4. Central Nervous System

4.1.1 Hypnotics

The use of drug therapy should be avoided if at all possible. Conservative measures such as sleep hygiene and assessment of underlying reasons for sleeping difficulty (e.g. pain) should be explored first. For this reason, all hypnotic drugs are classed as ‘second line’.

Sleep hygiene measures

The implementation of these may be sufficient to resolve the sleeping problem.

 Increase daily exercise but not in the evening.  Reduce daytime napping.  Avoid caffeine and alcohol before bedtime.  Only use the bed for sleeping.  Use anxiety management or relaxation techniques.  Develop a regular routine of rising and retiring at the same time each day.

Drug therapy

Hypnotics should be avoided in the elderly if at all possible as they are at increased risk of falls and confusion. Prescribers are strongly encouraged to devote time to explaining the reduced need for sleep and altered sleeping patterns that occur in old age. Benzodiazepines in particular should be used at reduced dosage if they are used at all due to increased half lives and enhanced side effects such as morning sedation, disturbed gait, cognitive impairment, hypotension, memory impairment and reduced psychomotor performance.

NICE Guidance on Insomnia - Newer Hypnotic Drugs: Guidance (TAG77) 2005 recommend:-

 If hypnotic drug therapy is considered appropriate for the management of severe insomnia interfering with normal daily life, it is recommended that hypnotics should be prescribed for short periods of time only, in strict accordance with their licensed indications.  It is recommended that, because of the lack of compelling evidence to distinguish between zaleplon, zolpidem, zopiclone or the shorter-acting benzodiazepine hypnotics, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed.  It is recommended that switching from one of these hypnotics to another should only occur if a patient experiences adverse effects considered to be directly related

4. Central Nervous System 03/04/2018 Page | 1 to a specific agent. These are the only circumstances in which the drugs with the higher acquisition costs are recommended.  Patients who have not responded to one of these hypnotic drugs should not be prescribed any of the others.

The Guidelines of the Royal College of Psychiatrists:-

 Use the lowest effective dose.  Use intermittent dosing (alternate nights or less) where possible.  Prescribe for no more than 4 weeks in the majority of cases.  Discontinue slowly.  Be alert for rebound insomnia and withdrawal symptoms.  Advise patients of additive effects with alcohol and other sedating drugs.  Avoid use altogether in patients with respiratory disease, severe hepatic impairment and in addiction prone individuals.

Short Term Use Only

Zopiclone Tablets 3.75mg, 7.5mg £1.34 - £1.35

Temazepam Tablets 10mg £3.42 Tablets 20mg £2.24

Nitrazepam Tablets 5mg £0.98 Nitrazepam has a longer duration of action and more likely to cause a 'hangover' effect

Notes

1. There is no good evidence that any hypnotic is more efficacious than any other. 2. Temazepam has a long history of a drug of abuse and a ‘street’ value. Prescribers should consider this before prescribing.

4. Central Nervous System 03/04/2018 Page | 2 Stopping benzodiazepines

Section 4.1 of the BNF contains detailed guidance on withdrawal of benzodiazepines and provides a table of dose equivalence for some of the commonly encountered benzodiazepines.

Prices updated on this page 1st December 2010

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 3 4.1.2 Anxiolytics

NICE Guidance on Insomnia is available on the management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care.

Before starting treatment

Drug Treatment Before medication is prescribed there are six questions to be answered:

1. Is the anxiety harmful or disabling? 2. Will the drug produce unwanted side effects? 3. How long will it be required? 4. Will it be effective? 5. Will it produce dependence - is it likely to be abused? 6. Would a non-drug strategy be more appropriate?

Psychological Treatment This is designed to teach skills in managing the cognitive and somatic components of anxiety and is as effective as drugs but with fewer drawbacks. Brief counselling and structured problem solving techniques are effective and may be delivered in general practice. NICE guidance states that there is greater evidence for psychological therapy than for pharmacological therapy for the longest duration of benefit.

There are several disorders within the spectrum of anxiety disorders (generalised anxiety, panic disorder, obsessive compulsive disorder, social phobia and agoraphobia). Each of these is associated with its own clinical presentation. Whilst drug treatment of these is similar, this formulary contains specific guidance for some of the disorders. The WHO has produced an anxiety checklist which may be useful in assessing anxiety spectrum disorder.

4. Central Nervous System 03/04/2018 Page | 4 WHO anxiety checklist

Initial questions A. Feeling tense or anxious? B. Worrying about a lot of things?

If the answer to the above is positive, then continue below.

1. Symptoms of arousal and anxiety?

2. Experienced intense or sudden fear unexpectedly or for no apparent reason?

Fear of dying Fear of loosing control Pounding of heart Sweating Trembling or shaking Chest pains or difficulty breathing Feeling dizzy, light-headed or faint Numbness or tingling sensation Feelings of unreality Nausea

3. Experienced fear/anxiety in specific situations?

Leaving familiar places Travelling alone, e.g. train, car, plane Crowds/confined places/public spaces

4. Experienced fear/anxiety in social situations?

Speaking in front of others Social events Eating in front of others, worry about what others think or self conscious Summing up

Positive to A, B and 1 recurring regularly, negative to 2, 3 and 4 indicates generalised anxiety disorder. Positive to 1 and 2 indicates panic disorder. Positive to 2 and 3 indicates agoraphobia. Positive to 3 and 4 indicates social phobia.

4. Central Nervous System 03/04/2018 Page | 5 Generalised Anxiety Disorder

Benzodiazepines have been widely used in the management of anxiety for many years and provide rapid symptomatic relief. Due to the potential of these drugs to produce dependence and withdrawal reactions, they should be used in the minimum effective dose for the shortest period of time (maximum duration 4 weeks). SSRIs take longer to act (up to 6 weeks) and there is thus a limited role for benzodiazepines in the treatment of patients whose symptoms are severe enough to warrant immediate treatment, whilst other measures, which may include drug and non-drug treatment, are put into place. Some tricyclics may be helpful although none are specifically licensed, and none are mentioned in the NICE guidance.

1. Emergency short term treatment for distressing and disabling symptoms

Diazepam Tablets 2mg three times daily increased if necessary £2.67 for 4 weeks treatment

Notes

1. Diazepam has a rapid onset of action and is relatively free from side effects. Use should usually be short term (up to 2 weeks) because of the development of tolerance and addiction. Long term use is recognised in small sub-groups of patients, e.g. chronic anxiety and a history of long exposure to benzodiazepines.

2. Longer term treatment

Paroxetine Tablets 20mg £2.29 Liquid 10mg/5ml £18.24 Dose 20mg daily Paroxetine is licensed but do we want to consider citalopram or fluoxetine first line - NICE does state that if first SSRI is not effective after 12 weeks.

Notes

1. Treatment of anxiety may prevent the development of depression. 2. Many SSRIs may be effective in anxiety although paroxetine is specifically licensed for generalised anxiety disorder (GAD). Fluoxetine is licensed for depression with anxiety. Venlafaxine XL is licensed for moderate to severe GAD characterised by

4. Central Nervous System 03/04/2018 Page | 6 chronic and excessive worry sufficient to cause impairment to everyday functioning for 6 months. 3. Before prescribing venlafaxine, prescribers should take into account the increased likelihood of patients stopping treatment because of side effects, and its higher cost, compared with equally effective SSRIs [NICE Guidance]. Venlafaxine should not be prescribed for patients with uncontrolled hypertension. The dose of venlafaxine should not exceed 75mg daily. Blood pressure should be monitored regularly and patients checked for signs of cardiac dysfunction. Venlafaxine should not be prescribed for patients with a high risk of cardic arrhythmias or recent MI. 4. Some experts suggest initiating SSRIs at half the usual dosage as an initial worsening of symptoms has been reported to occur on commencing drug treatment. However, the licensed dose for paroxetine is 20mg daily. 5. Paroxetine has been associated with significant withdrawal reactions and increased risk of suicide in certain patient groups when being used to treat depression.

3. Alternative Agents

Clomipramine and impramine are not mentioned in the NICE Guidance. Venlafaxine - see notes above.

Panic Disorder

Benzodiazepines, SSRIs and tricyclics have all found use in the management of panic in the past. NICE guidance states that benzodiazepines should not be prescribed for the treatment of panic disorder because they have a less good outcome. Sedating antihistamines and antipsychotics should also be avoided. NICE guidance also states that psychological therapy has greater evidence for the longest duration of effect. For pharmacological therapy the two classes of medication that have evidence for effectiveness are tricylics and SSRIs.

