▼ Lisdexamfetamine▼ Methylphenidate Capsules 10mg, 18mg, 25mg, 40mg, 60mg Tablets 5mg Intuniv® Tablets, prolonged release 1mg, 2mg, 3mg, 4mg Elvanse® Capsules 20mg,30mg, 40mg 50mg,60mg 70mg Tablet 5mg, 10mg, 20mg Tablet M/R (Matoride® XL) 18mg, 36mg, 54mg Capsule M/R (Equasym XL®) 10mg, 20mg, 30mg Capsule M/R (Medikinet XL) 10mg, 20mg, 30mg, Prescribe MR preparations by brand name 40mg The different brands of methylphenidate MR preparations are not bioequivalent and contain different ratios of immediate release to modified release drug. They should therefore be prescribed by brand name. Matoride® XL – 20% immediate release, 80% modified release (bioequivalent to Concerta®) Equasym® XL – 30% immediate release, 70% modified release Medikinet® XL – 50% immediate release, 50% modified release Standard release formulations should be prescribed generically NICE Clinical Guideline CG 72: Attention Deficit Hyperactivity Disorder - Diagnosis and management of ADHD in children, young people and adults (September 2008) Summary: Care should be managed by specialist ADHD teams for children (Age 3-11), young people (age 12-18) and adults. In moderate ADHD in children or young people drug treatment is not recommended first line. A parenttraining/education programme and/or cognitive behavioural therapy should be tried first. In school-age children and young people with severe ADHD, drug treatment should be offered as first line along with a parent-training/education programme If a child or young person needs treatment with medication for ADHD doctors should consider the following: Methylphenidate for ADHD without significant co-morbidity First line drugs Second line drugs Specialist drugs 17 Specialist only drugs Methylphenidate for ADHD with comorbid conduct disorder Methylphenidate or atomoxetine when tics, Tourette’s syndrome, anxiety disorder, stimulant misuse or risk of stimulant diversion are present Atomoxetine if methylphenidate has been tried and has been ineffective at the maximum tolerated dose, or the child or young person is intolerant to low or moderate doses of methylphenidate the side effects of each medicine factors that might make it difficult for the person to take the medicine at the right time (for example, if it is difficult to take a dose during school hours) the individual preference of the child or adolescent and/or their family or carer. Drug treatment in all patients with ADHD should always form part of a comprehensive treatment programme that includes psychological, behavioural and educational/occupational needs. If drug treatment is indicated in adults, methylphenidate should normally be tried first. Methylphenidate and dexamfetamine and do not currently have UK marketing authorisation for use in adults with ADHD. Lisdexamfetamine is licensed for the treatment of ADHD in children aged 6 years and over when response to previous methylphenidate treatment is considered clinically inadequate. At least 2 forms of modified release methylphenidate should be tried as different release parameters of the MR products may provide more effective symptom control or minimise side effects. Treatment with methylphenidate, lisdexamfetamine, atomoxetine or dexamfetamine in children and young people (Under 18) should only be started after a specialist who is an expert in ADHD has thoroughly assessed the individual and confirmed the diagnosis. Once treatment has been started it can be continued and monitored by a GP in accordance with shared care guidelines . Guanfacine is a non-stimulant treatment for ADHD licensed for use in 6-17 year olds. It is for third line treatment after stimulant treatments and atomoxetine have failed. Inititation, prescribing and monitoring should remain with the specialist. Additional NICE Guidance NICE CG 142 June 2012 (rev Aug 2016): Autism spectrum disorder in adults: diagnosis and management Modafinil Tablet 100 mg, 200mg For narcolepsy Notes: 1. Narcolepsy should be diagnosed and treatment initiated by a specialist. 2. There is little evidence to support routinely changing current patients, well-controlled on amphetamines, to modafinil. 3. For newly diagnosed patients and those intolerant of amphetamines, there may be a role for using modafinil, but treatment should be agreed between patient and specialist. 4. MHRA Drug Safety Update - August 2010 The European Medicines Agency has recommended that the use of modafinil should be restricted to treat only sleepiness associated with narcolepsy and that it should no longer be used for the treatment of excessive sleepiness associated with obstructive sleep apnoea or chronic shift work sleep disorder. 5. MHRA Drug Safety Update – March 2011 Further information and advice is available to support safer use of modadafinil. 4.5 Drugs used in the treatment of obesity Notes: Obesity is associated with many health problems including cardiovascular disease, diabetes mellitus, gallstones and osteoarthritis. Factors that aggravate obesity may include depression, other psychological problems and some drugs. NICE CG 189 Obesity (November 2014) offers guidance on the management of obesity. When to consider drug treatment: Discuss with the patient the potential benefits and limitations, including the mode of action, adverse effects and their potential impact on the patient’s motivation. When prescribing, make arrangements for appropriate healthcare professionals to offer information, support and counselling on additional diet, physical activity and behavioural strategies. Give information on patient support programmes. First line drugs Second line drugs Specialist drugs 18 Specialist only drugs Follow the drug’s summary of product characteristics. Continued prescribing and withdrawal Review regularly, to monitor the effect of drug treatment, and to reinforce lifestyle advice and need for adherence. Drug treatment may be used to help people to maintain weight loss, as well as to continue to lose weight. Consider withdrawing drug treatment if the person does not lose enough weight Consider less strict goals for people with type 2 diabetes, because they may lose weight more slowly. Agree goals with the person and review regularly. If concerned about micronutrient intake, consider recommending a supplement providing the reference nutrient intake for all vitamins and trace elements, particularly for vulnerable groups such as older people, who may be at risk of malnutrition. If withdrawing a person’s drug treatment, offer support to help maintain weight loss because their self-confidence and belief in their ability to make changes may be low. 4.5.1 Anti-obesity drugs acting on the gastro-intestinal tract Capsules 120mg Orlistat Notes: Prescribe only as part of an overall plan for managing obesity in adults who have: – a BMI of 28.0 kg/m2 or more with associated risk factors, or – a BMI of 30.0 kg/m2 or more. Continue treatment for longer than 3 months only if the person has lost at least 5% of their initial body weight since starting drug treatment (less strict goals may be appropriate for people with type 2 diabetes). Continue for longer than 12 months (usually for weight maintenance) only after discussing potential benefits and limitations with the patient. 4.5.2 Centrally acting appetite suppressants NB: The European Medicines Agency suspended the marketing authorisation for rimonobant (Acomplia) on 23rd October 2008 because of the high level of psychiatric side effects observed with this drug. Further information can be found here NB: The European Medicines Agency suspended the marketing authorisation for sibutramine (Reductil) on 21 January 2010 because of emerging evidence suggesting an increased risk of non-fatal heart attacks and strokes with this medicine. Further information van be found here 4.6 Drugs used in nausea and vertigo Anti-emetics should be prescribed only when the cause of vomiting is known because otherwise they may delay diagnosis, particularly in children. The following table and diagram summarise the actions and uses of the most commonly used anti-emetics and can be used as a guide to choosing an appropriate agent. Class of anti-emetic Anti-emetic Anticholinergic (also known as sphincter modulators) Antihistamine Hyoscine Cannabinoid Nabilone Dopamine antagonist Gastroprokinetic agents Metoclopramide Domperidone Phenothiazine and related drugs Prochlorperazine Cyclizine Promethazine Histamine analogue Betahistine 5-HT3 antagonist Granisetron Odansetron First line drugs Useful for vomiting caused by… Motion sickness Motion sickness Post-operative vomiting Pregnancy Cytotoxic therapy, unresponsive to conventional antiemetics Migraine Cytotoxic therapy Labyrinthitis Migraine Post-operative vomiting Pregnancy Labyrinthitis Cytotoxic therapy Second line drugs Specialist drugs 19 Mode of action Act on the vomiting centre as well as on the gastrointestinal tract directly Act on H1 receptors in the vomiting centre, as well as having weak anticholinergic and sedating effects Thought to act on opiate receptors Act on the chemo receptor trigger zone and has direct effects on the gastrointestinal tract Act on the chemo receptor trigger zone Thought to reduce endolymphatic pressure by improving the microcirculation in the inner ear Exact mode of action unclear, but is probably both central and peripheral Specialist only drugs Palonosetron (with netutipant) Nausea and vomiting – main sites of action Notes: 1. The underlying cause of the nausea should be treated before starting treatment with an anti-emetic wherever possible. 2. Anti-nausea drugs (including haloperidol) should be prescribed prophylactically when giving opioid analgesics. Palliative Care Guidelines in Chapter 16 contain details for special situations. 