Suspected Parkinson's disease

• Refer people with suspected Parkinson's disease quickly, and untreated, to a specialist (with expertise in the differential diagnosis of this condition) for diagnosis.

Confirmed Parkinson's disease: primary care management

• Only start or alter anti-parkinsonian medication on the advice of the person's Parkinson's disease physician or nurse specialist.
• Do not suddenly stop any anti-parkinsonian medication as this can precipitate acute akinesia or neuroleptic malignant syndrome.
• Manage comorbidities: avoid, or use with caution, any drugs that could exacerbate parkinsonism or interact with anti-parkinsonian medication.
• Identify worsening motor symptoms and motor complications and manage these appropriately, usually by referring to the person's Parkinson's disease specialist team.
• Identify and appropriately manage non-motor symptoms and complications.
• Identify any adverse effects from anti-parkinsonian medication, and manage these appropriately, often by liaising with the person's Parkinson's disease specialist team.
• Ensure access to local services for people with Parkinson's disease, including physiotherapy, occupational therapy, and speech and language therapy.

• Refer people with suspected Parkinson's disease quickly, and untreated, to a specialist (with expertise in the differential diagnosis of this condition) for diagnosis.
• For further information, see Diagnosis and Differential diagnosis.

This recommendation is derived from a guideline produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• To be aware of local services for people with Parkinson's disease and to enable appropriate access to them. Services may include:
• A Parkinson's disease physician specialist.
• A Parkinson's disease nurse specialist (PDNS), if available.
• Speech and language therapy, physiotherapy, occupational therapy, social services, community nursing, continence and urology specialists, palliative care specialists, and psychology and mental health services.
• The Parkinson's Disease Society local branch, regional support, and free UK helpline (0808 800 0303).
• To liaise with the person's Parkinson's disease physician specialist and PDNS (if available), particularly in relation to changes in medication.
• Only start or alter anti-parkinsonian medication on the advice of a specialist.
• Ensure that changes to repeat medication are made promptly.
• Titrate therapy between specialist review appointments according to recommendations from secondary care.
• Do not suddenly stop any anti-parkinsonian medication as this can precipitate acute akinesia or neuroleptic malignant syndrome.
• To identify worsening motor symptoms and motor complications (which may be caused by the disease itself or by anti-parkinsonian medication), and manage these appropriately.
• This will usually require the advice of a specialist or an interim referral.
• To identify and appropriately manage non-motor symptoms and complications, which may be caused by the disease itself or by anti-parkinsonian medication.
• Advice or referral to a specialist may be needed.
• To manage comorbidities: avoid or use with caution any drugs that could exacerbate parkinsonism or interact with anti-parkinsonian medication — see Drugs to avoid.
• To advise care staff in nursing or residential homes of the need for the correct timing of anti-parkinsonian medication.
• To offer a regular medication review, including adherence and adverse effects.
• To offer support to family and carers.
• To ensure that palliative care requirements are met throughout all phases of the disease, particularly at the end of life.

The recommendations regarding the role of primary care in the ongoing management of people with confirmed Parkinson's disease are generally based on expert opinion.

Access to local services

• This recommendation is derived from the National Institute for Health and Clinical Excellence (NICE) guideline on Parkinson's disease and from a Scottish Patient Pathway for Parkinson's disease.
• NICE stresses the importance of access to allied healthcare services, in particular nurse specialists, occupational therapy, physiotherapy, and speech and language therapy [NICE, 2006].
• The Patient Pathway highlights the importance of awareness by primary care practitioners of all the services that could be used by people with Parkinson's disease and of appropriate referral to these services when necessary [Centre for Change and Innovation, 2005].

Liaison with specialists

• The importance of effective multidisciplinary team working is broadly expressed [Parkinson's Disease Society, 2003; Kale and Menken, 2004; Centre for Change and Innovation, 2005].
• The recommendation to only start or alter anti-parkinsonian medication on the advice of a specialist is pragmatic, on the basis that drug management becomes increasingly complex as the disease advances, and an average GP's list will have only 2–4 people with Parkinson's disease, making it difficult to acquire sufficient experience of the condition [Dodel et al, 1998; Playfer, 2000]. However, the Parkinson's Disease Society suggests that, if a GP has a special interest, a local shared-care protocol could be used [Parkinson's Disease Society, 2007].
• The recommendation to ensure that changes to repeat medication are made promptly is based on a retrospective survey (published as a research letter) which found that 29% of medication changes recommended at specialist outpatient clinic appointments were not completed [Ng et al, 2007]. The authors acknowledged that there may be abundant reasons for this level of non-completion.
• A Scottish Patient Pathway recommends that GPs should titrate therapy between specialist visits according to recommendations from secondary care [Centre for Change and Innovation, 2005].
• Suddenly stopping anti-parkinsonian medication can precipitate acute akinesia or neuroleptic malignant syndrome, which can be serious [NICE, 2006; Parkinson's Disease Society, 2007].

Management of worsening motor symptoms and motor complications

• A role for primary care in the detection of motor complications is recommended by the Parkinson's Disease Society [Parkinson's Disease Society, 2003].

Management of non-motor symptoms

• A role for primary care in the management of non-motor symptoms is recommended by the Parkinson's Disease Society [Parkinson's Disease Society, 2007].
• Surveys of people with Parkinson's disease have found that non-motor symptoms contribute significantly to poor quality of life, suggesting that they should be 'targeted for intervention' and that they require a multidisciplinary approach [National Collaborating Centre for Chronic Conditions, 2006; Rahman et al, 2008; Visser et al, 2008].

Management of comorbidities

• Whilst it is self-evident that comorbidities will be managed by primary care, this is specifically stated in an editorial, Who should look after people with Parkinson's disease? [Kale and Menken, 2004].
• The recommendation to take care to avoid using any drugs that could exacerbate parkinsonism or that interact with anti-parkinsonian medication is derived from a Parkinson's Disease Society publication, The professional's guide to Parkinson's disease [Parkinson's Disease Society, 2007].

Advising care home staff of the need for correct timing of anti-parkinsonian medication

• Allowing levels of anti-parkinsonian medication to fall can precipitate acute akinesia or neuroleptic malignant syndrome, which can be serious [NICE, 2006; Parkinson's Disease Society, 2007].

Medication reviews

• A regular medication review is a quality indicator in the Quality and Outcomes Framework guidance [BMA and NHS Employers, 2008].
• A review of adherence to treatment is recommended by the Parkinson's Disease Society [Parkinson's Disease Society, 2007].

Supporting family and carers

• The importance of offering support to family and carers is emphasized by NICE and the Parkinson's Disease Society [NICE, 2006; Parkinson's Disease Society, 2007].

Palliative care

• The recommendation to ensure that palliative care requirements are met throughout all phases of the disease, particularly at the end of life, is based on the NICE guideline [NICE, 2006].