SSRIs

Citalopram Tablets 10mg, 20mg. Start with 10mg daily for one week then increase to 20-30mg daily £2.33 (30mg) Dose increases up to a maximum of 60mg may be beneficial - see notes Oral drop formulation (dose difference) also available - see BNF

4. Central Nervous System 03/04/2018 Page | 7 Paroxetine Tablets 20mg, 30mg. Start with 10mg (half a 20mg tablet) daily for one week, increase by 20mg per week up to 40mg daily £4.58 (40mg)

Notes

1. SSRIs should be started at low dose in the treatment of panic. They may have a slow onset of beneficial action with an initial worsening of symptoms. The dose of paroxetine should be titrated up at weekly intervals to a dose which is in the higher end of the dose range for the drug, although with citalopram moderate doses in the range 20-30mg may give the best balance between side effects and efficacy.

Obsessive compulsive disorder

NICE Guidance is available (CG31, November 2005) on Obsessive-compulsive disorder: Core interventions in the treatment of obsessive-compulsive disorder and body dysmorphic disorder.

Fluoxetine Capsules 20mg daily £1.84

Clomipramine Capsules 10mg, 25mg, 50mg. Start at 25mg daily and increase over 2 weeks to 100-150mg daily £5.50(100mg)

Notes

1. Only anti-depressants acting on the serotonin system have been shown to be effective (other TCAs not appropriate). 2. Although a dose response has not been demonstrated for fluoxetine, some patients may benefit from higher doses. 3. A response to treatment may not be seen for several weeks.

Prices updated on this page 1st December 2010

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 8 4.3 Antidepressant Drugs

NICE issued guidance on the management of depression in October 2009 CG90. this recommendations are:-

 Low-intensity psychosocial interventions  For people with persistent subthreshold depressive symptoms or mild to moderate depression, consider offering one or more of the following interventions, guided by the person’s preference:  individual guided self-help based on the principles of cognitive behavioural therapy (CBT)  computerised cognitive behavioural therapy (CCBT)  a structured group physical activity programme

 Drug treatment  Do not use antidepressants routinely to treat persistent subthreshold depressive symptoms or mild depression because the risk–benefit ratio is poor, but consider them for people with:  a past history of moderate or severe depression or  initial presentation of subthreshold depressive symptoms that have been present for a long period (typically at least 2 years) or  subthreshold depressive symptoms or mild depression that persist(s) after other interventions.  Although there is evidence that St John’s wort may be of benefit in mild or moderate depression, practitioners should:  not prescribe or advise its use by people with depression because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants)  advise people with depression of the different potencies of the preparations available and of the potential serious interactions of St John’s wort with other drugs.

 Treatment for moderate or severe depression  For people with moderate or severe depression, provide a combination of antidepressant medication and a high-intensity psychological intervention (CBT or IPT).

4. Central Nervous System 03/04/2018 Page | 9  Continuation and relapse prevention  Support and encourage a person who has benefited from taking an antidepressant to continue medication for at least 6 months after remission of an episode of depression. Discuss with the person that:  this greatly reduces the risk of relapse  antidepressants are not associated with addiction.

 Psychological interventions for relapse prevention  People with depression who are considered to be at significant risk of relapse (including those who have relapsed despite antidepressant treatment or who are unable or choose not to continue antidepressant treatment) or who have residual symptoms, should be offered one of the following psychological interventions:  individual CBT for people who have relapsed despite antidepressant medication and for people with a significant history of depression and residual symptoms despite treatment  mindfulness-based cognitive therapy for people who are currently well but have experienced three or more previous episodes of depression.

Antidepressant Drugs

Choice of antidepressant

Discuss antidepressant treatment options with the person with depression, covering:

 the choice of antidepressant, including any anticipated adverse events, for example side effects and discontinuation symptoms and potential interactions with concomitant medication or physical health problems

 their perception of the efficacy and tolerability of any antidepressants they have previously taken

 When an antidepressant is to be prescribed, it should normally be an SSRI in a generic form because SSRIs are equally effective as other antidepressants and have a favourable risk–benefit ratio. Also take the following into account:  SSRIs are associated with an increased risk of bleeding, especially in older people or in people taking other drugs that have the potential to damage the gastrointestinal mucosa or interfere with clotting. In particular, consider

4. Central Nervous System 03/04/2018 Page | 10 prescribing a gastroprotective drug in older people who are taking non- steroidal anti-inflammatory drugs (NSAIDs) or aspirin.  Fluoxetine, fluvoxamine and paroxetine are associated with a higher propensity for drug interactions than other SSRIs  Paroxetine is associated with a higher incidence of discontinuation symptoms than other SSRIs.

 Take into account toxicity in overdose when choosing an antidepressant for people at significant risk of suicide. Be aware that:  compared with other equally effective antidepressants recommended for routine use in primary care, venlafaxine is associated with a greater risk of death from overdose  tricyclic antidepressants (TCAs), except for lofepramine, are associated with the greatest risk in overdose.

 When prescribing drugs other than SSRIs, take the following into account:  The increased likelihood of the person stopping treatment because of side effects (and the consequent need to increase the dose gradually) with venlafaxine, duloxetine and TCAs.  The specific cautions, contraindications and monitoring requirements for some drugs. For example:  the potential for higher doses of venlafaxine to exacerbate cardiac arrhythmias and the need to monitor the person’s blood pressure  the possible exacerbation of hypertension with venlafaxine and duloxetine  the potential for postural hypotension and arrhythmias with TCAs  the need for haematological monitoring with mianserin in elderly people  Non-reversible monoamine oxidase inhibitors (MAOIs), such as phenelzine, should normally be prescribed only by specialist mental health professionals.  Dosulepin should not be prescribed.

Starting and initial phase of treatment  When prescribing antidepressants, explore any concerns the person with depression has about taking medication, explain fully the reasons for prescribing, and provide information about taking antidepressants, including:  the gradual development of the full antidepressant effect  the importance of taking medication as prescribed and the need to continue treatment after remission

4. Central Nervous System 03/04/2018 Page | 11  potential side effects  the potential for interactions with other medications  the risk and nature of discontinuation symptoms with all antidepressants, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine), and how these symptoms can be minimised  the fact that addiction does not occur with antidepressants.

 Offer written information appropriate to the person’s needs.

 For people started on antidepressants who are not considered to be at increased risk of suicide, normally see them after 2 weeks. See them regularly thereafter, for example at intervals of 2 to 4 weeks in the first 3 months, and then at longer intervals if response is good.

 A person with depression started on antidepressants who is considered to present an increased suicide risk or is younger than 30 years (because of the potential increased prevalence of suicidal thoughts in the early stages of antidepressant treatment for this group) should normally be seen after 1 week and frequently thereafter as appropriate until the risk is no longer considered clinically important.

 If a person with depression develops side effects early in antidepressant treatment, provide appropriate information and consider one of the following strategies:  monitor symptoms closely where side effects are mild and acceptable to the person or  stop the antidepressant or change to a different antidepressant if the person prefers or  in discussion with the person, consider short-term concomitant treatment with a benzodiazepine if anxiety, agitation and/or insomnia are problematic (except in people with chronic symptoms of anxiety); this should usually be for no longer than 2 weeks in order to prevent the development of dependence.

 People who start on low-dose TCAs and who have a clear clinical response can be maintained on that dose with careful monitoring.

4. Central Nervous System 03/04/2018 Page | 12  If the person’s depression shows no improvement after 2 to 4 weeks with the first antidepressant, check that the drug has been taken regularly and in the prescribed dose.

 If response is absent or minimal after 3 to 4 weeks of treatment with a therapeutic dose of an antidepressant, increase the level of support (for example, by weekly face-to-face or telephone contact) and consider:  increasing the dose in line with the SPC if there are no significant side effects or  switching to another antidepressant if there are side effects or if the person prefers.

 If the person’s depression shows some improvement by 4 weeks, continue treatment for another 2 to 4 weeks. Consider switching to another antidepressant if:  response is still not adequate or  there are side effects or  the person prefers to change treatment.

Sequencing treatments after initial inadequate response  When reviewing drug treatment for a person with depression whose symptoms have not adequately responded to initial pharmacological interventions:  check adherence to, and side effects from, initial treatment  increase the frequency of appointments using outcome monitoring with a validated outcome measure  be aware that using a single antidepressant rather than combination medication or augmentation is usually associated with a lower side-effect burden  consider reintroducing previous treatments that have been inadequately delivered or adhered to, including increasing the dose  consider switching to an alternative antidepressant.

Switching antidepressants  When switching to another antidepressant, be aware that the evidence for the relative advantage of switching either within or between classes is weak. Consider switching to:  initially a different SSRI or a better tolerated newer-generation antidepressant

4. Central Nervous System 03/04/2018 Page | 13  subsequently an antidepressant of a different pharmacological class that may be less well tolerated, for example venlafaxine, a TCA or an MAOI.

 Do not switch to, or start, dosulepin because evidence supporting its tolerability relative to other antidepressants is outweighed by the increased cardiac risk and toxicity in overdose.