3. Nausea in the first trimester of pregnancy does not require drug therapy. On rare occasions, if vomiting is severe, short-term treatment with an antihistamine (e.g. promethazine) may be required. Prochlorperazine or metoclopramide may be considered as second line treatments. If symptoms do not settle in 24 to 48 hours then specialist advice should be sought. 4. Please refer to BNF Chapter 8: Malignant disease for guidance on nausea and vomiting in patients receiving chemotherapy. 5. Haloperidol and levomepromazine (section 4.2.1) are also used for the relief of nausea. See also Chapter 16 – Palliative Care. Antihistamines Cyclizine Tablet 50mg Injection 50mg in 1ml Promethazine hydrochloride Tablets 10mg, 25mg Elixir 5mg/5ml Injection 25mg/ml Note: Cyclizine should be used with caution in the community because of its potential for abuse. Phenothiazines and related drugs Prochlorperazine First line drugs Tablet 5mg Syrup 5mg in 5ml Suppository 5mg, 25mg Intramuscular injection 12.5mg in 1ml Buccal tablet 3mg Second line drugs Specialist drugs 20 Specialist only drugs Notes: 1. Severe reactions to prochlorperazine should be treated with procyclidine injection, 5mg to 10mg given intramuscularly, repeated if necessary after 20 minutes, maximum of 20mg daily. In children, the dose range is as follows: Age 1-2yrs, 500micrograms to 2mg, age 2-12yrs 2mg to 5mg, age 12-18yrs 5mg to 10mg. Subsequent oral doses may be needed for the next 2 or 3 days. 2. Prochlorperazine should not be prescribed for patients with Parkinson’s disease and should be used with caution in the elderly. 3. Prochlorperazine buccal tablets have been included only for use as an alternative to injection in certain circumstances (e.g. GP call out). They should be prescribed in small quantities not exceeding 10 tablets. Domperidone and metoclopramide Metoclopramide Domperidone Tablet 10mg Syrup 5mg in 5ml Injection 10mg in 2ml Tablet 10mg Suspension 5mg in 5ml Suppository 30mg Notes: 1. Metoclopramide is not as effective as prochlorperazine or cyclizine for the treatment of postoperative nausea and vomiting. 2. Metoclopramide (and to a lesser degree prochlorperazine) is associated with a high risk of dystonias and oculogyric crises particularly in children, young adults and the elderly. It is not licensed for use in people under 20 years of age. Other anti-emetics are preferred for these groups of patients. 3. Severe reactions to metoclopramide should be treated with procyclidine injection, 5mg to 10mg given intramuscularly, repeated if necessary after 20 minutes, maximum of 20mg daily. In children, the dose range is as follows: Age 1-2yrs, 500micrograms to 2mg, age 2-12yrs 2mg to 5mg, age 12-18yrs 5mg to 10mg. Subsequent oral doses may be needed for the next 2 or 3 days. 4. Metoclopramide should not be prescribed for patients with Parkinson’s disease. Domperidone does not readily cross the blood-brain barrier and is therefore the preferred option. It may also be useful in reducing the side effects of levodopa and bromocriptine. 5. In August 2013 the EMA advised that the benefits of metoclopramide were outweighed by the risks for high dose and long- term use and recommended a restriction on dosing and duration of treatment. For adults, the maximum dose in 24 hours is 30 mg (or 0.5 mg per kg bodyweight). The usual dose is 10 mg up to three times a day. In children age 1 year or older, the recommended dose is 0.1–0.15 mg per kg bodyweight, repeated up to three times a day. The maximum dose in 24 hours is 0.5 mg per kg bodyweight. For further information on indication, use and administration, see here . 6. In May 2014 the MHRA advised that because domperidone is now associated with a small increased risk of serious cardiac side effects, its use is now contraindicated in patients with underlying cardiac conditions and is restricted to the relief of nausea and vomiting and for short periods of time only (see MHRA Safety Update May 2014). 5HT3 antagonists Granisetron Tablet 1mg Paediatric liquid 1mg in 5ml Sterile solution for dilution and use as either infusion or injection, 1mg, 3mg Ondansetron Tablet 4mg, 8mg Syrup SF 4mg in 5ml Injection 4mg in 2ml, 8mg in 4ml Akynzeo® 0.5mg/300mg capsule Palonosetron and Netupitant▼ Notes: 1. The place of 5HT3 antagonists in non-chemotherapy induced nausea and vomiting is not yet clear. They may be useful in drug or biochemical induced emesis and stimulation of GI receptor 2. Antiemetic requirements in chemotherapy vary depending on how emetogenic the regimen is and individual patient response. See also Palliative Care Guidelines, Chapter 16. 3. Antiemetics should be supplied as a full course by secondary care as part of the treatment. It is not anticipated First line drugs Second line drugs Specialist drugs 21 Specialist only drugs that GPs would be asked to prescribe. 4. Granisetron is the preferred treatment for adults. 5. In paediatrics, ondansetron is preferred for post-operative nausea and vomiting, whereas granisetron is preferred for paediatric oncology. 6. 5HT3 antagonists should only be used 2nd line in post-operative nausea and vomiting where prochlorperazine/cyclizine is not effective. 7. Akynzeo® (netupitant and palonosetron) is indicated for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic chemotherapy in accordance with the chemotherapy induced nausea and vomiting (CINV) guidelines Cannabinoid Nabilone Capsule 1mg Note: Nabilone is used for nausea and vomiting caused by cytotoxic chemotherapy that is unresponsive to conventional anti-emetics. Kwells® ‘melt in the mouth’ tablet 300micrograms Hyoscine Joy-Rides® chewable tablet 150micrograms hydrobromide Scopaderm® TTS Patch 1mg/ 72hrs Injection 400micrograms in 1ml, 600micrograms in 1ml Other drugs for Ménière’s disease Betahistine Tablet 8mg, 16mg Notes: 1. Vertigo and nausea associated with Ménière’s syndrome and middle ear surgery may be difficult to treat. Hyoscine, antihistamines, and phenothiazines (such as prochlorperazine) are effective in the prophylaxis and treatment of such conditions. In the acute attack prochlorperazine may be given rectally or by intramuscular injection or cyclizine may be given by intramuscular injection. 2. Betahistine is of benefit solely in treatment of Ménière’s syndrome and prescribers should ensure that betahistine is not being prescribed to treat side effects of other medication. 4.7 Analgesics Refer to: Chapter 10 for Non-steroidal anti-inflammatory drugs Palliative care formulary for prescribing analgesics in palliative care Notes: 1. Pain control must be reviewed frequently. 2. It is important that analgesics are given regularly for chronic pain as they are more effective in preventing the development of pain than relieving established pain. 3. Specific dosage instructions should be written on the prescription, i.e. “X to be taken x hourly when required for pain”, rather than simply “prn”. 4. Whilst standard release formulations should be considered first line, in some chronic pain management cases, slow release analgesia may be an advantage. 5. Standard release formulations should be used for exacerbations of pain. Analgesic Ladder (Adults) STEP 1: Mild Pain Simple analgesia STEP 2: Moderate Pain Weak opioid + simple analgesia STEP 3: Severe Pain Strong opioid + simple analgesia Adjuvant analgesics: e.g. tricyclic antidepressants or anticonvulsants for pain with neuropathic elements (see relevant section) At whatever step on the ladder, if inflammation is present, consider adding an NSAID, e.g. ibuprofen, naproxen, or topical NSAID (refer to Chapter 10). This may minimise the requirement for other analgesics. 1. It is not necessary to start at the bottom of the ladder. Analgesia should be tried in a logical sequence and given appropriate to the degree of pain. First line drugs Second line drugs Specialist drugs 22 Specialist only drugs 2. NSAIDs should only be used after careful assessment of risk and consideration of the alternatives. Regular critical re-assessments of continued use should be made and repeat prescribing avoided. Refer to Chapter 10. 3. Analgesics should be taken regularly in order to achieve and maintain best efficacy. 4. If a NSAID is used for analgesia alone it is recommended the drug should be changed if no response is obtained after 1 week. 5. If an anti-inflammatory action is required a trial of 3 weeks should be allowed. 6. Prophylactic laxatives should always be prescribed when strong opioids are used, see section 1.6. 7. Prophylactic anti-emetics should always be considered when prescribing opioids if vomiting is likely to be problematic, see section 4.6. 8. For adjunctive therapy refer to section 4.7.3. 9. Where appropriate refer to the Palliative Care Guidelines. 4.7.1 Non-opioid analgesics Paracetamol Co-codamol (Paracetamol and codeine) Tablet 500mg Dispersible tablet 500mg Oral Suspension (SF) 120mg/5ml, 250mg/5ml, Suppository 60mg, 120mg, 240mg, 500mg Oral Suspension 500mg/5ml (Unlicensed) Intravenous infusion 10mg/ml Tablets 8/500, 30/500 Effervescent tablets 8/500, 30/500 Paediatric Analgesic Dosage Guidelines Child’s weight (kg) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 First line drugs Paracetamol dose (oral/PR) 20mg/kg loading dose followed by 15mg/kg Max dose 60mg/kg over 24 hours 120mg QDS Ibuprofen dose (oral) Diclofenac dose (oral/PR) 12.5mg 16hrly 50mg QDS 12.5mg BD 168mg QDS 240mg QDS (oral) 240mg QDS (PR) 100mg QDS 12.5mg TDS 25mg BD 360mg QDS (oral) 365mg QDS (PR) 150mg QDS 400mg QDS 25mg TDS 500mg QDS (oral) 500mg QDS (PR) 200mg QDS 250mg QDS 650mg QDS (oral) 625mg QDS (PR) Second line drugs Specialist drugs 23 50mg BD 37.5mg TDS Specialist only drugs 1g QDS 50 and above PR loading dose Max total daily dose 30mg/kg STAT 90mg/kg (max 4g) 300-400mg QDS 40mg/kg (max 2400mg) 50mg TDS 3mg/kg (max 150mg) Notes: 1. Paracetamol is usually the simple analgesia of choice. 