• At the time of diagnosis, all people with Parkinson's disease who drive should be advised to inform the Driver and Vehicle Licensing Agency (DVLA) and their car insurer of their condition.
• Sudden onset of sleep without awareness or warning signs has been reported rarely during treatment with levodopa or dopamine agonists (including apomorphine).
• People taking these drugs should be informed of this and advised not to drive, and also to consider any other occupational hazards if sudden onset of sleep occurs.
• However, in relation to people with Parkinson's disease, the Driver and Vehicle Licensing Agency (DVLA) states that:
• For Group 1 entitlement (to drive cars and motorcycles), 'Providing medical assessment confirms that driving performance is not impaired, can be licensed. A 1-, 2-, or 3-year licence may be required. Should the driver require a restriction to certain controls, the law requires this to be specified on the licence'.
• For Group 2 entitlement (to drive large lorries and buses), 'Licence refused or revoked if condition is progressive or disabling. If driving would not be impaired and condition stable, can be considered for licensing subject to satisfactory reports and annual review (individual basis)'.
• The latest information from the DVLA regarding medical fitness to drive can be obtained at www.dvla.gov.uk/medical/ataglance.

These recommendations are based on guidance from the European Agency for the Evaluation of Medicinal Products, the Committee on Safety of Medicines (now the Commission on Human Medicines), and the National Institute for Health and Clinical Excellence [EMEA, 2002; CSM, 2003; National Collaborating Centre for Chronic Conditions, 2006].

• Details of restrictions are derived from the DVLA publication, For medical practitioners: at a glance guide to the current medical standards of fitness to drive [DVLA, 2010].

• Worsening motor symptoms or motor complications may include:
• Deteriorating function — immobility, slowness, withdrawal from activities, communication difficulties.
• Loss of drug effect.
• Motor fluctuations — end-of-dose fading (wearing off), on-off phenomenon (rapid and unpredictable fluctuations between 'on' and 'off' periods), or dose failures.
• Dyskinesia (involuntary movements) — chorea (quick fidgety movements) or dystonia (slow, distorted postures).
• Freezing of gait.
• Falls.
• Look for and treat any acute illness (such as an infection or constipation) that could be exacerbating motor symptoms.
• Check adherence with anti-parkinsonian medication, including the correct doses and timings.
• If symptoms or complications persist, contact the person's Parkinson's disease specialist team for advice (on changes to treatment), or make an interim referral.
• For details of strategies that may be used in secondary care to manage worsening motor symptoms and motor complications, see Secondary care management of motor complications.

These recommendations are based on a guide for primary care teams developed by the Parkinson's Disease Society [Parkinson's Disease Society, 2003], with examples of symptoms derived from an evidence-based review [Pahwa et al, 2006].

• Consider a stepped approach to the management of constipation due to colonic dysmotility in Parkinson's disease:
• Increase dietary fibre and fluid intake (advise at least eight glasses of water per day).
• Increase exercise.
• Use fibre supplements (such as ispaghula husk).
• Use a stool softener (such as docusate).
• Use an osmotic laxative, such as lactulose or macrogols (Movicol^® or Laxido^®).
• Enemas may occasionally be required.
• See the CKS topic on Constipation.

• See Autonomic disturbances for background details on constipation in people with Parkinson's disease.

These recommendations are derived from the National Institute for Health and Clinical Excellence publication, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• Advise people who have sudden onset of sleep without awareness or warning signs not to drive and to consider any occupational hazards.
• Initial management of daytime hypersomnolence depends on its likely cause:
• Anti-parkinsonian medication (such as dopamine agonists):
• Seek specialist advice.
• Sedating medication (such as antihistamines, antipsychotics, and some antidepressants):
• Reduce, stop, or use an alternative medication; seek specialist advice if necessary.
• Inadequate rest at night:
• See Sleep disturbance.
• Dementia.
• Consider requesting advice from, or an interim referral to, the hospital or nurse specialist, so that:
• Medication that could be causing or contributing to daytime hypersomnolence can be reduced or stopped.
• Modafinil can be considered for daytime hypersomnolence (off-licence use). However:
• Modafinil is contraindicated in people with uncontrolled moderate to severe hypertension, and in people with arrhythmias.
• Modafinil is associated with skin and subcutaneous tissue reactions, and with the development of neuropsychiatric disorders.

• See Mental health problems for background details on daytime hypersomnolence in people with Parkinson's disease.

These recommendations are in line with a guideline produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [NICE, 2006].

• The European Medicines Agency (EMEA) has recently advised that modafinil should be used only for the treatment of narcolepsy. The EMEA considers that the risks (cardiovascular, neuropsychiatric, skin reactions) outweigh the benefits for other indications such as excessive daytime hypersomnolence [EMEA, 2010].

• Treat any condition that may be causing or exacerbating cognitive impairment, such as depression or acute infection.
• Consider safely reducing or discontinuing (on specialist advice if necessary) any drugs that may be causing or exacerbating cognitive impairment, including:
• Drugs with an antimuscarinic action, including tricyclic antidepressants, tolterodine, and oxybutynin.
• H₂-receptor antagonists such as ranitidine.
• Benzodiazepines.
• Amantadine.
• Dopamine agonists.
• Refer for specialist assessment for:
• Optimization of anti-parkinsonian drug regimen, and/or
• Use of a cholinesterase inhibitor. Currently, only rivastigmine is licensed for use in people with Parkinson's disease dementia in the UK.

• See Mental health problems for background details on dementia in people with Parkinson's disease.

These recommendations are based on: two National Institute for Health and Clinical Excellence publications, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006] and Guideline on supporting people with dementia and their carers in health and social care [National Collaborating Centre for Mental Health, 2007]; and an evidence-based review, Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES) on late (complicated) Parkinson's disease [Horstink et al, 2006]. In particular:

• A Cochrane systematic review identified one randomized, double-blind, placebo-controlled trial (n = 541) that compared rivastigmine with placebo in Parkinson's disease dementia. Rivastigmine was associated with statistically significant, though modest, improvements in cognition and function, but it was poorly tolerated due to nausea, tremor, and vomiting [Maidment et al, 2006].
• NICE identified seven studies, including just two randomized controlled trials (one each of rivastigmine and donepezil), of cholinesterase inhibitors for Parkinson's disease dementia, concluding that they are effective in treating cognitive decline and psychosis, but that not all people respond [National Collaborating Centre for Chronic Conditions, 2006].
• Optimization of dopaminergic drugs is recommended in an evidence-based review [Leroi et al, 2006] on the basis of a study which randomized 82 people newly-diagnosed with Parkinson's disease to levodopa, bromocriptine (a dopamine agonist), or antimuscarinic drugs. The review reported the study finding that the dopaminergic drugs (levodopa and bromocriptine) improved memory and cognition, whereas antimuscarinic medication worsened registration.

In general terms, depression in people with Parkinson's disease should be diagnosed and treated in the same way as for people without Parkinson's disease — see the CKS topic on Depression.

• However, there are specific considerations in relation to diagnosis and assessment, and the choice of drug treatment in people with Parkinson's disease.
• See Mental health problems for background details on depression in people with Parkinson's disease.

• Have a low threshold for diagnosing depression in people with Parkinson's disease.
• Consider using a depression rating scale to screen for and assess the severity of depression.

Rating scales

• Of the depression rating scales recommended in the Quality and Outcomes Framework [BMA and NHS Employers, 2008], in people with depression and Parkinson's disease:
• The Beck Depression Inventory is the only rating scale that is useful and valid for both screening and assessing severity. However, it is not freely available, and has to be purchased commercially.
• The Hospital Anxiety and Depression Scale is a useful instrument for screening, but not for assessing severity [Schrag et al, 2007]. It is available on most primary care computer systems.