 When switching to another antidepressant, which can normally be achieved within 1 week when switching from drugs with a short half-life, consider the potential for interactions in determining the choice of new drug and the nature and duration of the transition. Exercise particular caution when switching:  from fluoxetine to other antidepressants, because fluoxetine has a long half- life (approximately 1 week)  from fluoxetine or paroxetine to a TCA, because both of these drugs inhibit the metabolism of TCAs; a lower starting dose of the TCA will be required, particularly if switching from fluoxetine because of its long half-life  to a new serotonergic antidepressant or MAOI, because of the risk of serotonin syndrome  from a non-reversible MAOI: a 2-week washout period is required (other antidepressants should not be prescribed routinely during this period).

Combining and augmenting medications

The use of combinations of medications should only normally be started in primary care in consultation with a consultant psychiatrist - see the NICE Guidance for further information on combinations and augmentation.

Continuation and relapse prevention  Support and encourage a person who has benefited from taking an antidepressant to continue medication for at least 6 months after remission of an episode of depression. Discuss with the person that:  this greatly reduces the risk of relapse  antidepressants are not associated with addiction.

 Review with the person with depression the need for continued antidepressant treatment beyond 6 months after remission, taking into account:  the number of previous episodes of depression  the presence of residual symptoms  concurrent physical health problems and psychosocial difficulties.

4. Central Nervous System 03/04/2018 Page | 14  For people with depression who are at significant risk of relapse or have a history of recurrent depression, discuss with the person treatments to reduce the risk of recurrence, including continuing medication, augmentation of medication or psychological treatment (CBT). Treatment choice should be influenced by:  previous treatment history, including the consequences of a relapse, residual symptoms, response to previous treatment and any discontinuation symptoms  the person’s preference.

Using medication for relapse prevention  Advise people with depression to continue antidepressants for at least 2 years if they are at risk of relapse. Maintain the level of medication at which acute treatment was effective (unless there is good reason to reduce the dose, such as unacceptable adverse effects) if:  they have had two or more episodes of depression in the recent past, during which they experienced significant functional impairment  they have other risk factors for relapse such as residual symptoms, multiple previous episodes, or a history of severe or prolonged episodes or of inadequate response  the consequences of relapse are likely to be severe (for example, suicide attempts, loss of functioning, severe life disruption, and inability to work).

 When deciding whether to continue maintenance treatment beyond 2 years, re- evaluate with the person with depression, taking into account age, comorbid conditions and other risk factors.

 People with depression on long-term maintenance treatment should be regularly re-evaluated, with frequency of contact determined by:  comorbid conditions  risk factors for relapse  severity and frequency of episodes of depression.

 People who have had multiple episodes of depression, and who have had a good response to treatment with an antidepressant and an augmenting agent, should remain on this combination after remission if they find the side effects tolerable and acceptable. If one medication is stopped, it should usually be the augmenting agent. Lithium should not be used as a sole agent to prevent recurrence.

4. Central Nervous System 03/04/2018 Page | 15 Stopping or reducing antidepressants  Advise people with depression who are taking antidepressants that discontinuation symptoms

 When stopping an antidepressant, gradually reduce the dose, normally over a 4- week period, although some people may require longer periods, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine). This is not required with fluoxetine because of its long half-life. may occur on stopping, missing doses or, occasionally, on reducing the dose of the drug. Explain that symptoms are usually mild and self-limiting over about 1 week, but can be severe, particularly if the drug is stopped abrupt.

 Inform the person that they should seek advice from their practitioner if they experience significant discontinuation symptoms. If discontinuation symptoms occur:  monitor symptoms and reassure the person if symptoms are mild  consider reintroducing the original antidepressant at the dose that was effective (or another antidepressant with a longer half-life from the same class) if symptoms are severe, and reduce the dose gradually while monitoring symptoms.

The Royal College of Psychiatrists produce a series of fact sheets aimed at patients covering a variety of aspects of depression. These are available from their website (www.rcpsych.ac.uk/mentalhealthinfoforall.aspx).

4. Central Nervous System 03/04/2018 Page | 16 4.3.1 Tricyclic and Related Antidepressant Drugs

See general write up on Antidepressant Drugs for information about place in therapy.

Amitriptyline Tablets 10mg, 25mg, 50mg £3.00 (150mg daily) Liquid 25mg/5ml, 50mg/5ml £53.22 (150mg daily) Dose: Titrate up to 150mg daily

Lofepramine Tablets 70mg twice daily £5.69 Liquid 70mg/5ml twice daily £44.44

Trazodone Capsules 100mg: dose 100mg-300mg at night £4.72 - £7.27 Tablets 150mg: dose 150-300mg £4.57 - £9.14 Liquid 50mg/5ml £93.59 (300mg)

Notes

1. All patients receiving antidepressants should be assessed for suicide risk. Amitriptyline and dosulepin are particularly toxic in overdose. Lofepramine is less dangerous in overdose. 2. Lofepramine is associated with fewer anticholinergic side effects than amitriptyline or dosulepin and causes less sedation. 3. Trazodone is associated with fewer anticholinergic side effects than traditional TCAs but can be quite sedating. 4. Tricyclics are contra-indicated in: recent MI, arrhythmias particularly heart block, severe liver disease (seek specialist advice), manic phase. They should be used with caution in epilepsy, prostatism, narrow angle glaucoma, pregnancy and breast feeding (seek specialist advice). 5. Dosulepin (dothiepin) is no longer recommended for prescribing in depression - NICE Clinical Guideline CG90

Prices updated on this page 7th December 2010

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 17 4.3.3 Selective Serotonin Reuptake Inhibitors (SSRIs)

See general write up on Antidepressant Drugs for information about place in therapy. The NICE Clinical Guideline (CG90) on depression suggests:

 When an antidepressant is to be prescribed, it should normally be an SSRI in a generic form because SSRIs are equally effective as other antidepressants and have a favourable risk–benefit ratio.

 The choice of agent should therefore take into account:-  side-effect profile  patient preference  previous experience of treatments  propensity to cause discontinuation symptoms  safety in overdose  cost.  Potential interactions with concomitant medications or physical illness  fluoxetine, fluvoxamine and paroxetine have a higher propensity for drug interactions.  citalopram or sertraline as these have a lower propensity for interactions with existing conditions.  paroxetine is associated with a higher incidence of discontinuation symptoms.

 SSRIs are associated with an increased risk of bleeding. Consider prescribing a gastroprotective drug in older people who are taking NSAIDs or aspirin.

Citalopram Tablets 20mg daily £1.30 Oral drops 2mg/drop (16mg drop = 20mg tablet) £17.50

Sertraline Tablets 50mg, 100mg £1.15-£1.53

Fluoxetine Capsules 20mg daily £1.77 Liquid 20mg/5ml £10.08

4. Central Nervous System 03/04/2018 Page | 18 Notes

1. SSRIs should be used with caution in patients with epilepsy, history of mania, cardiac disease, history of bleeding disorders, hepatic and renal impairment. 2. GI bleed risk increases in those aged over 80 years old and in patients taking NSAIDs. 3. All SSRIs have similar efficacy and choice can often be made on grounds of cost. 4. Fluoxetine and citalopram are available generically and are the least expensive choices. Fluoxetine has a long half-life which should be taken into account when adjusting the dose or before changing to an alternative antidepressant. Paroxetine has been associated with significant withdrawal reactions (CSM) and increased risk of suicide in certain patient groups and must not be used in under 18 year olds. 5. NICE guidance recommends sertraline in patients with a recent MI or unstable angina.

Prices updated on this page 7th December 2010

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 19 4.3.4 Other Antidepressant Drugs

These are second line agents where the patient has not responded to or is intolerant to first line agents.

Mirtazapine Tablets 15mg, 30mg, 45mg £2.59 - £3.71 note unusual Dose initially 15mg at bedtime, max 45mg daily pricing structure at some doses the orodispersible table is cheaper than the plain tablet

Venlafaxine Tablets 75mg £4.71 (75mg bd) Dose initially 75mg twice daily, £18.70 (150mg od as MR increased in steps of 75mg Tablets) MR preparation

Notes

1. Mirtazepine is a pre-synaptic alpha-2 antagonist. It has few anticholinergic side effects but can produce sedation. It has been associated with blood dyscrasias and patients should report fever, sore throat, stomatitis or other signs of infection. 2. Venlafaxine acts in a dose-dependent way on neurotransmitter pathways. At lower doses it resembles an SSRI, whilst at higher doses it also interferes with noradrenaline reuptake. Its role is seen as a second line agent at doses of at least 75mg twice daily in those who have failed to respond to first line agents. The use of lower doses makes this an expensive SSRI option. Blood pressure should be checked on initiation and ensure hypertension is controlled. Blood pressure should be checked regularly during treatment particularly during dose titration. It should be used with caution in patients with heart disease. Prescribers should also note its higher propensity for withdrawal symptoms if stopped abruptly, its toxicity in overdose and its higher cost. 3. Other options such as MAOIs and lithium may be initiated in secondary care for patients who have failed to improve on first and second line therapies. 4. Venlafaxine MR Tablets are significantly cheaper than venlafaxine MR Capsules and so are the preferred option if modified release venlafaxine is required.