2. Dispersible / effervescent preparations should be reserved for patients who cannot swallow solid forms. They are also more expensive. 3. Taking 8 tablets per day of soluble paracetamol or co-codamol may increase intake of sodium chloride by 8g daily. This may be a significant risk in patients with heart failure or hypertension. 4. Suppositories are very expensive and other forms should be substituted as soon as convenient. 5. Intravenous paracetamol has been included for post-operative analgesia in theatres and protocol driven treatment elsewhere within ESHT. 6. Co-codamol: There may be advantages to prescribing the opioid and non-opioid separately e.g. paracetamol 500mg tablets and codeine 30mg tablets prescribed separately. This gives flexibility in both the adjustment of the doses and in the selection of the most appropriate combination. Some patients are unable to metabolise codeine to morphine and therefore codeine will be ineffective in these patients. 7. Co-codamol containing 8mg codeine phosphate may not provide significant additional relief of pain but is enough to cause opioid side effects and can complicate the treatment of over dosage. It may be considered where patients cannot tolerate high doses of codeine. 8. When co-codamol is prescribed and no strength stated, formulations containing codeine 8mg and paracetamol 500mg will be dispensed. 9. Co-proxamol has little more analgesic effect than paracetamol alone in acute pain and is associated with significant opiate type side-effects including dependence, sedation and increased risk of falls. At recommended doses, co-proxamol provides sub optimal therapeutic dose of paracetamol. 10. Co-proxamol is dangerous in overdose and reports show that fatal overdoses due to co-proxamol are the second most frequent means of suicide with prescribed drugs in England and Wales. The risk of death with coproxamol overdose seems to be higher than for either tricyclic antidepressants or paracetamol. This product is being withdrawn and is no longer recommended. 11. Post Immunisation Analgesia: The recommended dose is 60mg (2.5ml of 120mg/5ml suspension) paracetamol, repeated if necessary by a second dose 4-6 hours later. Premature babies should not be denied paracetamol post vaccination, if required. However, as their weight may be significantly less than the 5kg expected for a 2 month old born at term, paracetamol should be prescribed on a mg/kg basis (see table on previous page). The recommended dose is 20mg/kg, followed if necessary by a second lower dose of 15mg/kg 4-6 hours later. The maximum dose is 60mg/kg over a 24-hour period as the liver is immature. 12. The dosing for liquid paracetamol products for children available to buy over the counter has been revised to one that is based on narrower age bands with a single dosing option per band. For details of the new dosing regimes see the MHRA Drug Safety Update July 2011 13. MHRA has issued new simplified guidance on the use of intravenous acetylcysteine for the treatment of acute paracetamol overdose. See the MHRA Drug Safety Update September 2012 4.7.2 Opioid analgesics Notes 1. Opioid analgesics are usually used to relieve moderate to severe pain, particularly of visceral origin. 2. Although repeated administration may cause dependence and tolerance, this should be no deterrent in the control of pain. Success is demonstrated by monitoring of functional improvements. 3. Regular use of a potent opioid may be appropriate for certain cases of chronic non-malignant pain. 4. Opioid analgesics share many side effects, though qualitative and quantitative differences exist. The most common side effects include nausea, vomiting, constipation and drowsiness. Larger doses produce respiratory depression and hypotension. NPSA 2008/RRR05 Reducing dosing errors with opiates – July 2008 This guidance applies when the following opioid medicines are prescribed dispensed or administered: Buprenorphine, diamorphine, dipipanone, fentanyl, hydromorphone, meptazinol, methadone, morphine, oxycodone, papaveretum, pethidine When opioid medicines are prescribed, dispensed or administered, in anything other than acute emergencies, the healthcare practitioner concerned, or their clinical supervisor, should: • Confirm any recent opioid dose, formulation, frequency of administration and any other analgesic medicines prescribed for the patient. This may be done for example through discussion with the patient or their representative (although not in the case of treatment for addiction), the prescriber or through medication records. First line drugs Second line drugs Specialist drugs 24 Specialist only drugs • Ensure where a dose increase is intended, that the calculated dose is safe for the patient (e.g. for oral morphine or oxycodone in adult patients, not normally more than 50% higher than the previous dose). • Ensure they are familiar with the following characteristics of that medicine and formulation: usual starting dose, frequency of administration, standard dosing increments, symptoms of overdose, common side effects. Morphine sulphate except for oral solution 10mg in 5ml 4 hourly dosing Oral solution 10mg in 5ml, 100mg in 5ml Tablet 10mg, 20mg, 50mg Injection 10mg in 1ml, 30mg in 1ml 12 hourly dosing Zomorph® m/r capsule 10mg, 30mg, 60mg, 100mg, 200mg Diamorphine hydrochloride Codeine phosphate Dihydrocodeine Tramadol Oxycodone Injection 5mg, 10mg, 30mg, 100mg, 500mg Tablet 15mg, 30mg, 60mg Oral solution 25mg in 5ml Injection 60mg in 1ml Tablets 30mg Capsules 50mg Capsules M/R 50mg, 100mg, 150mg, 200mg Tablets M/R 100mg, 150mg, 200mg Capsules 5mg, 10mg, 20mg Oral solution 10mg in 1ml Injection ▼ 10mg/ml 12 hourly dosing Longtec® M/r tablet 5mg, 10mg, 20mg, 40mg, 80mg Notes: 1. In the post-operative period, patients should be closely monitored for adequate pain relief as well as for signs of possible side-effects especially respiratory depression. 2. For peri-operative analgesia see separate anaesthesia formulary. 3. Morphine remains the most valuable opioid analgesic for severe pain although it frequently causes nausea and vomiting. In addition to pain relief, morphine also confers a state of euphoria and mental detachment. 4. Following titration, except for stat doses, for example for dressing changes, morphine should be given regularly every four hours, unless m/r preparations are required. If pain recurs because of prn dosing, it is likely that increased dose or frequency of analgesia may be needed to regain pain control. 5. Modified-release morphine preparations should be prescribed as Zomorph®. MST® products have not been included in the formulary as they are more expensive than Zomorph® and offer no further advantage. For those with swallowing problems, Zomorph® capsules can be opened and the contents sprinkled on soft food or dispersed in water. 6. ‘As required’ doses of immediate release product should be prescribed in case of breakthrough pain. 7. Opioid patches are expensive but there is a group of patients in whom their use is justifiable and appropriate e.g. those with intolerable side effects to morphine, dysphagia, poor compliance or poor response to oral medication. Patches provide constant plasma levels and can be useful for patients with early morning moderate to severe pain. They should be reserved for patients requiring strong opioid analgesia who cannot tolerate large, oral, regular doses or who are unable to comply with a frequent analgesia regimen. Patches are not suitable for management of acute pain. Caution should be exercised in the elderly with regard to the slow onset and long duration of action with the patches. Drowsiness can be a particular problem. There can be increased absorption with febrile patients or with the use of electric blankets or heat pads. 8. Fentanyl patches: it is important to prescribe by brand e.g. Durogesic® D-Trans® as there are significant differences in bioavailability. Available as 12 microgram/hour, 25 microgram/hour, 50 microgram/hour, 75 microgram/hour and 100 microgram/hour for 3 days (72 hours). Starting dose is 25 microgram/hour. The 12 microgram/hour is purely available as a titration dose for patients moving from 25 microgram to 50 microgram/hour patches. 9. Buprenorphine patches: available as Butrans® 5 microgram/hour, 10 microgram/hour and 20 microgram/hour for 7-days and Transtec® 35 microgram/hour, 52.5 microgram/hour and 70 microgram/hour for 4 days. Neither patch has been approved for use by the SMC. There are some situations where local specialists in pain management may recommend use of these patches. 