• The recommendation to have a low threshold for diagnosing depression in people with Parkinson's disease is derived from the National Institute for Health and Clinical Excellence (NICE) guideline, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [NICE, 2006].
• Depression is very common in people with Parkinson's disease — around 40–50% of people are affected.
• It may be difficult to detect because the clinical features, such as reduced facial expression and psychomotor slowing, overlap with those of Parkinson's disease [Hely et al, 2005; National Collaborating Centre for Chronic Conditions, 2006; Lemke, 2008].
• The recommendation to consider using a depression rating scale is based on: the Quality and Outcomes Framework guidance, which recommends the use of an tool validated for use in primary care to assess severity at the outset of treatment in people newly diagnosed with depression [BMA and NHS Employers, 2008]; and a systematic review of depression rating scales in Parkinson's disease commissioned by the Movement Disorders Society, which found that all reviewed scales had some utility [Schrag et al, 2007].
• The Quality and Outcomes Framework guidance suggests three severity measures: the Patient Health Questionnaire (PHQ-9), the Beck Depression Inventory Second Edition (BDI-II), and the Hospital Anxiety and Depression Scale (HADS) [BMA and NHS Employers, 2008].
• In the systematic review of depression rating scales in Parkinson's disease [Schrag et al, 2007]:
• The BDI was the only rating scale that was found to be useful and valid for both screening and assessing severity. (The BDI is also recommended for screening in the Report of the Quality Standards Subcommittee of the American Academy of Neurology [Miyasaki et al, 2006].)
• The HADS was found to be a useful instrument for screening, but not for assessing severity.
• The PHQ-9 was not reviewed.

• In addition to individual preference, the choice of antidepressant medication should depend on evidence of efficacy, the likely impact of potential adverse effects, and the person's current medication:
• Selective serotonin reuptake inhibitors (SSRIs) are most commonly used.
• SSRIs can worsen motor symptoms, but this occurs rarely.
• SSRIs should not be used by people taking selegiline or rasagiline (risk of serotonin syndrome).
• Use SSRIs with caution in people taking entacapone or tolcapone (theoretical risk of serotonin syndrome).
• Tricyclic antidepressants may be more effective than SSRIs in people with Parkinson's disease, but their use is limited by the risk of adverse effects. They should only be used with caution.
• Avoid tricyclic antidepressants in people with postural (orthostatic) hypotension, falls, or dementia.
• Tricyclic antidepressants should not be used without specialist advice by people taking selegiline or rasagiline (risk of serotonin syndrome).
• Use tricyclic antidepressants with particular caution in people taking entacapone or tolcapone (theoretical risk of serotonin syndrome).
• People taking selegiline or rasagiline may cautiously use trazodone or mirtazapine (off-label use for selegiline).
• There are no known contraindications to the use of any type of antidepressant in people taking amantadine, apomorphine, or oral and transdermal dopamine agonists.
• Other antidepressants:
• Irreversible monamine oxidase-A inhibitors (phenelzine, isocarboxazid, tranylcypromine) should not be used with levodopa, selegiline, rasagiline, entacapone, or tolcapone (risk of hypertension).
• Moclobemide should not be used with selegiline or rasagiline, and should be used with caution in people taking entacapone, tolcapone, and levodopa (risk of hypertension).
• Venlafaxine and duloxetine should not be used by people taking selegiline or rasagiline, and used with caution in those taking entacapone, or tolcapone (risk of serotonin syndrome).
• Consider contacting the person's Parkinson's disease specialist to ensure that their anti-parkinsonian medication regimen is optimal.
• Seek specialist advice if:
• There is doubt about whether an antidepressant can be safely prescribed.
• There is suspicion that the antidepressant prescribed may be affecting motor control or causing adverse effects.

• The National Institute for Health and Clinical Excellence guideline, Depression: the treatment and management of depression in adults with chronic physical health problems includes a table of drug interactions and recommended antidepressants for people with Parkinson's disease who are taking anti-parkinsonian medication. For further details, see Appendix 16 (pdf).

These recommendations are in line with a guideline published by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [NICE, 2006], and the NICE guideline Depression in adults with a chronic physical health problem [NICE, 2009].

• On the basis of a Cochrane systematic review (last assessed as up-to-date in February 2003) of three small randomized controlled trials (RCTs) [Ghazi-Noori et al, 2003] and two subsequent small RCTs, NICE concluded that there was insufficient evidence of the efficacy or safety of any form of treatment for depression in Parkinson's disease [National Collaborating Centre for Chronic Conditions, 2006].
• Other systematic or evidence-based reviews have differing conclusions: that antidepressant drugs are ineffective for depression in Parkinson's disease [Weintraub et al, 2005]; that they are effective for depression in Parkinson's disease [Raskind, 2008]; or, that tricyclic antidepressants may be more effective than SSRIs [Miyasaki et al, 2006; Frisina et al, 2008a]. However, most primary studies are small and of poor quality.
• Three small RCTs have been published since the NICE guideline [Antonini et al, 2006; Devos et al, 2008; Menza et al, 2008]. In particular, one small but well-conducted trial found the tricyclic antidepressant nortriptyline to be significantly more efficacious than paroxetine, and equally well tolerated [Menza et al, 2008].
• A survey of US neurologists carried out in the 1990s (when SSRIs were a relatively new class of antidepressant) found that, even then, more than half used SSRIs as first-line treatment for depression in people with Parkinson's disease [Richard and Kurlan, 1997].
• Although there are case reports of SSRIs worsening motor symptoms [Jimenez-Jimenez et al, 1994; Lemke, 2008], this is thought to be rare.
• An evidence-based review reported that data from around 500 participants in open-label or retrospective studies suggest that worsening of motor symptoms by SSRIs is rare [Lemke, 2008].
• A systematic review reported that, in open-label trials, 86% (202/234) of people taking an SSRI completed active treatment [Weintraub et al, 2005].
• The recommendation to avoid tricyclic antidepressants in people with postural (orthostatic) hypotension and falls is pragmatic and based on expert opinion [Miyasaki et al, 2006].
• Other recommendations with regard to potential drug interactions are derived from: publications from the Parkinson's Disease Society aimed at primary care professionals [Parkinson's Disease Society, 2003; Parkinson's Disease Society, 2007]; a narrative review, Depressive symptoms in Parkinson's disease [Lemke, 2008]; and the textbook, Stockley's drug interactions [Baxter, 2008].
• SSRIs or tricyclic antidepressants should not be used with selegiline or rasagiline because of the risk of serotonin syndrome. Entacapone and tolcapone should be used with caution with SSRIs and tricyclic antidepressants because serotonin syndrome is a theoretical risk. However, there are no documented reports of this occurring.
• There are no case reports of serotonin syndrome or an increase in adverse effects occurring when trazodone or mirtazapine are used with drugs for Parkinson's disease, or when dopamine agonists, apomorphine, or amantadine are used with any type of antidepressant.
• However, the manufacturer's Summary of Product Characteristics for selegiline states that it should not be given with any type of antidepressant [ABPI Medicines Compendium, 2010].
• Irreversible monoamine oxidase inhibitors should not be used with levodopa, selegiline, rasagiline, entacapone, or tolcapone because of an increased risk of hypertension. Moclobemide should not be used with selegiline or rasagiline for the same reason.
• Venlafaxine and duloxetine should be used with caution in people taking selegiline, rasagiline, entacapone, or tolcapone because of an increased risk of serotonin syndrome.
• The recommendation to consider contacting the person's Parkinson's disease specialist to ensure that their anti-parkinsonian medication regimen is optimal is based on very limited evidence from narrative reviews that some anti-parkinsonian medications (selegiline and pramipexole) may have antidepressant properties [Horstink et al, 2006; Lemke, 2008; Raskind, 2008].