Prices on this page updated 7th December 2010

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 20 Prescribing Antidepressants in Special Situations

Pregnancy

 Antidepressants should be avoided if possible in pregnancy, and alternative measures considered as first option. If there is any doubt about management, please discuss with a consultant obstetrician/psychiatrist.  There is currently more experience with amitriptyline than with fluoxetine during pregnancy.  If an SSRI is to be prescribed during pregnancy, then fluoxetine is the one of choice.  There are currently concerns about the use of paroxetine during the first trimester due to a possible connection with fetal anomaly.  If starting an antidepressant during breast-feeding paroxetine or sertraline are the treatment of choice.

4. Central Nervous System 03/04/2018 Page | 21 4.4 CNS Stimulants and Drugs for ADHD

These drugs should be prescribed in Secondary Care - see NICE Guidance on Methylphenidate, Atomoxetine and Dexamfetamine for Attention Deficit Hyperactivity Disorder (March 2006).

4. Central Nervous System 03/04/2018 Page | 22 4.5 Drugs Used in the Treatment of Obesity

The NICE Clinical Guideline on obesity provides strategic guidance on the prevention, identification, assessment and management of overweight and obesity in adults and children. It provides key priorities for implementation that includes public health support, drug therapy and surgery.

General: indications and initiation

Pharmacological treatment should be considered only after dietary, exercise and behavioural approaches have been started and evaluated.

Adults

Drug treatment should be considered for patients who have not reached their target weight loss or have reached a plateau on dietary, activity and behavioural changes alone. The decision to start drug treatment, and the choice of drug, should be made after discussing with the patient the potential benefits and limitations, including the mode of action, adverse effects and monitoring requirements, and their potential impact on the patient’s motivation. When drug treatment is prescribed, arrangements should be made for appropriate healthcare professionals to offer information, support and counselling on additional diet, physical activity and behavioural strategies. Information on patient support programmes should also be provided.

Children

Drug treatment is not generally recommended in children under 12 years of age. For children 12 years and older treatment may be used in certain circumstances but should be initiated specialist paediatric setting, by multidisciplinary teams with experience of prescribing in this age group.

The following information therefore relates to adults only.

Continued prescribing and withdrawal

Pharmacological treatment may be used to maintain weight loss, rather than continue to lose weight.

If there is concern about the adequacy of micronutrient intake, a supplement providing the reference nutrient intake for all vitamins and minerals should be considered, particularly for vulnerable groups such as older people (who may be at risk of

4. Central Nervous System 03/04/2018 Page | 23 malnutrition) and young people (who need vitamins and minerals for growth and development).

People whose drug treatment is being withdrawn should be offered support to help maintain weight loss, because their self-confidence and belief in their ability to make changes may be low if they did not reach their target weight.

Regular review is recommended to monitor the effect of drug treatment and to reinforce lifestyle advice and adherence. Withdrawal of drug treatment should be considered in people who do not lose enough weight (see recommendations below)

Rates of weight loss may be slower in people with type 2 diabetes, so less strict goals than those for people without diabetes may be appropriate. These goals should be agreed with the person and reviewed regularly.

Orlistat

Orlistat should be prescribed only as part of an overall plan for managing obesity in adults who meet one of the following criteria:

 a BMI of 28.0 kg/m2 or more with associated risk factors  a BMI of 30.0 kg/m2 or more.

Therapy should be continued beyond 3 months only if the person has lost at least 5% of their initial body weight since starting drug treatment. The decision to use drug treatment for longer than 12 months (usually for weight maintenance) should be made after discussing potential benefits and limitations with the patient.

The coprescribing of orlistat with other drugs aimed at weight reduction is not recommended.

Orlistat Adult over 18 years old - 120mg taken immediately before, during or up to 1 hour after each main meal (up to max 360mg daily) Note - if a meal is missed or contains no fat, the dose of orlistat should be omitted.

4. Central Nervous System 03/04/2018 Page | 24 Sibutramine

Sibutramine please note that the marketing authorisation for sibutramine (Reductil) has now been withdrawn (21st January 2010). This is following a safety review by the European Medicines Agency on the basis of new safety information from a large clinical trial, the Sibutramine Cardiovascular OUTcomes (SCOUT) study. The review has found that the cardiovascular risks of sibutramine outweigh its benefits. The EMA's Committee for Medicinal Products for Human Use (CHMP) has recommended suspension of the marketing authorisation for this medicine across the European Union.

 Doctors should not issue any new prescriptions for sibutramine, and should review the treatment for those who are currently taking this medicine.  Pharmacists should not dispense any prescriptions for sibutramine and should advise patients to make an appointment to see their doctor at the next convenient time.  Patients who are currently being treated with sibutramine should be advised to schedule an appointment at the next convenient time with their doctor to discuss alternative measures to lose weight, including use of diet and exercise regimes. Patients may stop treatment before their appointment if they wish.  Further information can be found in the Healthcare Professional notification here (external link).

Rimonabant

The marketing authorisation for rimonabant has been suspended following a review by the CHMP. The CHMP concluded that the benefits of rimonabant treatment do not outweigh the risks of psychiatric adverse reactions. Prescribers should not issue prescriptions for rimonabant, treatment of patients who are taking rimonabant should be reviewed.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 25 4.6 Drugs Used in Nausea and Vertigo

Vomiting is a complicated process, mediated by a central co-ordinating ‘vomiting centre’, which is located in the brain stem. The vomiting centre receives input via the nervous system from many sources, including the chemoreceptor trigger zone (CTZ), the pharynx, the gastrointestinal tract, pain receptors and the vestibular apparatus. CTZ activity is modified by a variety of receptors, including histaminic, muscarinic and serotonergic. Most antiemetic drugs have antagonist activity at one or more of these receptors.

Anti-emetics should be prescribed only when the cause of vomiting is known, particularly in children, otherwise the symptomatic relief that they produce may delay diagnosis. Anti-emetics are unnecessary and sometimes harmful when the cause can be treated, e.g. as in diabetic ketoacidosis, or in excessive digoxin or anti-epileptic dosage.

Drug Condition Recommenda Information tions

Avoid cyclizine in patients with Prochlorperazine severe heart disease. Opioids & Anaesthetics po/im/pr Cyclizine may be associated Cyclizine po/im/iv with tachycardia

Prochlorperazine

po/im/pr Avoid cyclizine in patients with severe heart disease. Post-operative Cyclizine po/im/iv Cyclizine may be associated Dexamethasone with tachycardia

Ondansetron

Domperidone 10mg

tds po Domperidone is less likely to Parkinson's Disease cross the blood brain barrier. Domperidone 30mg tds pr

Gastroduodenal, hepatic, and biliary Metoclopramide po/iv disease

Cytotoxics Metoclopramide

4. Central Nervous System 03/04/2018 Page | 26 Ondansetron

Add betahistine in Meniere's

Hyoscine po disease. Treatment of chronic vertigo is seldom fully effective, Vertigo Cyclizine po/im/iv though drug therapy may help.

Prochlorperazine po Caution with the useof prochlorperazine in the elderly.

Hyoscine 300 30 mins before travel and two Motion sickness micrograms po subsequent doses

Cyclizine po

Cyclizine po/im/iv Refer to a specialist if vomiting Hyperemesis gravidum does not resolve in 24 - 48 Prochlorperazine 5mg hours. tds

See palliative care Palliative Care section

4. Central Nervous System 03/04/2018 Page | 27 4.7 Analgesics Including NSAIDs

General Notes

 Before starting or altering pain relief, an assessment of the degree of pain should be made using a validated rating scale.  Analgesics should be given by the oral route if possible and prescribed on a regular basis. As required analgesia is acceptable if the expected pain intensity and patient response is unpredictable.  This section does not include information on Palliative Care which may require a different approach.

Mild Pain

Paracetamol should be used as a first line analgesic unless contraindicated.

Moderate Pain

Prescribe Paracetamol +/- weak opioid +/- NSAID.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 28 4.7.1 Non-Opioid Analgesics

Paracetamol Dose 500mg - 1g up to four times a day Tablets 500mg Soluble tablets 500mg Suspension 120mg/5ml, 250mg/5ml Suppositories

Notes

 See section on NSAIDs.  Paracetamol should be used as a first line agent unless contraindicated.