10. Pethidine tablets have been omitted from the formulary because the evidence favours the use of the intramuscular route; there is a danger of the accumulation of nor-pethidine with repeated dosing especially in the renally impaired. Stat doses of NSAID suppositories may be useful in renal and biliary colic (see Chapter 10). First line drugs Second line drugs Specialist drugs 25 Specialist only drugs 11. Although tramadol has been included, the CSM have cautioned its use in patients with a history of epilepsy, as there may be an increased risk of convulsions. Psychiatric reactions have been reported. It is used in secondary care for acute post-operative pain short-term. In primary care tramadol should be limited to patients for whom cocodamol is not effective, when standard release formulations should be considered, although in some chronic pain management cases, slow release analgesia may be an advantage. Additional NICE Guidance CG140 May 2012 (Rev Aug 2016): Palliative care for adults: strong opioids for pain relief NG61 (Dec 2016): End of life care for infants, children and young people with life-limiting conditions: planning and management 4.7.3 Neuropathic pain Definition: Neuropathic pain is pain secondary to a lesion or dysfunction of normal sensory pathways in either the peripheral or central nervous system. Pain in ‘an area of numbness’ together with neuronal hyperexcitability causing continuous, spontaneous or evoked pain e.g. allodynia, hyperpathia, stabbing pain, may be found. Examples: Many different types of pathology may cause neuropathic pain – this heterogeneity results in a wide variety of mechanisms and presentations of pain, for example: infection: post-herpetic neuralgia; metabolic: diabetic neuropathy; trauma: phantom limb pain, some back pain and sciatica, complex regional pain syndrome; ischaemia: post-stroke central pain. Treatment: Up to 40% of patients may be refractory to drug treatment, so it is very important to avoid the development of secondary ‘chronic pain disorder’ by: Maintaining emotional and physical ‘fitness’ – explanation and advice about the pain, maintenance of normal activities and exercise – treatment of secondary depression, support etc. There is a lot of information and self-help resources that patients can access to support them to live with chronic pain: http://www.nhs.uk/Livewell/Pain/Pages/Painhome.aspx http://chronicpainscotland.org/patients-area/living-well-with-chronic-pain/ These resources include information on Exercise and Activity, Dealing with Stress and relaxation, and Workplace issues/advice Physiotherapy – very important especially in Complex Regional Pain Syndrome to maintain function. TENS (transcutaneous nerve stimulation) – some patients find this method effective. Machines are available to purchase. Patients will need to be taught how to use the TENS machine correctly. TENS is not suitable for patients with pacemakers. Referral to the pain clinic for multidisciplinary pain management if persistent distressing symptoms NICE CG 173 Neuropathic pain – pharmacological management: The pharmacological management of neuropathic pain in adults in non-specialist settings (Nov 2013) describes the recommended treatment pathway for neuropathic pain in the non-specialist setting. FOR ALL NEUROPATHIC PAIN EXCEPT TRIGEMINAL NEURALGIA Unlicensed Tablet 10mg, 25mg, 50mg Amitriptyline Licensed for peripheral neuropathic pain Capsules 100mg, 300mg, 400mg Gabapentin only Tablets 600mg Duloxetine Cymbalta® Capsules 30mg, 60mg Pregabalin Capsules 25mg, 50mg, 75mg, 100mg, 200mg, 300mg Capsaicin Cream 0.075% (Axsain®) Cream 0.025% (Zacin®) First line drugs Second line drugs Licensed for diabetic peripheral neuropathic pain only Licensed for post-herpetic neuralgia and painful diabetic peripheral polyneuropathy Unlicensed Specialist drugs 26 Specialist only drugs 1. Offer a choice of amitriptyline, gabapentin or capsaicin as initial treatment for neuropathic pain taking into account individual patient factors (see table below) and the cost of treatment 2. When prescribing capsaicin, use the lower strength first (unlicensed). Consider the higher strength for patients that have tolerated the lower strength but have had an inadequate response to it. 3. If the initial treatment is not effective or is not tolerated, offer one of the remaining drugs, and consider switching again if the second and third drugs tried are also not effective or not tolerated. 4. Pregabalin should normally only be considered following a discussion of treatment options with a pain specialist 5. Consider tramadol only if acute rescue therapy is needed. Amitriptyline Gabapentin Capsaicin cream Duloxetine Pregabalin 1st line 1st line 0.025%, 0.075% 2nd line Specialist 1st line recommendation Helpful if patient has problems with sleep Helpful where pain described as burning, shooting, stabbing, pricking Helpful for localised pain Helpful if patient also requires antidepressant Helpful where pain described as burning, shooting, stabbing, pricking Best taken in the evening to reduce ‘hangover effect’ e.g. 6-8pm Median effective dose is 600mg three times daily Patients who do not wish to take oral medicine Very low risk of diversion/abuse, therefore useful in patients with history of substance misuse Median effective dose is 150mg twice daily Consider nortriptyline if excess sedation occurs Reduce dose in renal impairment Patients who cannot tolerate oral medicines No dose titration necessary Reduce dose in renal impairment Analgesic effect is separate from antidepressant effect Avoid in patients with memory problems Lower strength unlicensed for neuropathic pain Nausea common on initiation Avoid in patients with memory problems Median effective dose is 25-50mg daily Some indications unlicensed* Some indications unlicensed* Some indications unlicensed* Unlicensed indication* Consider risk of falls in elderly patients Consider risk of falls in elderly patients Consider risk of falls in elderly patients Avoid in patients with active history of substance misuse Avoid in patients with active history of substance misuse **Risk of suicidal ideation **Risk of suicidal ideation Figure3. Prescriber Decision Aid *NICE guidance re off label use. At the time of publication (November 2013), amitriptyline did not have a UK marketing authorisation for this indication, duloxetine is licensed for diabetic peripheral neuropathic pain only, and gabapentin is licensed for peripheral neuropathic pain only, so use for other conditions would be off-label. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing and managing medicines and devices for further information. **Risk of suicidal ideation. Treatment with any anticonvulsant drug increases the risk of suicidal ideation and behaviour in all patient groups, regardless of prescribed indication, as early as one week after starting treatment. All patients should be monitored for signs of depression and/or suicidal ideation throughout treatment and particular care should be taken when prescribing these drugs in those with a history of mental health disorder and/or suicidal behaviour. TRIGEMINAL NEURALGIA First line drugs Second line drugs Specialist drugs 27 Specialist only drugs Carbamazepine Tablets, 100mg, 200mg, 400mg, SF Liquid 100mg in 5ml MR Tablets, 200mg, 400mg 1. Offer carbamazepine as initial treatment for trigeminal neuralgia. 2. If initial treatment with carbamazepine is not effective, is not tolerated or is contraindicated, consider seeking expert advice from a specialist and consider early referral to a specialist pain service or a condition-specific service. Other Lidocaine (Versatis®) medicated plaster 5% Use outside of license by specialist palliative care team only. Treatment of Headache NICE Clinical Guideline 150: Headaches (Sept 2012) gives guidance on the diagnosis and management of different types of headache. Key priorities for implementation focus on: Correct diagnosis of tension type, migraine and cluster headache (see table below); The possibility of medication overuse headache in people whose headache developed or worsened while they were taking the following drugs for 3 months or more: o triptans, opioids, ergots or combination analgesic medications on 10 days per month or more or o paracetamol, aspirin or an NSAID, either alone or any combination, on 15 days per month or more. The use of a headache diary o to record the frequency, duration and severity of headaches; o to monitor the effectiveness of headache interventions o as a basis for discussion with the person about their headache disorder and its impact. Diagnosis of tension-type headache, migraine and cluster headache Headache feature Tension-type headache Migraine (with or without aura) Cluster headache Pain location1 Bilateral Unilateral or bilateral Unilateral (around the eye, above the eye and along the side of the head/face) Pain quality Pressing/tightening (nonpulsating) Pulsating (throbbing or banging in young people aged 12–17 years) Variable (can be sharp, boring, burning, throbbing or tightening) Pain intensity Mild or moderate Moderate or severe Severe or very severe Effect on activities Not aggravated by routine activities of daily living Aggravated by, or causes avoidance of, routine activities of daily living Restlessness or agitation Other symptoms None Unusual sensitivity to light and/or sound or nausea and/or vomiting On the same side as the headache: Aura 2 red and/or watery eye Symptoms can occur with or without headache and: nasal congestion and/or runny nose are fully reversible swollen eyelid develop over at least 5 minutes last 5−60 minutes. forehead and facial sweating constricted pupil and/or drooping eyelid Typical aura symptoms include visual symptoms such as flickering lights, spots or lines and/or partial loss of vision; sensory symptoms such as numbness and/or pins and needles; and/or speech disturbance. Duration of headache 30 minutes–continuous Frequency < 15 days of headache per month First line drugs 4–72 hours in adults 15–180 minutes 1–72 hours in young people aged 12–17 years ≥ 15 days per < 15 days per month month for more than 3 months Second line drugs ≥ 15 days per month for 1 every other day 1 every other more than 3 months to 8 per day3, with day to 8 per remission4 day3, Specialist drugs 28 Specialist only drugs Diagnosis 1 Episodic tensiontype headache Chronic tension-type headache 5 Episodic migraine Chronic migraine (with or without aura) (with or without aura) > 1 month with a continuous remission4 <1 month in a 12-month period Episodic cluster headache Chronic cluster headache Headache pain can be felt in the head, face or neck. 2 See recommendations 1.2.2, 1.2.3 and 1.2.4 for further information on diagnosis of migraine with aura. 3 The frequency of recurrent headaches during a cluster headache bout. 4 The pain-free period between cluster headache bouts. 