• Psychological treatments, such as cognitive-behavioural therapy, may be considered for depression in people with Parkinson's disease.
• The use of psychological treatment should depend on the individual's preference and needs, and on other factors, such as cognitive impairment.
• See Psychological interventions in the CKS topic on Depression for more detailed information.

• In the absence of recommendations from the National Institute for Health and Clinical Excellence (NICE), the recommendation to consider psychological treatments (such as cognitive-behavioural therapy [CBT]) for depression in people with Parkinson's disease is extrapolated from evidence of the efficacy of psychological treatments for depression in the general population (see the section on Psychological interventions in the CKS topic on Depression).
• NICE found no studies of the efficacy of psychological treatments for depression in people with Parkinson's disease [National Collaborating Centre for Chronic Conditions, 2006].
• CKS found one subsequent, small, uncontrolled study which suggested that CBT may be beneficial in this group [Dobkin et al, 2007].
• The recommendation that the use of psychological treatment should depend on the individual's preference and needs, and on other factors, such as cognitive impairment, is pragmatic.

• Consider referral to a speech and language therapist for:
• Full assessment of swallowing ability.
• Advice, and a trial of behavioural management techniques to encourage regular saliva swallows.
• Use of a portable metronomic brooch as a reminder for saliva swallows.
• Lip-seal and swallow exercises.
• Consider referral to the person's Parkinson's disease specialist team.

• See Autonomic disturbances for background details on sialorrhoea in people with Parkinson's disease.
• The following off-licence treatments may be offered in secondary care:
• Sublingual 1% atropine ophthalmic solution twice-daily.
• Injection of salivary glands with botulinum toxin A.
• Hyoscine hydrobromide patch.

These recommendations are in line with the National Institute for Health and Clinical Excellence publication, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• Severe sweating may occur as an end-of-dose 'off' phenomenon. It may also occur during the 'on' motor state, when it is usually associated with dyskinesia.
• Exclude other causes of excessive sweating. See the section on Initial assessment in the CKS topic on Hyperhidrosis.
• Consider referral to the person's Parkinson's disease specialist team for a review of medication — sweating may respond to adjustments in anti-parkinsonian treatment.

These recommendations are in line with the National Institute for Health and Clinical Excellence publication, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• If falls occur soon after the onset of parkinsonism, suspect an alternative diagnosis, such as progressive supranuclear palsy.
• Refer to the person's Parkinson's disease specialist for review of the diagnosis.
• Assess and treat Postural (orthostatic) hypotension.
• Consider referral for multifactorial and multidisciplinary assessment and interventions to prevent falls.
• This is likely to be delivered by a specialist falls service and, ideally, will include a professional with understanding of Parkinson's disease.
• For more information, see the CKS topic on Falls - risk assessment.

• See Other complications for background details about falls in people with Parkinson's disease.

These recommendations are in line with guidelines produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006] and Falls: the assessment and prevention of falls in older people [NICE, 2004].

• Refer promptly to a speech and language therapist for:
• Assessment and swallowing advice.
• Further investigations such as videofluoroscopy or fibre-optic endoscopic examination of swallow safety (particularly if silent aspiration is suspected).
• Liaison with the person's Parkinson's disease specialist team is also recommended as symptoms may respond to alterations to anti-parkinsonian medication.

• See Autonomic disturbances for background details on dysphagia in people with Parkinson's disease.

These recommendations are based on the National Institute for Health and Clinical Excellence publication, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• Dysphagia (impaired swallowing) can lead to asphyxiation, aspiration pneumonia, malnutrition, dehydration, and difficulty in taking medicines.
• Where dysphagia is severe, specialist services may consider:
• Enteral feeding (either short term with a nasogastric tube, or long term with a percutaneous endoscopic gastrostomy [PEG]).
• Cricopharyngeal myotomy.

• If an impulse control disorder (such as hypersexuality, pathological gambling, or compulsive buying) or dopamine dysregulation syndrome is suspected, contact the person's Parkinson's disease specialist team.
• Explanation may be beneficial, and non-pharmaceutical measures, such as restriction of spending and internet access (for example to gambling sites), could be advised.

• See Mental health problems for background details about impulse control disorders and dopamine dysregulation syndrome in people with Parkinson's disease.
• Treatment (which should only be by a specialist) is difficult and may include:
• Discontinuing or reducing the dopamine agonist, or switching to another dopamine agonist.
• Reducing the levodopa dose.
• Using amantadine (off-licence use).
• Using an atypical antipsychotic (off-licence use).

These recommendations are based on limited evidence from four narrative, evidence-based reviews:

• Adverse events from the treatment of Parkinson's disease [Chou, 2008].
• Impulse control and related disorders in Parkinson's disease: review [Lim et al, 2008].
• Dopamine and impulse control disorders in Parkinson's disease [Weintraub, 2008].
• Parkinson's disease-related disorders in the impulsive-compulsive spectrum [Wolters et al, 2008].

For nausea or vomiting after starting or increasing the dose of a dopaminergic drug

• Initially, if nausea is mild:
• Reassure that nausea often settles over time as tolerance occurs.
• Advise the person to take their medication with food.
• Advise people taking levodopa not to increase their intake of high-protein foods.
• If nausea persists or is more severe:
• Prescribe domperidone, reducing or stopping it when the nausea or vomiting settles.
• Do not use metoclopramide or prochlorperazine.
• Consider seeking the advice of a specialist, who may recommend one or more of the following:
• An increase in the proportion of decarboxylase inhibitor to levodopa (only feasible for co-careldopa).
• A slower titration of the anti-parkinsonian drug.
• A switch to an alternative.

For nausea or vomiting unrelated to medication

• If an anti-emetic is required, use domperidone, reducing or stopping it when the nausea settles. Avoid metoclopramide or prochlorperazine.

• See Other complications for background details about nausea and vomiting in people with Parkinson's disease.
• The 5HT3 antagonists, granisetron, ondansetron, and topisetron, can also be used safely to treat nausea and vomiting in people with Parkinson's disease.

These recommendations are mainly based on an evidence-based review, Adverse events from the treatment of Parkinson's disease [Chou, 2008], and on a publication by the Parkinson's Disease Society, The professionals guide to Parkinson's disease, which is likely to represent expert opinion [Parkinson's Disease Society, 2007].