4. Central Nervous System 03/04/2018 Page | 29 4.7.1 NSAIDs

Ibuprofen Dose 400-600mg three times daily Tablets 200mg, 400mg, 600mg Suspension 100mg/5ml

Naproxen Dose 250-500mg twice daily Tablets 250mg, 500mg

Diclofenac Dose 75-150mg daily in 2-3 divided doses Tablets 25mg, 50mg Soluble tablets 50mg Slow release capsules 75mg Suppositories 12.5mg, 25mg, 50mg, 100mg

Notes

 NICE guidance for both Rheumatoid Arthritis and Osteoarthritis recommends co- prescription of a Proton Pump Inhibitor.  Other NICE recommendations for NSAIDs;  Prescribe at the lowest effective dose for the shortest possible period of time.  Owing to potential gastrointestinal, liver and cardio-renal toxicity:  take into account individual patient risk factors, including age, when choosing the NSAID/COX-2 inhibitor and dose to be prescribed  assess and/or monitor patient risk factors  consider prescribing an alternative analgesic if the patient is already taking low-dose aspirin for another condition.  NSAID use comes under two targets for the National Prescribing Indicators  Ibuprofen and Naproxen as % of NSAIDs  DDDs per 1000 PUs

Thrombotic Cardiovascular Risk of Oral NSAIDs  All users of NSAIDs may be at some increased thrombotic cardiovascular risk.  The greatest concern relates to chronic use of high doses (especially for coxibs and diclofenac)

4. Central Nervous System 03/04/2018 Page | 30  The Commission on Human Medicines have previously stated that diclofenac 150mg/day appears to be associated with a similar excess risk to that of coxibs: about 3 CV events per 1000 users per year.  The absolute risk for diclofenac at doses less than 150mg/day remains uncertain.  Patients should use the lowest effective dose and the shortest duration of treatment necessary to control symptoms.  The need for long-term treatment should be reviewed periodically,  Overall evidence continues to indicate that naproxen is associated with a lower thrombotic risk than coxibs. However, naproxen is associated with a higher Gastrointestinal risk, consider co-prescribing a Proton Pump Inhibitor.  For ibuprofen, no significant risk has been identified for doses of up to 1200 mg daily.

Topical NSAIDs Ibuprofen Gel 5% or 10% Apply up to 3 times daily

Notes

 NICE Guidance on the management of osteoarthritis CG59 Feb 2008, states  Healthcare professionals should consider offering topical NSAIDs for pain relief in addition to core treatment for people with knee or hand osteoarthritis. Topical NSAIDs and/or paracetamol should be considered ahead of oral NSAIDs, COX-2 inhibitors or opioids.  Low plasma levels are produced and systemic efficacy is not expected. Systemis adverse events such as dyspepsia and reduced renal function have been reported but these are at lower levels than with systemic NSAIDs.

COX-2 Inhibitors In light of the MHRA advice on the safety of COX-2 Inhibitors (external link) this formulary does not contain a specific drug choice recommendation for a COX-2 inhibitor. Prescribers are reminded that, like NSAIDs, COX-2 inhibitors have a propensity to cause gastrointestinal adverse events and that renal side effects are a class effect shared with NSAIDs. The MHRA consider that increased thrombotic risk is a class effect of selective COX-2 inhibitors. COX-2 inhibitors should only be prescribed after careful consideration of the risks and benefits.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 31 4.7.2 Opioid Analgesics

Weak LOpioids

Codeine Dose 30-60mg up to four times daily Tablets 15mg, 30mg, 60mg Syrup 25mg/5ml

Dihydrocodeine Dose 30-60mg up to four times daily Tablets 30mg, 60mg, Modified release tablets

Co-Codamol 30/500 Max 8 tablets daily Note effervescent tablets have a high Na+ content

Co-Codamol 8/500 Max 8 tablets daily Note effervescent tablets have a high Na+ content

Co-dydramol 10/500 Max 8 tablets daily

Tramadol Dose 50-100mg four times daily Capsules 50mg Injection 100mg/2ml

Buprenorphine (BuTrans) patches

Restricted use - Guidelines for Prescribing Buprenorphine Patches

Notes

 Consider co-prescribing a laxative.  The capacity to metabolise codeine can vary considerably and can lead to either reduced therapeutic effect or marked increase in side effects. Dihydrocodeine does not require metabolism for action and so may be a useful alternative.  Tramadol may be a second line alternative if codeine is not tolerated or effective. However is must be noted that tramadol can be associated with significant central nervous system side effects.

4. Central Nervous System 03/04/2018 Page | 32  Tramadol is licensed for moderate to severe pain. However, it is neither more effective nor better tolerated than other weak opioid analgesics, and, in severe pain, strong opioids are more effective (NPC May 2006).  The CSM has previously advised that treatment with tramadol should be short term and intermittent, thereby suggesting that a place for the MR formulation is difficult to position. Great caution is required in patients with a history of addiction or dependence. Patients with a history of seizures should only take tramadol if there are compelling reasons and it should be used with caution in patients taking drugs that can lower the seizure threshold.  Because tramadol enhances serotonergic pathways there is an increased risk of precipitating serotonin syndrome with SSRI’s.  Tramadol has also been know to cause psychiatric side effects particularly in the eldery.  See NICE guidance on Neuropathic Pain CG 96 March 2010. Powys formulary section - Neuropathic Pain  Co-codamol can be useful for patients requiring regular codeine and paracetamol prescription who are stabilised on the separate compenents.

4. Central Nervous System 03/04/2018 Page | 33 Opioids

Morphine Solution 10mg/5ml Tablets, Modified Release Tablets, Suspension

Diamorphine For Chest Pain and Palliative Care use Injection 5mg, 10mg, 30mg, 100mg, 500mg

Oxycodone Solution 5mg/5ml Capsules (immediate release), Modified Release Tablets, Injection Fentanyl Transdermal Patches 12, 25, 50, 75, 100 microgram/hr

Pethidine For use by Midwives, Endoscopy and Theatres only Injection 50mg, 100mg

Fentanyl Injection - for use in Theatres

Alfentanil Injection - for use in Theatres

Morphine Injection - for use in Theatres Notes

 Stop codeine (co-codamol 30/500 or tramadol) before initiating stronger opioid.  Initiate treatment with morphine sulphate solution 10mg/5ml (use 5mg in the elderly) every 4 hours as required and titrate upwards.  Check compliance before increasing dose.  Once pain is stabilised convert to slow release morphine tablets and prescribe morphine sulphate solution 10mg/5ml for breakthrough pain. To calculate the 4 hourly breakthrough pain dose, divide the total daily dose of morphine by 6.  The side effects of morphine are usually transient, if they remain problematic use anti-emetics/laxative as appropriate.  The British Pain Society have produced a patient information booklet on the use of opioids for the treament of pain.

4. Central Nervous System 03/04/2018 Page | 34  Oxycodone and Fentanyl should ONLY be used in the following circumstances:  Oxycodone has a similar analgesic effect profile to morphine and should ONLY be used for genuine morphine intolerant patients (a very small proportion of patients) To convert from morphine to oxycodone divide total daily dose of morphine by 2, then by 6 to give the 4 hourly dose (e.g 240mg of morphine = 120mg oxycodone = 20mg every 4 hours Using Oxynorm capsules) Once pain is stabilised convert to modified release Oxycodone (Oxycontin) as bd dose plus Oxycodone normal release (Oxynorm) for breakthrough pain.  Fentanyl can be used in dysphagia, intractable nausea/vomiting or persistent adverse effects to morphine, oxycodone, or diamorphine (e.g. severe constipation, nausea, drowsiness). DO NOT use fentanyl patches for patients with unstable opioid requirement, wait until dose is stabilised. Note the potency of fentanyl patches one 25 microgram patch is equivalent to 90mg morphine daily.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 35 4.7.3 Neuropathic Pain & Diabetic Neuropathy

Neuropathic Pain

Some drugs used for neuropathic pain are not licensed for this purpose but are commonly used in practice and are incorporated in the BNF. In March 2010 NICE produced the clinical guideline - Neuropathic Pain: The pharmacological management of neuropathic pain in adults in non-specialist settings. CG 96.

Drug Information Comments

initial dose 10mg at night; Not licensed for this increase by 10mg at weekly indication. intervals If satisfactory pain reduction is obtained with amitriptyline but the person Amitriptyline cannot tolerate the adverse effects, consider oral imipramine or nortriptyline as an alternative (unlicensed indications)

100mg three times a day for 1 week increasing by 100mg three times daily each week assessing response and tolerability. In some Side effects may be reduced Gabapentin situations it may be appropriate to by gradual introduction. start at higher doses e.g. 300mg daily increasing to twice daily and then three times a daily.

Initally 75mg twice daily. Increased after 7 days to 150mg Twice daily dosing is Pregabalin twice daily. Further increases if significantly cheaper than necessary to a maximum of three times daily. 600mg per day.

Imipramine or

Nortriptyline

4. Central Nervous System 03/04/2018 Page | 36 50 - 100mg not more often than While waiting for referral every 4 hours. Maximum 400mg consider oral tramadol daily instead of or in combination with a second line Tramadol treatment. Note side effects and potential interactions of tramadol.

Apply to intact, dry, non-hairy, Consider topical lidocaine non-irritated skin once daily for up for treatment of localised to 12 hours, followed by a 12 hour pain for people who are plaster free period. Discontinue if unable to take oral no response after 4 weeks. Note: medication because of up to 3 plasters may be used to medical conditions and/or Lidocaine Patches cover larger areas. Plasters may be disability. cut. Note lidocaine patches are licensed for post herpetic neuralgia, but not for other neuropathic pain conditions.