5 Chronic migraine and chronic tension-type headache commonly overlap. If there are any features of migraine, diagnose chronic migraine. 4.7.4 Antimigraine drugs 4.7.4.1 Treatment of acute migraine NICE Clinical Guideline 150: Headaches recommends: 1. Offering combination therapy with an oral triptan and an NSAID, or an oral triptan and paracetamol, for the acute treatment of migraine 2. For young people aged 12–17 years consider a nasal triptan in preference to an oral triptan 3. If ineffective or not tolerated, offer a non-oral preparation of metoclopramide or prochlorperazine and consider adding a non-oral NSAID or triptan if these have not been tried. 5HT1 agonists (triptans) Tablet 50mg, 100mg Sumatriptan Injection 6mg/0.5ml syringe Nasal spray 10mg/0.1ml actuation Naratriptan Tablet 2.5mg Zolmitriptan Tablet 2.5mg Nasal spray 5mg/0.1ml actuation Orodispersible tablet 2.5mg, 5mg Notes: 1. All 5HT1 agonists (triptans) are effective and well tolerated. 2. Headaches can recur within 24 hours in about 30-40% of patients treated with triptans. 3. Triptans are contraindicated in ischaemic heart disease, previous myocardial infarction and uncontrolled hypertension. 4. If the first triptan fails, it is worth trying an alternative one. Antiemetics Refer to: Section 4.6 for antiemetic preparations 4.7.4.2 Prophylaxis of migraine Propranolol See section 2.4 Topiramate Botulinum toxin type A Tablet 25mg, 50mg, 100mg Sprinkle Capsule 15mg, 25mg, 50mg Botox® Injection for reconstitution 50 unit, 100 unit, 200 unit vial First line drugs Second line drugs Specialist drugs 29 Specialist only drugs Notes: 1. Where migraine attacks are frequent, consideration should be given to the avoidance of trigger factors such as stress or diet (such as cheese, chocolate etc). 2. In patients with more than two attacks per month, prophylaxis should be tried. 3. Propranolol is first line choice for prophylaxis of migraine, unless contraindicated. It is useful where a co-existing disease, e.g. hypertension or anxiety, is present. 4. Topiramate is indicated in adults for the prophylaxis of migraine headache. 5. Women and girls of childbearing potential should be informed that topiramate is associated with a risk of fetal malformations and can impair the effectiveness of hormonal contraceptives. Ensure they are offered suitable contraception. 6. The evidence for the use of pizotifen is limited and weight gain and sedation are often unacceptable side effects of this drug. 7. Amitriptyline [unlicensed] may be useful when migraine coexists with tension-type headaches, insomnia or depression. To minimise side effects, treatment should be started at a low dose (10-25mg ON) and increased to a maintenance dose of 50-75mg ON. 8. Refer to this section of the BNF for more detailed guidance on prophylaxis. Details include the following unlicensed alternatives: amitriptyline (also included in Section 4.3.1); sodium valproate 300mg bd (also included in Section 4.8.1); verapamil [cluster headache] (also included in Section 2.6.2). Gabapentin has been used but is unlicensed for this indication. 9. Botulinum toxin type A is recommended By NICE as an option for the prophylaxis of headaches in adults with chronic migraine (defined as headaches on at least 15 days per month of which at least 8 days are with migraine) see TA 260: Botulinum toxin type A for chronic migraine for more detail. 10. Patients should have failed to respond to at least three prior pharmacological prophylaxis therapies and have been managed for headache medication overuse prior to being referred for this treatment. 11. For acute treatment of cluster headaches, offer oxygen and/or a subcutaneous or nasal triptan. When using oxygen for the acute treatment of cluster headache: use 100% oxygen at a flow rate of at least 12 litres per minute with a non-rebreathing mask and a reservoir bag and arrange provision of home and ambulatory oxygen. 4.8 Antiepileptics 4.8.1 Control of epilepsy NICE CG 137: The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (January 2012) , NICE TA 76: Newer drugs for epilepsy in adults (Mar 2004) and NICE TA 79: Newer drugs for epilepsy in children (April 2004) have been replaced by NICE CG 137: The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (Jan 2012) The guidance recommends that all anti-epileptic drugs (AEDs) are initiated in children and adolescents by a specialist. In adults AED therapy should be initiated by or on the recommendation of a specialist. When possible, AED choice should be made on the basis of the presenting epilepsy syndrome. If the epilepsy syndrome is not clear at presentation, the decision should be based on the presenting seizure type(s). It is recommended that children, young people and adults should be treated with a single AED (monotherapy) wherever possible. If the initial treatment is unsuccessful, then monotherapy using another drug can be tried. Caution is needed during the changeover period. Combination therapy (adjunctive or 'add-on' therapy) should only be considered when attempts at monotherapy with AEDs have not resulted in seizure freedom. If trials of combination therapy do not bring about worthwhile benefits, treatment should revert to the regimen (monotherapy or combination therapy) that has proved most acceptable to the child, young person or adult, in terms of providing the best balance between effectiveness in reducing seizure frequency and tolerability of side effects. Consistent supply to the child, young person or adult with epilepsy of a particular manufacturer's AED preparation is recommended, unless the prescriber, in consultation with the child, young person, adult and their family and/or carers as appropriate, considers that this is not a concern. Different preparations of some AEDs may vary in bioavailability or pharmacokinetic profiles and care needs to be taken to avoid reduced effect or excessive side effects. When prescribing sodium valproate to women and girls of present and future childbearing potential, the possible risk of malformation and neurodevelopmental impairments in an unborn child should be discussed, particularly with high doses of this AED or when using as part of polytherapy. CSM advice has been issued for the following drugs: Carbamazepine Ethosuximide Lamotrigine Oxycarbazepine First line drugs Phenytoin Sodium valproate Topiramate Vigabatrin Please refer to the individual drug entries in the BNF, section 4.8.1. Second line drugs Specialist drugs 30 Specialist only drugs Choice of antiepileptic drug (listed alphabetically) Seizure type First-line AEDs Adjunctive AEDs Generalised tonic–clonic Carbamazepine Lamotrigine Oxcarbazepinea Sodium valproate Tonic or atonic Sodium valproate Clobazama Lamotrigine Levetiracetam Sodium valproate Topiramate Lamotriginea Absence Ethosuximide Lamotriginea Sodium valproate Ethosuximide Lamotriginea Sodium valproate Myoclonic Levetiracetama Sodium valproate Topiramatea Levetiracetam Sodium valproate Topiramatea Focal Carbamazepine Lamotrigine Levetiracetam Oxcarbazepine Sodium valproate Carbamazepine Clobazama Gabapentina Lamotrigine Levetiracetam Oxcarbazepine Retigabine Sodium valproate Topiramate Other AEDs that may be considered on referral to tertiary care Rufinamidea Topiramatea Clobazama Clonazepam Levetiracetama Topiramatea Zonisamidea Clobazama Clonazepam Piracetam Zonisamidea Eslicarbazepine acetate Lacosamide Phenobarbital Phenytoin Pregabalina Tiagabine Vigabatrin Zonisamidea a At the time of publication of guidance (January 2012) this drug did not have UK marketing authorisation for this indication and/or population. Informed consent should be obtained and documented. Notes: 1. Controlled release preparations of carbamazepine are preferable to standard release formulations. 2. MHRA advice (April 2017): Children exposed in utero to valproate are at a high risk of serious developmental disorders (in up to 30-40% of cases) and/or congenital malformations (in approximately 10% of cases) o do not prescribe valproate medicines for epilepsy or bipolar disorder in women and girls unless other treatments are ineffective or not tolerated; migraine is not a licensed indication o ensure women and girls taking valproate medicines understand the 30–40% risk of neurodevelopmental disorders and 10% risk of birth defects and are using effective contraception o valproate use in women and girls of childbearing potential must be initiated and supervised by specialists in the treatment of epilepsy or bipolar disorder . 3. Lamotrigine and oral contraceptives: The Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit could find no evidence that lamotrigine reduces the effectiveness of hormonal contraception, but there is evidence that seizure control worsens in some women when starting a combined oral contraceptive pill (COC) containing ethinylestradiol and desogestrel, and that side effects associated with lamotrigine can increase when women using lamotrigine discontinue COC. 4. Phenytoin has a narrow therapeutic index and the relationship between dose and plasma concentration is nonlinear; a small dose increase in some patients may produce large rises in plasma concentration with acute toxic side effects. 