• Summaries of Product Characteristics of the available anti-parkinsonian drugs state that they can all be taken with food (see the Electronic Medicines Compendium), although a narrative review stated that co-administration with food should only be undertaken for a short period because food can reduce absorption, resulting in reduced efficacy and increased risk of motor fluctuations [Chou, 2008]. However, the manufacturers state that rates and extents of absorption are minimally reduced. For example, the manufacturers of Madopar^® (co-beneldopa) state that food can reduce the rate of absorption of levodopa by 15%, and yet they still advise that the drug should be taken with or after food.
• There are case reports of levodopa preparations taken with high-protein foods or supplements resulting in reduced response or worsening motor symptoms [Micromedex, 2009].

• Liaise with, or refer to, the person's Parkinson's disease specialist team for the following types of pain, as they may require an alteration to anti-parkinsonian medication:
• Dystonic pain.
• Primary or central neuropathic pain.
• Akathisia-related pain.
• The following types of pain can initially be managed in primary care, but liaise with, or refer to, the person's Parkinson's disease specialist team if pain cannot be controlled with these measures:
• Musculoskeletal pain:
• Treat with simple analgesics and regular exercise; consider physiotherapy.
• If appropriate, see the CKS topics on Shoulder pain and Back pain - low (without radiculopathy).
• Radicular neuropathic pain:
• Treat with simple analgesics, drugs specifically for neuropathic pain such as gabapentin, and gentle exercise.
• If appropriate, see the CKS topics on Neck pain - cervical radiculopathy, Neuropathic pain - drug treatment and Sciatica (lumbar radiculopathy).

• Opiates may be used, but can induce akinesia at high doses [Drake et al, 2005].
• One external reviewer advises against the use of baclofen, stating that it is ineffective and may cause confusion in people with Parkinson's disease.
• See Other complications for background details about pain in people with Parkinson's disease.

The National Institute for Health and Clinical Excellence (NICE) makes no recommendations about the management of pain as very little research has been done in this area, other than pointing out that pain due to dystonia is often responsive to dopaminergic medications [National Collaborating Centre for Chronic Conditions, 2006]. The efficacy of analgesics specifically in people with Parkinson's disease is unknown [Nègre-Pagès et al, 2008].

• The categories of pain are widely recognized, by NICE and others [Ford, 1998; National Collaborating Centre for Chronic Conditions, 2006; Parkinson's Disease Society, 2006; Nègre-Pagès et al, 2008; Beiske et al, 2009].
• Recommendations for treatment approaches are derived from an information leaflet published by the Parkinson's Disease Society [Parkinson's Disease Society, 2006] and three narrative reviews [Ford, 1998; Drake et al, 2005; Coelho et al, 2008], which are themselves based on low-grade evidence, such as case series or expert opinion.

• Consider a stepped approach to the management of postural (orthostatic) hypotension in Parkinson's disease.
• Stop or reduce the dose of antihypertensive medications.
• Reduce or change anti-parkinsonian drugs after discussion with specialist services.
• Advise the person to increase their dietary salt and fluid intake, to avoid caffeine at night, to eat frequent, small meals, and to avoid alcohol.
• Advise the person to elevate the head of their bed by 30–40 degrees.
• Consider prescribing compression stockings after excluding arterial insufficiency (see the CKS topic on Compression stockings).
• Consider referring people with persistent or troublesome symptoms to a unit with expertise in falls and syncope.
• A salt-retaining steroid (such as fludrocortisone) may be recommended.
• Occasionally, midodrine (a direct-acting sympathomimetic) may be prescribed, but this is only available on a named-patient basis.

• See Autonomic disturbances for background details on postural hypotension in people with Parkinson's disease.

These recommendations are based on the National Institute for Health and Clinical Excellence publication, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• Compression stockings are recommended on the basis of expert opinion from several external reviewers.

• Have a low threshold for suspecting psychotic symptoms in people with Parkinson's disease.
• Consider excluding causes besides Parkinson's disease itself, anti-parkinsonian drugs, and dementia, including:
• Delirium caused by other physical illness or drug treatments.
• Other comorbid mental illness, such as depression.
• Liaise with, and promptly refer to, specialist services all people with Parkinson's disease who develop psychotic symptoms.
• Mild psychotic symptoms may not need to be actively treated if they are well tolerated by the person and carer.
• More severe psychotic symptoms may require gradual withdrawal of precipitating anti-parkinsonian medication or the use of an atypical antipsychotic (such as clozapine, under the care of a mental health specialist).

• See Mental health problems for background details on psychosis in people with Parkinson's disease.
• A published narrative review recommends that anti-parkinsonian medications should be discontinued (on specialist advice) in this order:

1. Antimuscarinic agents.
2. Monoamine oxidase inhibitors.
3. Amantadine.
4. Dopamine agonists.
5. Catechol-O-methyl transferase (COMT) inhibitors.

[Chou, 2008]

These recommendations are based on the National Institute for Health and Clinical Excellence publication, Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• If hypersexuality is reported:
• Suspect that it may be caused by dopaminergic therapy (even when there is erectile dysfunction) and contact the person's Parkinson's disease specialist team.
• If erectile dysfunction or anorgasmia is reported:
• Exclude comorbid endocrine abnormalities (such as hypothyroidism or hyperprolactinaemia).
• Consider the possibility of underlying depression.
• Consider discontinuing drugs associated with erectile dysfunction (such as alpha-blockers) or anorgasmia (such as selective serotonin reuptake inhibitors [SSRIs]).
• Consider prescribing a phosphodiesterase type-5 inhibitor for erectile dysfunction (sildenafil, tadalafil, or vardenafil), which are available on the NHS for men with Parkinson's disease. The prescription must be endorsed 'SLS' by the prescriber.
• Avoid these drugs in people with hypotension (systolic blood pressure less than 90 mmHg), and use with caution in people with postural (orthostatic) hypotension.
• For more information, see the CKS topic on Erectile dysfunction.
• Consider referral to a urological specialist or specialist services for erectile dysfunction.

• See Autonomic disturbances for background details on sexual dysfunction in people with Parkinson's disease.

These recommendations are in line with a guideline produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• The recommendation to avoid phosphodiesterase type-5 inhibitors in people with hypotension (systolic blood pressure less than 90 mmHg) is derived from the British National Formulary [BNF 57, 2009].
• The recommendation that these drugs should be used with caution in people with postural (orthostatic) hypotension is pragmatic.

• If the person presents with an abrupt change in voiding pattern, exclude urinary tract infection.
• If frequency or polyuria are present, consider testing for diabetes.
• Consider discussing the use of an antimuscarinic drug (such oxybutynin or tolterodine) with the person's Parkinson's disease specialist team.
• Such treatment can induce a toxic confusional state and may worsen symptoms of dementia.
• Drugs that do not cross the blood–brain barrier (such as trospium chloride) may be less likely to induce confusion.
• Consider referral to a urological specialist if there are refractory or persistent bladder problems.

• See Autonomic disturbances for background details on urinary dysfunction in people with Parkinson's disease.