Notes

 First line treatment - offer amitriptyline or pregabalin.  If satisfactory pain reduction is obtained with amitriptyline but the person cannot tolerate the adverse effects, consider oral imipramine or nortriptyline as an alternative.  Second line treament - offer treatment with another drug instead of or in combination with the original drug, after informed discussion with the person.  If first line treatment was with amitriptyline (or imipramine or nortriptyline), switch to or combine with pregabalin.  If first line treatment was with pregabalin, switch to or combine with amitriptyline (or imipramine or nortriptyline as an alternative if amitriptyline is effective but the person cannot tolerate the adverse effects).  If satisfactory pain reduction continue treatment - consider gradually reducing dose over time if improvement is sustained.  Third line treatment - Refer the person to a specialist pain service and/or a condition specific service  While waiting for referral  Consider tramadol instead of or in combination with second line treatment.

4. Central Nervous System 03/04/2018 Page | 37  Consider topical lidocaine for treatment of localised pain for people who are unable to take oral medication because of medical conditions and/or disability.  Other treatments - do not start treatment with opiods (such as morphine or oxycodone) other than tramadol without an assessment by a specialist pain service or a condition specific service.  Other pharmacological treatments that are started by a specialist pain service or a condition specific service may continue to be prescribed in non-specialist settings, with a multidisciplinary care plan, local shared care agreements and careful management of adverse effects.  Note Pregabalin is still a black triangle drug and so all adverse drug reactions need to be reported to the CHM.  Primary Care D&T Decision (June 2010) agree to continued use of gabapentin in the treatment of neuropathic pain.

Diabetic Neuropathy

Drug Information Comments

60mg/day (a lower starting dose may be appropriate for Duloxetine some people). Maximum 120mg/day.

initial dose 10mg at night; Amitriptyline increase by 10mg at weekly Not licensed for this indication. intervals

Initally 75mg twice daily. Increased after 7 days to Twice daily dosing is significantly Pregabalin 150mg twice daily. Further cheaper than three times daily. increases if necessary to a maximum of 600mg per day.

While waiting for referral consider oral tramadol instead of 50 - 100mg not more often or in combination with a second Tramadol than every 4 hours. Maximum line treatment. Note side effects 400mg daily and potential interactions of tramadol.

4. Central Nervous System 03/04/2018 Page | 38 Consider topical lidocaine for treatment of localised pain for people who are Apply to intact, dry, non-hairy, non- unable to take oral irritated skin once daily for up to 12 medication because of hours, followed by a 12 hour plaster medical conditions and/or Lidocaine Patches free period. Discontinue if no disability. response after 4 weeks. Note: up to Note lidocaine patches are 3 plasters may be used to cover licensed for post herpetic larger areas. Plasters may be cut. neuralgia, but not for other neuropathic pain conditions.

Notes:

 First line treatment - offer oral duloxetine.  Offer oral amitriptyline if duloxetine is contraindicated.  Second line treatment - offer treatment with another drug instead of or in combination with the original drug, after informed discussion with the person.  If first line treatment was with duloxetine, switch to amitriptyline or pregabalin, or combine with pregabalin.  If first line treatment was with amitriptyline switch to or combine with pregabalin.  Notes then as for neuropathic pain above.  Note Duloxetine is still a black triangle drug and so all adverse drug reactions will need to be reported to the CHM.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 39 4.7.4 Antimigraine Drugs

Relief of Acute Migraine Attack

Step 1 NSAID ± paracetamol ± prokinetic agent

Paracetamol

Soluble tablets, dose 1g stat

NSAID

Aspirin

Soluble tablets, dose 900mg stat Ibuprofen tablets 400mg stat

Naproxen tablets 500mg stat

Diclofenac soluble tablets 50mg stat

Diclofenac suppositories 50mg stat

Prokinetic agent

Metoclopramide 10mg stat dose (care, increased risk of extrapyrimidial side effects in young adults particularly females). Metoclopramide Solution 5mg in 5ml Domperidone tablets 10mg tablets, 20mg stat dose Domperidone Suppositories 30mg, 60mg stat dose

Step 2 Triptans

Sumatriptan 50mg tablets, subcutaneous injection, nasal spray Zolmitriptan Tablets, nasal spray

4. Central Nervous System 03/04/2018 Page | 40 Notes

 Ensure diagnosis of migraine is correct. Triptans are expensive and ineffective in all other types of headache.  As many patients respond to simple analgesics, it is sensible to try these first.  Sumatriptan is also available in a wide variety of dose forms which may suit particular needs and tablets are available generically.  Sumatriptan 50mg and 100mg are equally efficacious and 50mg causes less side effects.  Whichever treatment is chosen, the patient should be encouraged to take the medication as soon as they feel an attack coming on.  Triptans are contra-indicated in ischaemic heart disease, previous MI/CVE/TIA, coronary vasospasm, uncontrolled hypertension and peripheral vascular disease.  Nasal or subcutaneous preparations should be considered in severe migraine or where vomiting precludes oral treatment or where oral triptans have been ineffective.  Orodispersible and ‘Melt’ formulations of triptans offer no clinical advantage.  Be alert for medication overuse headache.

4. Central Nervous System 03/04/2018 Page | 41 Treatment of Osteoarthritis

Pain Relief in Osteoarthritis

NICE guidance on the Care and Management of Osteoarthritis in Adults (CG59, Feb 2008) (external link).

Osteoarthritis (OA) is by far the most common joint disorder, but is neither a disease nor a single condition. It is associated with ageing and is a major cause of pain and disability in the elderly. Pain is the most common symptom and still presents a major therapeutic challenge. OA pain is typically:

 insidious in onset, variable or intermittent over time (‘good days, bad days’);  activity and weight bearing related, relieved by rest;  brief (<15 minutes) morning stiffness or ‘gelling’ after rest;  usually only one or a few joints affected.

Take into account the patient’s attitudes and knowledge, self treatments, constitutional factors (e.g. obesity, muscle weakness, non-restorative sleep), co-morbid disease and its therapy, treatment availability and costs.

Options include:

1. A prescription of exercise, e.g. quadriceps strengthening exercises. 2. Weight loss. 3. Address mechanical factors - activity modification, pacing, mobility aids, patella taping, footwear and orthoses. 4. Analgesia.

Analgesics in Osteoarthritis

1st step - trial of topical NSAID Ibuprofen 5% - see NSAID section 2nd step - oral paracetamol - see non-opioid analgesic section 3rd step - add codeine - see opioid section 4th step - oral NSAIDs Ibuprofen or Naproxen - see NSAID section Topical capsaicin may provide some relief 5th step referral to secondary care.

4. Central Nervous System 03/04/2018 Page | 42 Glucosamine and Chondroitin

NICE guidance CG59 Feb 2008 advises that:-

****Glucosamine or Glucosamine and chondroitin preparations must not prescribed on the NHS in Powys***

 Trials which used glucosamine sulphate as a single daily dose of 1500 mg, rather than hydrochloride 500 mg tds, showed a small benefit over placebo for treatment of knee OA.  However, the evidence is not strong enough to advise prescribing the sulphate on the NHS.  If patients which to try glucosamine then they should buy over the counter and trial for 3 months.  Patients should be advised on how to evaluate pain to self assess if treatment is effective.  Patients should purchase the preparation with the most evidence which is glucosamine sulphate 1500mg daily.  There is no evidence that chondroitin preparations are more effective and they should not be recommended.  Unusually it is the glucosamine hydrochloride preparation that is licensed but it is the sulphate that has the most evidence.

NSAIDs in Osteoarthritis

See also section on NSAIDs.

 NSAIDs should be a second line option after ‘conservative measures’ and paracetamol and codeine.  May not need to take regularly. Tailor prescription to need - begin with short acting, low dose NSAID, e.g. ibuprofen 400mg before activity.  GI bleeding and perforation, fluid retention, renal impairment, and drug interactions are not uncommon. Co-prescription with a proton pump inhibitor is recommended.  Some patients with nodal OA (Heberdens’s and Bouchard’s nodes) find topical preparations helpful. Ibuprofen gel is the formulary choice, therapeutic levels are obtained in soft tissues but not in the synovial fluid. Some patients find topical salicylate containing rubefacients such as transvasin helpful. These are available OTC at less cost than the prescription charge.  The role of COX-2 inhibitors in OA is unclear, though NICE guidelines may help identify those who may benefit. They are not more effective than traditional

4. Central Nervous System 03/04/2018 Page | 43 NSAIDs. There is no data to guide use in the most at risk groups for gastrointestinal toxicity. MHRA warnings should be considered.