5. On the basis of single dose tests, there are no clinically relevant differences in bioavailability between available phenytoin sodium tablets and capsules, but there may be a pharmacokinetic basis for maintaining the same brand in some patients. 6. 90mg of phenytoin (chewable tablets or suspension) is considered to be equivalent to 100mg of phenytoin sodium (capsules or tablets), so care is needed if patients are transferred from one preparation to another. 7. Retigabine has been approved by NICE as adjunctive treatment of partial onset seizures in adults. For guidance see: NICE TA 232: Retigabine as adjunctive treatment for the control of partial onset seizures (July 2011) 8. The CSM have issued a warning regarding vigabatrin and visual field defects. Patients need monitoring, with visual field assessment carried out every 6 months. See Current Problems in Pharmacovigilance November 1999 for details. 9. The risk of serious skin-related adverse drug reactions, including Stevens-Johnson syndrome, occurring with First line drugs Second line drugs Specialist drugs 31 Specialist only drugs carbamazepine may be increased in the presence of the HLA-A*3101 allele in patients of European descent or Japanese origin. However, there are currently insufficient data to support screening for this allele before starting carbamazepine treatment. Patients of European descent or Japanese origin who are known to be positive for this allele should only receive carbamazepine, oxcarbazepine or eslicarbazepine (not formulary) after careful consideration of the benefits and risks. Full Drug Safety Update (December 2012) 10. Epanutin Capsules (phenytoin) have been discontinued; all other presentations of Epanutin continue to be available. Phenytoin Sodium Flynn Hard Capsules are available which are identical to Epanutin capsules. Prescriptions should be written as ‘Phenytoin Sodium Flynn xmg Hard Capsules’, See Flynn Pharma Ltd Announcement 11. Perampanel is available on the formulary as adjunctive treatment for refractory epilepsies. The dose requires titration upwards according to response and tolerability over a period of at least 3 months. Titration upwards to a stable maintenance dose should be undertaken by the specialist. Once the patient is on a stable dose (at least 3 months after starting treatment) prescribing responsibility can be passed over to GPs under shared care arrangements. Antiepileptic drug formulations See section 11.6 Acetazolamide Tablet 100mg, 200mg, 400mg Tegretol® m/r tablet 200mg, 400mg Chewable tablet 100mg, 200mg SF Liquid 100mg/ml Suppository 125mg, 250mg Tablet 10mg Clonazepam Tablet 500microgram, 2mg Injection see 4.8.2 Ethosuximide Capsule 250mg Syrup 250mg/5ml Capsule 100mg, 300mg, 400mg. Tablets 600mg 800mg Tablet 25mg, 50mg, 100mg, 200mg Dispersible tablet 2mg, 5mg, 25mg, 100mg Tablets 250mg, 500mg, 1g Oral solution SF 100mg/ml Tablets 150mg, 300mg, 600mg Oral suspension SF 300mg/5ml Fycompa® Tablets 2mg, 4mg, 6mg, 8mg, 10mg 12mg Phenytoin sodium Epanutin® Capsule 25mg, 50mg, 100mg, 300mg Tablet 100mg Chewable tablet 50mg (scored) Suspension 30mg in 5ml Pregabalin Capsules 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 300mg Retigabine▼ Tablets 50mg, 100mg, 200mg, 300mg, 400mg Sodium valproate Crushable tablet 100mg E/c tablets 200mg, 500mg Epilim Chrono® m/r tablet 200mg, 300mg, 500mg SF Liquid 200mg/5ml Intravenous injection 400mg Tablets 5mg, 10mg, 15mg Topiramate Tablet 25mg, 50mg, 100mg, 200mg Sprinkle capsules 15mg, 25mg, 50mg Vigabatrin Tablet 500mg SF Powder 500mg Carbamazepine Clobazam SLS Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Perampanel▼ Tiagabine MHRA advice: Antiepileptic products – changing brands First line drugs Second line drugs Specialist drugs 32 Specialist only drugs In November 2013 the Commission of Human Medicines issued advice on the suitability of switching between different manufacturer’s products of antiepileptic drugs (AEDs). They have grouped the AEDs into categories depending on their suitability for switching (see table below). Further information can be found here. Category 1 Category 2 Category 3 Phenytoin, carbamazepine, phenobarbital, primidone Doctors are advised to ensure that their patient is maintained on a specific manufacturer’s product. Valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate. Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin. It is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific concerns such as patient anxiety, and risk of The need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with patient and/or carer taking into account factors such as seizure frequency and treatment history confusion or dosing errors. 4.8.2 Status epilepticus Buccolam® single dose oral syringe 2.5mg, 5mg, 7.5mg, 10mg Buccal midazolam Diazepam Rectal solution 2.5mg, 5mg, 10mg Intravenous injection (emulsion) (Diazemuls®) 5mg/ml Lorazepam Intravenous injection (into large vein) 4mg/ml Phenytoin sodium Intravenous injection 250mg/5 ml Clonazepam Intravenous injection 1mg/ml or infusion of 1mg Paraldehyde Rectally administered 5ml ampoule. For doses in children see BNF. Replaces unlicensed product (Epistatus) Notes: 1. Buccal midazolam (first line) or rectal diazepam (second line) should only be prescribed in the community for children, young people and adults who have had a previous episode of prolonged or serial convulsive seizures . 2. Buccal midazolam (as Buccolam®) is available in single use oral syringes colour coded by age 3. A single dose of buccal midazolam should be administered in accordance with the table below. Administration in children aged 3 to 6 months must be carried out in a hospital setting. Age range 3 to 6 months (hospital setting ) Dose 2.5mg Label colour Yellow > 6 months to < 1 year 1 year to < 5 years 5 years to < 10 years 10 years to < 18 years 2.5mg 5 mg 7.5 mg 10 mg Yellow Blue Purple Orange 4. Unlicensed versions of buccal midazolam should no longer be prescribed 5. In the community, treatment of status epilepticus with rectal diazepam should be considered if preferred by the patient or where buccal midazolam is not available 6. Major status epilepticus should be treated initially with i.v lorazepam. Intravenous diazepam may also be used but lorazepam has a longer duration of action. 7. Diazepam i.v is associated with a high risk of venous thrombophlebitis, which is reduced by using an emulsion (Diazemuls®). 8. Absorption from intramuscular injection or from suppositories is too slow for the treatment of status epilepticus. 9. Paraldehyde is also included for paediatric use in prolonged or recurrent seizures First line drugs Second line drugs Specialist drugs 33 Specialist only drugs 4.9 Drugs used in parkinsonism and related disorders For guidance on the management of Parkinson’s disease refer to NICE Clinical Guideline CG35: Parkinson's disease: quick reference guide (June 2006) Notes: 1. Parkinson’s disease is classically determined by the triad of rest tremor (usually starting in one arm) with bradykinesia (slowing of movement) and rigidity (which may manifest as cogwheel rigidity particularly in the arms). 2. Patients often display a generalised lack of movement both in terms of facial expression and general body movement. They often have reduced arm swing (usually asymmetrical at the beginning) with festinant gait. They may have impaired ability to correct their balance. 3. All patients with a suspected diagnosis of Parkinson’s disease should be referred for a specialist opinion prior to initiating any treatment. 4. There is currently no treatment that has been definitely proven to slow down the progression of Parkinson’s disease and therefore patients will not be adversely affected by waiting to commence treatment particularly if there is any doubt about the diagnosis. 5. Current drug therapy aims simply to correct the chemical imbalance. Although this approach fails to prevent the progression of the disease, it greatly improves the quality and expectancy of life of most patients. 6. It is important to eliminate the possibility of anti-dopaminergic drugs causing parkinsonian symptoms, for example prochlorperazine, metoclopramide, chlorpromazine, trifluoperazine, haloperidol and thioridazine. 7. Elderly: Antiparkinsonism drugs carry a special risk of inducing confusion in the elderly. It is particularly important to initiate treatment with low doses and to use small increments. 4.9.1 Dopaminergic drugs used in parkinsonism Levodopa plus peripheral decarboxylase inhibitor preparations Notes: 1. Levodopa in combination with a dopa-decarboxylase inhibitor is the treatment of choice for patients disabled by idiopathic Parkinson’s disease. It should not be used for neuroleptic-induced Parkinsonism. 2. Sudden onset of sleep: Excessive daytime sleepiness and sudden onset of sleep can occur with co-careldopa, co-beneldopa, and the dopamine receptor agonists. Patients starting on treatment with these drugs should be warned of the possibility of these effects and of the need to exercise caution when driving or operating machinery. Patients who have suffered excessive sedation or sudden onset of sleep, should refrain from driving or operating machines, until those effects have stopped. Co-beneldopa (Madopar®) Capsule 62.5mg, 125mg, 250mg Disp tablet 62.5mg, 125mg Madopar CR® m/r capsule 125mg Co-careldopa (Sinemet®) Tablet 62.5mg, 125mg (Sinemet Plus®) 275mg Half Sinemet CR ® m/r tablet 125mg Sinemet CR ®m/r tablet 250mg Co-careldopa/ entacapone (Stalevo) Tablets 50mg/12.5mg/200mg Tablets 75mg/18.75mg/200mg Tablets 100mg/25mg/200mg Tablets 125mg/31.25mg/200mg Tablets 150mg/37.5mg/200mg Tablets 200mg/50mg/200mg Notes: 1. The co-careldopa (10/100) formulation (Sinemet 110) should not generally be used as the dose of carbidopa may be insufficient to achieve full inhibition of extracerebral dopa-decarboxylase; co-careldopa 25/100 should therefore be used so that the daily dose of carbidopa is at least 75mg. 2. Levodopa therapy should be initiated with low doses and gradually increased, by small increments, at intervals of 2-3 days. The final dose is usually a compromise between increased mobility and dose-limiting side effects. 