These recommendations are in line with a guideline produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• Take a full sleep history and advise good sleep hygiene, which includes:
• Avoidance of stimulants (for example coffee, tea, caffeine) in the evening.
• Establishment of a regular pattern of sleep.
• Comfortable bedding and temperature.
• Provision of assistive devices, such as a bed lever or rails to aid with moving and turning, allowing the person to get more comfortable.
• Restriction of daytime naps.
• Advice about taking regular and appropriate exercise to induce better sleep.
• Reviewing medication, trying to avoid any drugs that may affect sleep or alertness, or that may interact with other medication (for example, selegiline, antihistamines, H₂-receptor antagonists, antipsychotics, and sedatives).
• Identify whether any of the following may be present and manage them appropriately, usually by requesting an interim referral or advice from the person's Parkinson's disease specialist team:
• Conditions related to Parkinson's disease:
• Restless legs syndrome.
• Periodic leg movements of sleep.
• Rapid eye movement (REM) sleep behaviour disorder.
• Nocturnal akinesia (inability to turn over in bed).
• Nocturia (see Urinary dysfunction).
• Conditions that may be caused by anti-parkinsonian medication (such as selegiline and dopamine agonists):
• Vivid dreams or nightmares.
• Hallucinations.
• See the CKS topic on Insomnia.

• Criteria for the diagnosis of restless legs syndrome are:
• A desire to move the extremities, usually associated with discomfort or disagreeable sensations in the extremities.
• Motor restlessness — people move to relieve the discomfort (such as walking about or rubbing the legs).
• Symptoms which are worse at rest, with at least temporary relief on activity.
• Symptoms which are worse later in the day or at night.
• Suspect REM sleep behaviour disorder if hallucinations occur, or vivid dreams or nightmares occur which are acted out (with jerking and sometimes violent limb or body movements).
• Clonazepam may be used (off-licence use).
• Modified-release levodopa preparations may be used for nocturnal akinesia in people with Parkinson's disease.
• See Mental health problems for background details on sleep disturbance in people with Parkinson's disease.

These recommendations are based a guideline produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

• Although unintended weight loss occurs in over 50% of people with Parkinson's disease, other medical causes for weight loss (such as malignancy and endocrine diseases) should also be considered.
• If other medical causes of weight loss can be safely excluded, consider:
• Liaising with the person's Parkinson's disease specialist team to arrange:
• Investigations of swallowing — see Impaired swallowing (dysphagia).
• Review of anti-parkinsonian medications, as weight loss appears to correlate with severity of dyskinesia.
• Referring to a dietitian, and the provision of dietary supplements on the advice of the dietitian.

These recommendations are in line with a guideline produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006].

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk), or the British National Formulary (BNF) (www.bnf.org).

• Ensure that any requested changes to repeat medication have been made since the last specialist visit, and check that doses and timings are correct.
• Check that any relevant drug monitoring has been undertaken if there is a local agreement for monitoring to take place in primary care.
• Ask about and monitor adherence to treatment and explore any barriers to taking medication.
• If the person is over-using dopaminergic medication, consider whether they may have dopamine dysregulation syndrome (compulsive overuse of dopaminergic drugs) — see Impulse control and related disorders.
• The National Institute for Health and Clinical Excellence has issued guidance on Medicines adherence that can be found at www.nice.org.uk.
• Ask about possible adverse effects of anti-parkinsonian medication.
• Ensure that no other medication is exacerbating the Parkinson's disease — see Drugs to avoid.
• Do not stop anti-parkinsonian medication abruptly because of the risk of causing neuroleptic malignant syndrome (which can be serious).
• Respond to any concerns about motor or non-motor symptoms of Parkinson's disease.
• Check that the person has appropriate access to support services — see Role of primary care.

• Arrangements for monitoring may vary depending on local agreements between primary and secondary care.
• The following medications require monitoring — see Drug monitoring for further details:
• Ergot-derived dopamine agonists (cabergoline, pergolide, and bromocriptine).
• The catechol-O-methyl transferase (COMT) inhibitor, tolcapone.
• Apomorphine.

Changes to repeat medication

• This recommendation is based on a retrospective survey (published as a research letter) which found that 29% of medication changes recommended at specialist outpatient clinic appointments were not completed [Ng et al, 2007]. The authors do, however, acknowledge that there may be abundant reasons for this level of non-completion.

Drug monitoring

• This recommendation is pragmatic.

Adherence to treatment

• The recommendation to monitor adherence to treatment is based on expert opinion in a Parkinson's Disease Society publication, The professionals guide to Parkinson's disease [Parkinson's Disease Society, 2007].
• The recommendation to explore any barriers to taking medication is based on the The National Service Framework for long term conditions, which also states that 50% of people do not take their prescribed medication [DH, 2005].
• The recommendation to consider dopamine dysregulation syndrome if the person is over-using dopaminergic medication is based on case reports described in an evidence-based narrative review [Lim et al, 2008].

Drugs to avoid

• The recommendation to ensure that no other medication is exacerbating the Parkinson's disease is based on expert opinion expressed in a Parkinson's Disease Society publication, The professional's guide to Parkinson's disease [Parkinson's Disease Society, 2007].

Not stopping medication abruptly

• The recommendation to not stop anti-parkinsonian medication abruptly because of the risk of causing neuroleptic malignant syndrome (which can be serious) is based on expert opinion expressed in a Parkinson's Disease Society publication, The professional's guide to Parkinson's disease [Parkinson's Disease Society, 2007].

Adverse effects, motor and non-motor symptoms, and support services

• The recommendations to ask about possible adverse effects of anti-parkinsonian medication, monitor motor and non-motor symptoms (if possible), and check access to support services are pragmatic, and not related to any published evidence.

Contact the person's Parkinson's disease specialist team if the following adverse effects of anti-parkinsonian medication occur, as alterations to the medication may be needed:

• Fibrotic reactions (such as cardiac valvulopathy and retroperitoneal fibrosis) related to ergot-derived dopamine agonists (bromocriptine, cabergoline, or pergolide) — see Drug monitoring.
• Nausea and vomiting related to anti-parkinsonian medication.
• Motor complications, including:
• Motor fluctuations.
• Dyskinesias.
• Dystonic or akathisia-related pain.
• Neuropsychiatric symptoms, including:
• Cognitive impairment.
• Confusion and vivid dreaming:
• As with psychotic symptoms, these symptoms can be caused by dopamine agonists and (less commonly) levodopa, selegiline, and amantadine, and by any medicine with an antimuscarinic action, including some antidepressants and antipsychotics.
• The causative drug may need to be withdrawn.
• Daytime hypersomnolence or excessive drowsiness.
• Impulse control and related disorders, including:
• Hypersexuality.
• Pathological gambling.
• Compulsive eating or buying.
• Punding — repetitive mechanical tasks, such as assembling or collecting.
• Dopamine dysregulation syndrome — compulsive dopaminergic drug use beyond that required for motor control.
• Psychotic symptoms.
• Sleep disturbance.
• Autonomic disturbances.
• Diarrhoea:
• May be caused by entacapone and tolcapone (catechol-O-methyltransferase inhibitors). Diarrhoea due to tolcapone tends to start several months after treatment is initiated, but no particular time-course has been identified with entacapone. The combination drug, Stalevo^®, contains entacapone.
• Dose reduction may be needed. However, diarrhoea is sometimes severe enough to warrant discontinuation.
• Excessive saliva (sialorrhoea).
• Excessive sweating (hyperhidrosis).
• Hypotension:
• Tends to occur at the start of treatment with levodopa, dopamine agonists, and selegiline.
• Can usually be managed by dose reduction and slower dose escalation.
• Peripheral oedema:
• May occur with amantadine and dopamine agonists, but is not dose dependent.
• Diuretics or discontinuation of the offending medication may be considered.
• Postural (orthostatic) hypotension.
• Weight loss.