Capsaicin

Capsaicin Cream 0.025% three to four times daily £17.71 for 45g (NB. not the higher strength product)

Notes:

 Acts by depleting substance P.  May be useful in knee OA and painful Heberden’s and Bouchard’s nodes (generalised nodal osteoarthritis).  Must use regularly for at least 4 weeks, as delayed onset of action.  Use a gloved finger or wash hands carefully with soap after application.  Initial burning sensations may be distressing (can pre-treat with EMLA) but reduce after the first few applications.

Price update on this page 7th December 2010

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 44 Management of Gout

 Hyperuricaemia and joint pain do not always add up to gout. The definitive diagnosis is established by the identification of negatively birefringent urate crystals on polarising light examination of joint fluid.  Serum uric acid levels may be normal during an acute attack of gouty arthritis.  Joint sepsis is an important differential diagnosis.

Treatment of an Acute Attack

1. High dose powerful NSAID for short period of acute inflammation, e.g. Indometacin 50mg tds. Consider gastroprotection. 2. If a NSAID is not appropriate then Colchicine 500mcg every 2 hours. The therapeutic-toxic window is very narrow. Stop when GI side effects ensue or when pain relief occurs, and then revert to 1-1.5mg daily in divided doses. Often, no more than 3mg on the 1st day can be tolerated. The maximum dose per course is 6mg (12 tablets). 3. Paracetamol and opioid analgesia. 4. Joint aspiration and intra-articular injection of corticosteroid (beware joint sepsis). 5. Corticosteroid ‘pulse’ 1. DepoMedrone® 80-120mg im 2. Prednisolone EC 20-30mg reducing over 7 days 6. Consider morphine if above fail or inappropriate.

Prevention of recurrent gouty arthritis

 One attack, or several attacks separated over many years, are not indications to institute preventative therapy with allopurinol.  Look for a cause of hyperuricaemia.  Do not start therapy until acute attack is over or it may become prolonged.  Cover initial period on allopurinol with NSAID or colchicine, often for several months.  A low purine diet and alcohol restriction may help (specifically the avoidance of dietary fats, alcohol, sardines, anchovies, liver and sweetbreads).

Allopurinol Tablets 100mg, 300mg. Max dose 900mg daily

Colchicine Tablets 500mcg Notes 4. Central Nervous System 03/04/2018 Page | 45 Allopurinol

1. Start therapy with allopurinol at 100mg and increase gradually as needed guided by uric acid levels, renal function and response. 2. Moderate to severe renal impairment requires the use of lower doses. 3. Allopurinol has a serious drug interaction with azathioprine and mercaptopurine. There may also be unpredictable interactions with many other medications, e.g. warfarin. 4. Hypersensitivity reactions are common. Stop the drug if a rash develops.

Colchicine

1. In the management of an acute attack, give 1mg initially followed by 500mcg every 2 hours until either the pain resolves, diarrhoea develops or 6mg in total has been taken (12 tablets). 2. For prophylaxis give 1-1.5mg daily in divided doses whilst hyperuricaemia is corrected.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 46 4.8 Control of Epilepsy

Antiepileptic Drugs

4. Central Nervous System 03/04/2018 Page | 47 4.9 Drugs used in Parkinsonism and Related Disorders

Each year 8,000 to 10,000 new cases of Parkinson’s disease are diagnosed in the UK. The disorder becomes more common with increasing age, with most patients developing the initial symptoms betwen 50 and 70 years. However, it may present at any age and 1 in 20 are under 40 years at diagnosis.

NICE Guidance on Parkinson's Disease Diagnosis and Management in Primary and Secondary Care CG35 (external link).

Principles of treatment

 There is currently no curative therapy and treatment is aimed at symptom alleviation and restoring or improving quality of life.  Correct diagnosis of the many parkinsonian and tremulous syndromes may be difficult, but is very important before the selection of appropriate therapies.  Patients with parkinsonism should be referred untreated to the movement disorder team, or other appropriate specialist, for diagnosis and assessment prior to starting drug therapy. These patients should be seen within 6 weeks.  There is often no immediate need to start medication in newly diagnosed patients, although this issue is frequently debated with some specialists arguing that if someone has stopped doing something because of the disease they may not restart and secondly treatment may offer some neuroprotection, allowing a better response to further treatment. Decisions should be made after discussions between the patient, their carer and the clinician about the degree of disability and the pros and cons of starting drug therapy.  In general, start only one new class of medication at a time. Dose titration should always be gradual - anti-Parkinsonian medication should never be started or stopped suddenly. It may take up to 3 months on a therapeutic dose before the full symptomatic benefits become apparent.

4. Central Nervous System 03/04/2018 Page | 48 4.9.1 Dopaminergic Drugs used in Parkinsonism

Levodopa

Locally preparations in this section are prescribed generically.

Madopar (co-beneldopa) Capsules 62.5mg

Capsules 125mg

Capsules 250mg

Dispersible tablets 62.5mg

Dispersible tablets 125mg Sinemet (co-careldopa) Tablets 62.5mg (12.5/50) Tablets 110mg (10/100)

Tablets 125mg (25/100)

Tablets 275mg (25/250) Notes:

 Co-careldopa 110mg (10/100) may not provide enough carbidopa to inhibit peripheral dopa-decarboxylase. At least 70mg carbidopa daily is necessary to achieve full inhibition of peripheral dopa-decarboxylase.

Slow Release Preparations

Half Sinemet CR levodopa 100mg/carbidopa 25mg Sinemet CR levodopa 200mg/carbidopa 50mg

Madopar CR levodopa 100mg/benserazide 25mg

Notes: 4. Central Nervous System 03/04/2018 Page | 49 1. There is rarely any immediate need to commence therapy and patients should be referred to the movement disorder team for confirmation of diagnosis. 2. When therapy is started the patient will be commenced on the lowest dose and increased slowly in divided doses. 3. Modified release levodopa preparations are mainly for patients with significant nocturnal hypokinesia. There may also be some beneficial effects left by the following morning so that the patient has a longer period of sleep benefit. 4. Patients who require the dose provided by a Half Sinemet CR should be discouraged from breaking a Sinemet CR in half to obtain the dose. The preparation should be prescribed as Half Sinemet CR to avoid confusion. 5. Dispersible tablets may be useful for the first early morning dose.

Dopamine Agonists Pramipexole Tablets 88mcg, 180mcg, 700mcg (pramipexole base)

NB. Exercise caution when prescribing, dispensing and administering pramipexole as the packs also express dose as the dihydrochloride and print both doses in milligrams. Ropinirole Tablets 1mg, 2mg, 3mg (a starter pack containing 0.25mg and 0.5mg tablets is also available) MR Tablets 2mg, 4mg, 8mg

Rotigotine Patches 2mg, 4mg, 6mg, 8mg in 24 hrs see notes below

Parenteral Products Apomorphine Apomorphine is a very potent dopamine agonist administered subcutaneously by either intermittent injection or continuous infusion. It should only be initiated by a specialist and long-term specialist supervision is advisable throughout treatment. However, once established, patients may safely continue on treatment for many years in the community.

4. Central Nervous System 03/04/2018 Page | 50 Notes:

1. It is recommended that dopamine agonists are initiated by specialists although they are suitable for GP prescribing following specialist guidance on dose titration. 2. Cardiac-valve regurgitation due to leaflet and chordal thickening (overgrowth valvulopathy) has been associated with the use of some dopamine agonists (pergolide and cabergoline). It is currently not clear if other dopamine agonists are implicated, but it is postulated that the mechanism may involve activation of the serotonin 5-HT2B receptor by the drug or a metabolite. Pergolide and cabergoline are potent 5-HT2B agonists, whereas apomorphine, ropinirole and pramipexole have only low affinity for the 5-HT2B receptor and bromocriptine and lisuride have antagonistic properties. 3. Ergoline dopamine agonists (bromocriptine, cabergoline and pergolide) are associated with pulmonary, retroperitoneal and pericardial fibrosis (not to be confused with cardiac-valve regurgitation mentioned above). 4. Up-to-date advice on the frequency of echocardiography and other appropriate monitoring for patients on dopamine agonists should be obtained from the movement disorder team or the patient’s hospital specialist. 5. Bromocriptine is now rarely used in the treatment of Parkinson's Disease and so not included in this formulary. 6. Rotigotine has shown inferiority to ropinirole in early Parkinson’s disease and should not be used in preference to other dopamine agonists in this group. It should ideally be reserved where alternatives are not suitable (e.g. compliance issues, need for social care to administer other oral therapies, dysphagia), not tolerated (GI disturbance), or ineffective. Rotigotine is recommended for use only within its licensed indications.

Monoamine-oxidase type B inhibitors (MAOBI)

Selegiline Tablets 5mg, 10mg. Dose 10mg at breakfast or 5mg breakfast and noon

4. Central Nervous System 03/04/2018 Page | 51 Notes:

1. Doses may be initiated at 2.5mg to minimise side effects in older patients. 2. It is recommended that selegiline is only initiated by those experienced in the management of PD and familiar with the characteristics of the drug. Afternoon doses are not advised due to the alerting effects of the drug.