3. Modified release preparations may help with “end-of-dose” deterioration or nocturnal immobility and rigidity. 4. The triple combination product Stalevo is a useful aid to compliance in patients requiring treatment with L-dopa and the COMT inhibitor entacapone and facilitates the requirement for entacapone to be taken at the same time as L-dopa. First line drugs Second line drugs Specialist drugs 34 Specialist only drugs Dopamine receptor agonists Pramipexole Tablets 88microgram, 180microgram, 700microgram, Prolonged release tablets 260microgram, 520microgram, 1.05mg, 2.1mg, 3.15mg Ropinirole Tablets 1mg, 2mg, 5mg Starter pack (250microgram, 500microgram and 1mg tablets) Follow-on pack (500micrograms, 1mg and 2mg tablets) Rotigotine▼ Patches 2mg/24 hours, 4mg/24 hours, 6mg/24 hours, 8mg/24 hours 28 day Starter pack (7x2mg/24hr, 7x4mg/24hr, 7x6mg/24hr, 7x8mg/24hr patches) Apomorphine Injection 20mg in 2ml, 50mg in 5ml Injection 30mg in 3ml pen injector 50mg in 10ml pre-filled syringes MR▼ tablets 2mg, 4mg, 8mg For use in hospital only For intermittent s/c injection For continuous s/c infusion in the community Notes: 1. Doses of dopamine receptor agonists should be increased slowly according to response and tolerability. As doses are increased the strength should be increased as appropriate, rather than the number of tablets. 2. Ergot-derived dopamine receptor agonists: the CSM has advised that ergot-derived dopamine receptor agonists, bromocriptine, cabergoline, lisuride and pergolide have been associated with pulmonary, retroperitoneal, and pericardial fibrotic reactions. The ergot derivatives have therefore not been included in the formulary. However, many patients have been taking these drugs for years, with good symptom control and without side effects. Such patients should be monitored and the potential side effects discussed and only discontinued if the patient wishes. These patients should be treated under specialist supervision. No new patients should be initiated on these drugs. The CSM guidelines are that these agents should only be considered in patients who are intolerant of or fail to respond to non-ergot agonists. 3. Ropinirole MR and rotigotine formulations all have black triangle status (▼) and any suspected adverse reactions must be reported using the Yellow Card Scheme. 4. Ropinirole is likely to be most useful as an adjunct to levodopa. It can be used as monotherapy in younger patients who are at risk of developing disabling dyskinesia with long-term levodopa therapy. 5. The Scottish Medicines Consortium (SMC) advises that rotigotine is suitable for use as monotherapy in early stage disease (June 2007) but recommends restricted use in advanced Parkinson’s disease with levodopa where the transdermal route would facilitate treatment (July 2007) 6. Apomorphine is sometimes helpful in stabilising patients experiencing unpredictable “off” periods with levodopa treatment and can be given either by intermittent s/c injection or by continuous s/c infusion. It is essential to stabilise patients on domperidone for at least 2 days before starting treatment with apomorphine. All initiations must take place in secondary care under the direct supervision of the Parkinson’s Specialist Nurses. 7. Once assessment for suitability and response is undertaken in secondary care and patient has been stabilised on a tailored apomorphine schedule, patients are suitable for shared care. Details of shared care guidelines can be obtained from the Parkinson’s Specialist Nurses at both sites. Catechol-O-methyltransferase inhibitors (COMT inhibitors) Entacapone Tablets 200mg Tolcapone Tablets 100mg Notes: 1. The current guidance is that entacapone should be the first COMT inhibitor to be used, and tolcapone should only be used in cases of entacapone intolerance or failure. 2. Tolcapone is black triangle status (▼) and any suspected adverse reactions must be reported using the Yellow Card Scheme. 3. Tolcapone is associated with potentially life-threatening hepatotoxicity hence regular monitoring of liver function is necessary. MAO type B antagonist Tablet 5mg, 10mg Selegiline Rasagilene First line drugs Syrup 10mg in 5ml Oral lyophilisate 1.25mg Tablets 1mg Second line drugs Specialist drugs 35 Specialist only drugs Notes: 1. Selegiline is used in severe Parkinsonism in conjunction with levodopa to reduce “end-of-dose” deterioration. 2. The oral lyophilisate formulation of selegiline is significantly more expensive than standard tablets or syrup but allows once-daily dosing. 3. 1.25mg of selegiline oral lyophilisate is approximately therapeutically equivalent to 10mg selegiline tablets Mixed action Amantadine Capsules 100mg Syrup 50mg in 5ml Note: Amantadine has a modest effect on dyskinesias and only a small proportion of patients derive much benefit. Tolerance to its effect occurs. 4.9.2 Antimuscarinic drugs used in parkinsonism Tablets 50mg Orphenadrine Oral solution 50mg/5ml Procyclidine Tablet 5mg Syrup 2.5mg/5ml, 5mg/5ml Injection 10mg in 2ml Trihexphenidyl Tablet 2mg, 5mg Syrup 5mg in 5ml Notes: 1. Patients with mild symptoms of Parkinson’s disease, particularly where tremor predominates, may be treated initially with antimuscarinic drugs (alone or with selegiline), levodopa being added or substituted as symptoms progress. 2. They have value in post-encephalitic Parkinsonism. 3. They reduce tremor and rigidity but have little effect on bradykinesia. They are useful in reducing sialorrhoea. 4. The antimuscarinic drugs reduce the symptoms of drug-induced Parkinsonism. 5. Tardive dyskinesia is not improved by the antimuscarinic drugs and may be made worse. 6. Trihexphenidyl is the antimuscarinic of choice particularly in younger patients 7. Orphenadrine has been included for patients who may misuse procyclidine. 4.9.3 Drugs used in essential tremor, chorea, tics, and related disorders Note: BNF Section 4.9.3 gives information on choice of medication. See the current edition of the BNF for dose guidelines. Essential tremor Notes: 1. Propranolol (section 2.4) may be useful for tremors, or tremors associated with anxiety or thyrotoxicosis. 2. Primidone and clonazepam are alternatives. Tics etc Notes: 1. Haloperidol may be useful in improving motor tics and symptoms of Gilles de la Tourette syndrome and related choreas. 2. Pimozide (N.B. CSM warnings; see section 4.2.1), clonidine (section 4.7.4.2) and sulpiride (section 4.2.1) are also used in Gilles de Tourette syndrome. 3. Chlorpromazine and haloperidol (section 4.2.1) are used to relieve intractable hiccups. Huntington’s Chorea Tablet 25mg Tetrabenazine Notes: 1. Tetrabenazine has a useful action for movement disorders, only in the latter stage of the disease. 2. Tetrabenazine may cause depression and excessive sedation. It may also precipitate extrapyramidal side effects. It is therefore important to initiate treatment on the minimum effective dose and increase dosage no more frequently than on a weekly basis. First line drugs Second line drugs Specialist drugs 36 Specialist only drugs Myoclonus Piracetam Tablet 800mg, 1.2g Oral solution 333.3mg/ml Amyotrophic Lateral Sclerosis (Motor Neurone Disease) Tablet 50mg Riluzole Notes: 1. Riluzole is used to extend life or the time to mechanical ventilation in patients with motor neurone disease who have amyotrophic lateral sclerosis. 2. NICE guidance TA 20 (January 2001): Riluzole is recommended for the treatment of individuals with the amyotrophic lateral sclerosis (ALS) form of Motor Neurone Disease (MND). A neurological specialist should initiate therapy with expertise in the management of MND. Routine supervision of therapy should be managed by locally agreed shared care protocols undertaken by general practitioners. Torsion dystonias and other involuntary movements Injection 500 unit vial Botulinum A toxin (Dysport®) Notes: 1. Dysport® is indicated for the treatment of spasmodic torticollis, blepharospasm and hemifacial spasm in adults. 2. Please refer to product literature for further information. 4 .1 0 Drugs used in substance dependence Alcohol dependence Chlordiazepoxide See section 4.1.2 Disulfiram Acamprosate Nalmefene▼ Tablet 200mg Tablet e/c 333mg Selincro® Tablets 18ng Notes: NICE CG100 Alcohol use disorders (June 2010) gives guidance on the diagnosis and management of symptoms caused by alcohol dependence. 1. Acamprosate should only be prescribed in combination with counselling, when it may be helpful in maintaining abstinence in alcohol dependent patients. 