The following adverse effects can initially be managed in primary care, but liaison with or referral to the person's Parkinson's disease specialist team may be needed if initial measures fail:

• Constipation.
• Nausea and vomiting unrelated to anti-parkinsonian medication.

These recommendations are pragmatic and based on an evidence-based review, Adverse events from the treatment of Parkinson's disease [Chou, 2008].

• If possible, avoid the following drugs because they can worsen parkinsonism:
• The anti-emetics, metoclopramide and prochlorperazine.
• Anti-psychotics:
• On specialist advice only, clozapine may be used to treat psychosis in people with Parkinson's disease. Quetiapine appears to be well-tolerated with a good safety profile, but may not be effective for psychosis in people with Parkinson's disease.
• Some other drugs can also, less commonly, cause parkinsonism — see Differential diagnosis.
• If possible, also avoid the following drug combinations:
• Erythromycin and clarithromycin significantly increase the levels of bromocriptine and cabergoline. Azithromycin would not be expected to interact.
• Ciprofloxacin significantly increases the levels of ropinirole. Use an alternative antibiotic, or seek specialist advice about dose adjustment.
• Cough and cold preparations containing sympathomimetics (pseudoephedrine, ephedrine) should not be used with rasagiline or selegiline (risk of hypertension). Preparations containing dextromethorphan (a cough suppressant) should also not be used (risk of serotonin syndrome). People taking bromocriptine should also avoid sympathomimetics (increased risk of hypertension).
• Advise people to check with the pharmacist before purchasing over-the-counter cough and cold remedies.
• Pethidine should not be given with selegiline or rasagiline, or for 2 weeks after stopping these drugs (risk of central nervous system toxicity).
• Some antidepressant drugs should not be used with some drugs for Parkinson's disease:
• People taking rasagiline or selegiline should not use selective serotonin reuptake inhibitors, venlafaxine, duloxetine, or tricyclic antidepressants (risk of serotonin syndrome). Trazodone or mirtazapine may be cautiously used (off-label use for selegiline).
• See Drug treatment of depression for further details.

These recommendations are derived from: the British National Formulary [BNF 57, 2009]; a textbook, Stockley's drug interactions [Baxter, 2008]; the NICE guideline Depression in adults with a chronic physical health problem [NICE, 2009]; and publications by the Parkinson's Disease Society, which are likely to represent expert opinion [Parkinson's Disease Society, 2003; Parkinson's Disease Society, 2007].

• The palliative care requirements of people with Parkinson's disease should be considered throughout all phases of their disease.
• See the recommendations for the management of pain in people with Parkinson's disease.
• However, identification of the palliative phase may indicate that a more comprehensive range of palliative care services will be needed to control symptoms (including pain) and to meet the needs for personal, social, psychological, and spiritual support.
• People with Parkinson's disease are in the palliative phase when:
• They are unable to tolerate adequate dopaminergic therapy and they are unsuitable for surgery, or
• They have advanced comorbidity (such as severe dementia).
• Palliative care must address:
• Physical problems, including pain, breathlessness, anorexia, immobility, and constipation.
• When the person becomes immobile, high priority should be placed on assessing the risk for pressure ulcers, and managing any ulcers that do develop.
• When the benefits of dopaminergic drugs have been lost or adverse effects such as hallucinations become intolerable, it may be necessary to withdraw drugs; this should be done by (or on the advice of) a specialist, with the consent of the person and their carers.
• Social problems, including loss of employment, role change, and fear for dependants.
• Psychological problems, including depression, fear and anxiety, uncertainty, and guilt.
• Existential problems: religious, non-religious, the meaning of life, and 'why me?'.
• Stress on carers:
• Timely respite care can support carers and delay admission to a care home.
• End-of-life issues:
• People receiving palliative care should be supported so that they can live in, and die in, the place of their choice.
• The following CKS topics, although they apply to palliative cancer care, may also be helpful for managing particular problems in people with Parkinson's disease:
• Palliative cancer care - cough
• Palliative cancer care - dyspnoea
• Palliative cancer care - nausea & vomiting
• Palliative cancer care - oral
• Palliative cancer care - pain
• Palliative cancer care - secretions

• Rotigotine, a transdermal dopamine agonist, or apomorphine injections or infusion, can be considered if the person is unable to tolerate oral medication. These should only be initiated by a specialist.

These recommendations are in line with a guideline produced by the National Institute for Health and Clinical Excellence (NICE), Parkinson's disease: national clinical guideline for diagnosis and management in primary and secondary care [National Collaborating Centre for Chronic Conditions, 2006], as well as the quality standard for palliative care in the National service framework for long-term (neurological) conditions [DH, 2005].

• Recommendations about the need for risk assessment and management of pressure ulcers are derived from guidance from NICE and the Royal College of Nursing [NICE, 2005; RCN, 2005].

• It is not possible to identify a universal first-choice drug for people with early Parkinson's disease.
• The following options may be considered:
• Postponing treatment if symptoms are mild.
• Oral dopamine agonists (pramipexole or ropinirole).
• Monoamine oxidase-B (MAO-B) inhibitors (selegiline or rasagiline).
• Levodopa (routinely given with a dopa-decarboxylase inhibitor, benserazide or carbidopa, as co-beneldopa or co-careldopa respectively).
• This is usually used alone, but may be combined with an oral dopamine agonist.
• Rarely, antimuscarinics, beta-blockers, or amantadine may be considered.

[National Collaborating Centre for Chronic Conditions, 2006]

• Treatment will usually consist of levodopa (with a dopa-decarboxylase inhibitor) together with adjuvant treatment to help manage motor fluctuations and dyskinesias.
• First-choice adjuvant treatment:
• Oral dopamine agonists (usually pramipexole, ropinirole, or rotigotine).
• Monoamine oxidase-B (MAO-B) inhibitors (selegiline or rasagiline).
• Catechol-O-methyl transferase (COMT) inhibitors (entacapone or tolcapone).
• Second-choice adjuvant treatment:
• Amantadine.
• Subcutaneous apomorphine infusions.
• Intermittent apomorphine injections.
• Modified-release levodopa or levodopa gel by enteral tube (Duodopa^®) may be used, but should not be the drugs of first choice.
• Deep brain stimulation may also be considered.

[National Collaborating Centre for Chronic Conditions, 2006]

Levodopa

• Is a precursor of dopamine and is metabolized centrally and peripherally by dopa-decarboxylase, catechol-O-methyltransferase (COMT), and monoamine oxidase.
• Over time, the response may decrease and motor complications may occur, including:
• Motor fluctuations, such as unpredictable switching between 'on' and 'off' states (on-off phenomenon), wearing off between doses, and dose failures.
• Dyskinesias, such as athetosis (slow, writhing motions of fingers and hands) and dystonia (involuntary spasms of muscle contraction that cause abnormal movements and postures) occur.
• Modified-release levodopa preparations may be used to reduce motor complications in people with later Parkinson's disease but can increase 'off' time and are not the drugs of first choice.
• Oral dispersible levodopa may also be used to treat motor complications.
• A levodopa gel given by continuous infusion directly into the jejunum (Duodopa^®) is also licensed for the management of severe motor complications. It may reduce off-periods and improve motor function, activities of daily living, and quality of life, but its use may be limited by cost and the need for a jejunostomy.