3. Selegiline has a number of drug interactions, particularly with CNS active drugs. 4. Sudden withdrawal of selegiline may exacerbate symptoms. 5. Evidence found by the UK Parkinsons Disease Research Group (PDRGUK) that selegiline was associated with an increased mortality, has not been supported by meta-analysis of 5 long term studies and 4 other studies. Selegiline is regarded as a safe option for the adjunct treatment of Parkinson’s.

Catechol-O-methyltransferase inhibitors (COMTI)

Entacapone

Tablets 200mg

Must be taken with each dose of Levodopa product.

Max 10 tablets per day

Notes:

 May be useful to prescribe as the combination product Stalevo (levodopa, carbidopa and entacapone).  The dose should be increased or decreased slowly.  It may be necessary to reduce the concurrent levodopa dose by 10-30%.  COMTIs may be used appropriately for patients experiencing end-of-dose wearing off effects or other motor fluctuations.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 52 Drugs Used in Tremor

Tremor is steady rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction of opposing groups of muscles. A patient’s tremor should be carefully described and defined prior to treatment.

An attempt should also be made to measure, record and grade tremor severity.

The classification of tremor agreed by the International Tremor Foundation,

Tremor Investigation Group (TRIG) should be followed (see below). Although tremor may be physiological, there are many different pathological causes and the clinical differential diagnosis will determine the subsequent investigations and treatment pathway.

Tremor (TRIG Classification) Assessment of tremor

 Rest Tremor 1. Clinical ratin scales  Action Tremor 2. Spirography e.g. Archimedes

 Postural tremor spirals  Kinetic tremor 3. Handwriting assessment  Intention(terminal) tremor 4. Volumetric methods

 Isometric tremor 5. Activities of daiy living  Task-specific tremor questionnaires

Principles of Treatment

 Tremor is a symptom, not a diagnosis. Correct diagnosis of the many tremulous syndromes may be difficult, but is very important for the selection of appropriate therapies.  Treatment of tremor is usually aimed at restoring or improving quality of life. It is therefore important to be aware of the consequences of the tremor for the patient (e.g. diagnostic anxiety, social embarrassment) and the effects on their everyday life. The overall assessment of tremor severity should reflect these effects.  There is often no immediate need to start medication. Decisions should be made after discussions between the patient, their spouses or carer and the clinician about the degree of disability and the risks and benefits of starting drug therapy. If referral to a specialist is considered appropriate, it is preferable to delay starting treatment until they have been seen by the specialist.

4. Central Nervous System 03/04/2018 Page | 53  In general, start only one new class of medication at a time. Dose titration should always be gradual - medication intended to alter nervous system neurotransmission should never be started or stopped suddenly. It may take three months or more on a therapeutic dose before the full symptomatic benefits become apparent.  Tremor is often refractory to treatment.

Rest Tremor

The commonest example of a rest tremor is that seen in Parkinson’s disease.

Parkinsonian Tremors A tremor due to Parkinson’s disease is most likely to be a 4-6Hz resting tremor, often with a unilateral or asymmetric onset. There are, however, several common pitfalls.

1. Not all patients with Parkinson’s disease have a tremor and despite tremor being one of the cardinal features of Parkinson’s disease, it is not necessary for the diagnosis. 2. Some Parkinson’s disease patients have a postural component to their resting tremor. 3. Some patients present with a postural tremor alone, especially in the early course of the disease. 4. Head tremor is very unusual in Parkinson’s disease, although a jaw tremor may occur. 5. There remains some debate about the relationship between Parkinson’s disease and essential tremor and the possible overlap between the two disorders.

Parkinsonian tremor should be treated as Parkinson’s disease (see separate section).

There are also some additional treatment options which may be useful for parkinsonian tremor. Eg propanolol or an anti cholinergic agent but extreme caution

4. Central Nervous System 03/04/2018 Page | 54

Trihexyphenidyl (benzhexol) Tablets 2mg, 5mg. Starting dose 1mg daily increased slowly. Up to 5mg four times daily if needed Syrup 5mg/5ml Alternatives include

Orphenadrine Procyclidine - may also be given parenterally

Notes:

1. Antimuscarinics are sometimes used in patients under 50. They should be used with caution in those 50-60 years and are best avoided in those over 60. Use limited by anticholinergic side effects, particularly disorientation, confusion, hallucinations and memory disturbance in older patients 2. Some evidence to suggest that small doses may be just as effective as larger ones. 3. Doses should be increased or decreased slowly. 4. May be used alone or to supplement the action of other anti-parkinsonian drugs. 5. Although antimuscarinics may be more effective at suppressing parkinsonian tremor, there is no evidence to suggest they are more effective than levodopa in treating other symptoms.

Dopamine Release Enhancer

Amantadine Capsules 100mg Starting dose 100mg daily. Increase after one to two weeks to 100mg Twice daily Also available as a syrup 50mg/5ml

Notes:

1. Has been found to be helpful for parkinsonian tremor in a small proportion of patients. May be used alone or to supplement the action of other antiparkinsonian drugs. May also be helpful in parkinsonian dyskinesias

4. Central Nervous System 03/04/2018 Page | 55 2. Amantadine has been reported to be associated with an increased risk of valvular heart disease. As with dopamine agonists, echocardiographic monitoring may be required.

Dopamine Agonists

Pramipexole, Ropinirole, Bromocriptine See the main Parkinson’s disease section for information

Notes:

 Dopamine agonists may be used for tremor either alone or as an adjunct to other anti-parkinsonian therapies. There are unconfirmed suggestions that some dopamine agonists may be more useful for treating tremor than others.  Further information on dopamine agonists is given in the Parkinson’s disease section.

Action Tremor

Essential tremor is the commonest example of an action tremor. Essential tremor is not uncommonly misdiagnosed as Parkinson’s disease, but should also be distinguished from dystonic tremor.

Drugs Used in Essential Tremor

Essential tremor is usually a postural tremor of 4-10Hz. In contrast to Parkinson’s disease, it is a monosymptomatic disorder.

Propranolol Tablets 10mg, 40mg, 80mg 160mg

Primidone Tablets 250mg Start with 50mg at night (may need liquid prep) Increase slowly (at weekly intervals) to 250mg at night. If no effect, slowly increase further to a maximum of 750mg daily, if tolerated.

4. Central Nervous System 03/04/2018 Page | 56 Notes:

 The mechanism of action of beta-blockers in tremor is not known. Although lipid soluble beta-blockers are more likely to enter the brain and are thus assumed to be more effective in essential tremor, some (but not all) water soluble drugs such as sotalol do seem to work. Atenolol is not effective in tremor.  The mechanism of action of antiepileptic drugs on tremor is unknown. Dose is usually limited by side effects, particularly somnolence. Gabapentin may also be tried for this indication using the same dose schedule as for neuropathic pain and epilepsy.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 57 Other Problems Associated with Parkinson's Disease

Non-Pharmacological Therapies and Reablement

Successful long-term management requires multidisciplinary care and a team approach involving the General Practitioner, hospital specialist, district nurse and Parkinson’s Disease Nurse Specialist (PDNS) together with the patient and their carer(s). The skills and services of the physiotherapist, speech and language therapist, occupational therapist, clinical psychologist and pharmacist are likely to be required at various stages of the disorder. Access to nutrition and dietetic services, skilled dental care and health information and educational services are also needed as part of the team.

Other problems associated with Parkinson’s disease

Depression Depression occurs in 40-50% of patients and can easily be overlooked.

Limited studies have been performed to identify the best antidepressant in this disorder. It would seem prudent to commence with the TCAs before the use of the SSRIs. Note that selegiline interacts with most antidepressants and needs to be monitored carefully.

Anxiety Anxiety is an extremely common feature and may be difficult to manage.

Management may involve drug treatment (e.g. with tricyclics) and psychological treatments.

Constipation Constipation is nearly always present in Parkinson’s disease and after basic advice about adequate fluid and fibre intake is most effectively treated with a stimulant laxative such as Docusation, bisacodyl or senna The addition of a bulk forming laxative (e.g. ispaghula husk or sterculia) and/or an osmotic laxative such as macrogol ‘3350’ may also be required.

Dopa Disregulation and Impulse Control Disorder With dopamine agonists

REM Sleep Disorder Clonazepam may be useful to treat

Dementia Treatment of 4. Central Nervous System 03/04/2018 Page | 58

Management of Nausea and Vomiting

Domperidone 10mg to 20mg tds is the antiemetic of choice in Parkinson’s disease as it cannot easily cross the blood- brain barrier and cause additional motor disturbances. Metoclopramide and prochlorperazine should be avoided in patients with Parkinson’s disease.

Green = 1st line Blue = 2nd Line Orange = Specialist Use

4. Central Nervous System 03/04/2018 Page | 59 4.10 Drugs used in Substance Dependence

Substance Dependence

4. Central Nervous System 03/04/2018 Page | 60 4.11 Drugs for Dementia

Drugs for Dementia

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