2. Diazepam or oxazepam may be considered as alternatives to chlordiazepoxide 3. NICE TA 325 offers nalmefene in conjunction with psychosocial support for dependent drinkers who do not need immediate detoxification. Patients should be referred to the STAR service (East Sussex Drug and Alcohol service) who will assess for suitability, prescribe nalmefene where appropriate and provide psychosocial support. All prescribing will remain with the STAR service. Nalmefene should not be prescribed in primary care. Cigarette smoking: Nicotine replacement therapy (NRT), varenicline and bupropion are all proven to help patients quit smoking. Guidance on how they can be used is given in NICE guidance PH10: Smoking cessation services (August 2008) Offer NRT, varenicline or bupropion, as appropriate, to people who are planning to stop smoking. NRT, varenicline or bupropion should normally be prescribed as part of an abstinent-contingent treatment, in which the smoker makes a commitment to stop smoking on or before a particular date (target stop date). The prescription of NRT, varenicline or bupropion should be sufficient to last only until 2 weeks after the target stop date. Normally, this will be after 2 weeks of NRT therapy, and 3–4 weeks for varenicline and bupropion, to allow for the different methods of administration and mode of action. Subsequent prescriptions should be given only to people who have demonstrated on re-assessment that their quit attempt is continuing. Varenicline or bupropion may be offered to people with unstable cardiovascular disorders, subject to clinical judgement. Consider offering a combination of nicotine patches and another form of NRT (such as gum, inhalator, lozenge or nasal spray) to people who show a high level of dependence on nicotine or who have found single forms of NRT inadequate in the past. Do not favour one medication over another. The clinician and patient should choose the one that seems most likely to succeed. Neither varenicline or bupropion should be offered to young people under 18 nor to pregnant or breastfeeding First line drugs Second line drugs Specialist drugs 37 Specialist only drugs women. If a smoker’s attempt to quit is unsuccessful using NRT, varenicline or bupropion, do not offer a repeat prescription within 6 months unless special circumstances have hampered the person’s initial attempt to stop smoking, when it may be reasonable to try again sooner. Do not offer NRT, varenicline or bupropion in any combination. Smokers not wishing to quit straight away but wishing to follow the nicotine assisted reduction to stop (NARS) strategy should not be offered NRT until they are ready to fully quit. Nicorette® NiQuitin CQ® Gum 2mg, 4mg (Freshfruit and Icy White) Invisi Patch 10mg, 15mg, 25mg Inhalator 15mg cartridge Nasal Spray 500 micrograms per spray QuickMist® oromucosal spray 1mg per spray 30 and 105 pack sizes available Patch 7mg,14mg 21mg Minis Lozenge 1.5mg, 4mg 24 hour application. Packs of 7 16 hour application (take off at night) packs of 7 Available as starter pack and refil Available as a single or double pack 20 and 60 pack sizes available Notes: 1. Patches are first choice for most patients. The 16-hour patch (Nicorette®) is preferable as nicotine can cause sleep disturbances. However, if the patient has the first cigarette within 30 minutes of waking, the 24-hour patch (NiQuitin CQ®) would be more appropriate. 2. All listed products are licensed for use in children aged 12 and over. 3. All products are contra-indicated in the under 12’s 4. All the listed products can be used in pregnancy and lactation. However, patients should be advised to try and give up without the use of NRT due to the harmful effects of nicotine on the foetus and the fact that it also passes freely into breast milk. Bupropion Tablet m/r, f/c 150mg Notes: 1. Bupropion should be started 1-2 weeks before target stop date. The dose is initially 150mg DAILY for the first 6 days, only increasing to 150mg TWICE DAILY on day 7. Maximum period of treatment is 7 – 9 weeks. 2. Patients should only be prescribed bupropion if they are motivated to stop and (ideally) are receiving support from a Smoking Cessation Adviser. 3. GPs must assess the client’s suitability for bupropion. 4. In order to promote compliance and prevent wastage, the following prescribing schedule is recommended: 2 weeks 2 weeks dependent on continued abstinence 3 – 5 weeks as appropriate (Total course = 7 – 9 weeks) 5. Prescriptions should be linked to an appointment with a Smoking Cessation Adviser to check for continued abstinence. First line drugs Second line drugs Specialist drugs 38 Specialist only drugs 6. Bupropion is not recommended for smokers under the age of 18 years, as its safety and efficacy have not been evaluated in this group. Women who are pregnant or breastfeeding or those with a current or history of bipolar disorder should not be prescribed bupropion. 7. CSM advice: Bupropion is associated with a dose-related risk of seizure. In approximately 50% of cases, the patients had either a past history of seizure(s) and/or risk factors for their occurrence. Bupropion is therefore contraindicated in patients: - with a current seizure disorder or any history of seizures; - current or previous diagnosis of bulimia or anorexia nervosa; - with a known central nervous system (CNS) tumour; - experiencing abrupt withdrawal from alcohol or benzodiazepines Bupropion should not be prescribed in patients with other risk factors for seizures unless there is compelling justification for which potential benefit outweighs the increased risk of seizure. Such risk factors include: - concomitant administration of any drug known to lower the seizure threshold (e.g. antipsychotics, antidepressants, antimalarials, theophylline, systemic steroids, tramadol, quinolones and sedating antihistamines). - Alcohol abuse. - History of head trauma. - Diabetes treated with hypoglycaemics or insulin. - Use of stimulants or anorectic products. In such patients a lower dose of 150 mg daily throughout the entire treatment period should be considered. 8. Bupropion has considerable potential for interaction with other medicines. Further details can be found in the Summary of Product Characteristics (SPC). 9. Details of other side effects associated with bupropion can be found in the SPC. Doctors and pharmacists are asked to continue to report all suspected adverse reactions. Tablets 500 microgram, 1mg Starter pack containing 500mcg and 1mg tablets NICE guidance (TA123) July 2007 1. Varenicline is recommended within its licensed indications as an option for smokers who have expressed a desire to quit smoking. 2. Dose titration is necessary – see below Varenicline Days 1 – 3: 0.5 mg once daily Days 4 – 7: 0.5 mg twice daily Day 8 – End of treatment: 1 mg twice daily 3. Treatment should be started 1-2 weeks prior to the agreed quit date and continued for 12 weeks. 4. Varenicline is contra-indicated in the under 18’s during pregnancy and lactation. 5. The MHRA has recently issued a reminder in its Drug Safety Update (November 2008) of safety issues associated with varenicline. Psychiatric disorders are the most commonly reported suspected adverse reactions for varenicline in the UK. Depression and suicide-related events have been reported in patients using varenicline who are trying to stop smoking. Patients who are taking varenicline who develop suicidal thoughts or who develop agitation, depressed mood, or changes in behaviour that are of concern for the doctor, patient, family, or caregiver should stop their treatment and contact their doctor immediately. 4.11 Drugs for dementia NICE guidance: NICE TA 217 (March 2011) Donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer's Disease (rev May 2016) The acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine are recommended as options for managing mild to moderate Alzheimer’s disease under all of the conditions specified in below (1-4) Memantine is recommended as an option for managing Alzheimer’s disease for people with: • moderate Alzheimer’s disease who are intolerant of or have a contraindication to AChE inhibitors or • Severe Alzheimer’s disease. Treatment should be under the conditions specified below (1-3). Treatment should be in accordance with the following conditions: 1. Only specialists in the care of patients with dementia (that is, psychiatrists including those specialising in learning disability, neurologists and physicians specialising in the care of older people) should initiate treatment. Carers’ First line drugs Second line drugs Specialist drugs 39 Specialist only drugs views on the patient’s condition at baseline should be sought. 2. Treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms. 3. Patients who continue on treatment should be reviewed regularly using cognitive, global, functional and behavioural assessment. Treatment should be reviewed by an appropriate specialist team, unless there are locally agreed protocols for shared care. Carers’ views on the patient’s condition at follow-up should be sought. 4. If prescribing an AChE inhibitor (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). Donepezil hydrochloride Galantamine Rivastigmine Memantine Tablet 5mg, 10mg Tablet 8mg, 12mg Capsules M/R Reminyl® XL 8mg, 16mg, 24mg Oral solution 4mg/ml Capsule 1.5mg, 3mg, 4.5mg, 6mg Oral solution 2mg/ml Patches 4.6mg in 24 hours, 9.5mg in 24 hours 10mg, 20mg, 10mg/ml oral soln Notes: Behavioural and psychological symptoms can be part of the dementing process, but it is important to exclude any intercurrent illness. Behavioural and psychological approaches are important and the use of medication has a lower profile. If medication is used, the rule of start low, go slow, monitor effects frequently applies. It is important to review any drug at regular intervals and assess whether it can be stopped as the treatment symptoms may have remitted. Other Guidance: NICE CG42: Dementia: supporting people with dementia and their carers in health and social care First line drugs Second line drugs Specialist drugs 40 Specialist only drugs