Dopa-decarboxylase inhibitors (benserazide and carbidopa)

• Are given routinely with levodopa (as co-beneldopa or co-careldopa) to prevent its peripheral metabolism to dopamine; this reduces its peripheral adverse effects and increases the amount of levodopa available to cross the blood–brain barrier.

[American Medical Directors Association, 2002; National Collaborating Centre for Chronic Conditions, 2006]

• Oral and transdermal dopamine agonists act directly on post-synaptic dopaminergic receptors, and do not need to be converted in the brain to active compounds.
• When used as monotherapy in people with functionally-disabling early Parkinson's disease:
• Dopamine agonists are slightly less effective than levodopa in terms of treating motor impairments and disability, but may delay motor complications.
• However, treatment needs to be started slowly and carefully to avoid developing intolerable adverse effects. In particular:
• Neuropsychiatric adverse effects (such as hallucinations, especially in older people, and impulse control disorders) may occur.
• Drowsiness can be severe and may affect driving. In rare cases, sudden onset of sleep has occurred without awareness or warning signs; people should be informed of this.
• Postural hypotension can occur, and is often worse at the start of treatment.
• When used as an adjuvant to levodopa in later Parkinson's disease:
• Dopamine agonists reduce off-time and levodopa dose, and improve motor impairments and activities of daily living.
• This is at the expense of increased dopaminergic adverse effects that include dyskinesia, hallucinations, and postural hypotension.
• The National Institute for Health and Clinical Excellence (NICE) recommends that, if a dopamine agonist is being considered, a non-ergot dopamine agonist (ropinirole, pramipexole, or rotigotine) should be used because of the association of fibrotic reactions, particularly cardiac fibrosis, with the use of ergot-derived dopamine agonists (bromocriptine, cabergoline, and pergolide; lisuride has been discontinued in the UK).
• If an ergot-derived dopamine agonist (bromocriptine, cabergoline, or pergolide) is used (for instance, because a non-ergot dopamine agonist is ineffective or not tolerated), careful drug monitoring is required.
• Rotigotine is only available as a patch for transdermal administration.

[American Medical Directors Association, 2002; CSM, 2002; CSM, 2003; National Collaborating Centre for Chronic Conditions, 2006; MHRA, 2007; MHRA, 2008]

Monoamine oxidase-B inhibitors (selegiline, rasagiline)

• Inhibit central dopamine metabolism, thereby increasing nigrostriatal dopamine levels.
• Do not cause a reaction after consumption of tyramine-rich foods.
• When used as monotherapy in early Parkinson's disease:
• Improve motor symptoms, improve activities of daily living, and delay the need for levodopa. It is less clear whether they also delay motor complications.
• Dopaminergic adverse effects such as dyskinesia, hallucinations, or vivid dreaming may occur or worsen.
• When used as an adjuvant to levodopa in later Parkinson's disease:
• May be used to reduce motor fluctuations although evidence of efficacy is limited.

[National Collaborating Centre for Chronic Conditions, 2006]

Catechol-O-methyl transferase inhibitors (COMT) inhibitors (entacapone and tolcapone)

• Work by further inhibiting the peripheral metabolism of levodopa, thereby increasing its bioavailability to the brain and prolonging the action of dopamine. Tolcapone also inhibits central COMT metabolism.
• When used as an adjuvant to levodopa:
• COMT inhibitors reduce off-time and levodopa dose, and improve motor impairments.
• This is at the expense of increased dopaminergic adverse events such as nausea, vomiting, and dyskinesia.
• Entacapone and tolcapone have different methods of administration:
• Entacapone must be given with each dose of levodopa/dopa-decarboxylase inhibitor (that is, each dose of co-beneldopa or co-careldopa), which may be up to ten times a day.
• Tolcapone is given three times a day (and does not have to be taken at the same time as a levodopa dose).
• In view of problems with concordance, the National Institute for Health and Clinical Excellence (NICE) recommends that people requiring entacapone should be offered the triple-combination preparation of levodopa, carbidopa, and entacapone (Stalevo^®).
• Tolcapone was suspended by the Committee on Safety of Medicines in November 1998 because of unpredictable serious hepatic reactions. However, in April 2004 the suspension was lifted due, in part, to evidence of increased efficacy for tolcapone over entacapone in the control of motor fluctuations in advanced Parkinson's disease.
• Tolcapone is now indicated for people who fail to respond to, or are intolerant of, other COMT inhibitors, but may only be prescribed by specialists in managing Parkinson's disease.
• Drug monitoring is required for people taking tolcapone.

[CSM, 2004; National Collaborating Centre for Chronic Conditions, 2006]

• Apomorphine is a potent dopamine agonist used as an adjuvant to levodopa.
• There are two distinct delivery methods for giving apomorphine: subcutaneous bolus doses or continuous infusion.
• Intermittent subcutaneous bolus doses are used as a rescue agent in advanced disease to treat severe 'off' episodes. They provide rapid reversal of 'off' periods (within a few minutes) but the effect only lasts for about 1 hour.
• A continuous subcutaneous infusion is used when people respond well to apomorphine injections but their control remains poor and they require frequent injections. The continuous subcutaneous infusion provides a constant therapeutic effect.
• The evidence base for the use of both intermittent injections and continuous infusions of apomorphine is relatively poor, but both techniques are licensed for use in England and Wales. The National Institute for Health and Clinical Excellence guideline development group considered these to be useful treatments for people with severe 'off' periods that are not responsive to changes in oral medication. However, as with other dopaminergic medication, there is a risk of triggering serious adverse effects such as confusion and hallucinations. In addition, the risk of injection-site reactions is considerable.
• Long-term continuous apomorphine infusions can dramatically reduce both 'off' periods and dyskinesia, and allow withdrawal of oral medication.
• Apomorphine should only be initiated by expert units that can provide home monitoring by a suitably trained healthcare professional, such as a Parkinson's disease nurse specialist.
• See Drug monitoring.

[National Collaborating Centre for Chronic Conditions, 2006; ABPI Medicines Compendium, 2008b]

Amantadine

• Is an antiviral drug with relatively weak anti-parkinsonian activity. Its mechanism of action has not been established.
• May be used as an adjuvant to levodopa in the management of dyskinesias in later Parkinson's disease.
• May rarely be used in early, mild Parkinson's disease.
• Has a lack of evidence on safety and efficacy, and trials have been of poor quality.

[National Collaborating Centre for Chronic Conditions, 2006]

• Deep brain stimulation (DBS) involves the delivery of an electric current to a targeted area of the brain from a pulse generator, usually implanted in the chest wall, via fine cables tunnelled subcutaneously to electrodes placed in the brain.
• The pulse generator is similar to a cardiac pacemaker and can be programmed by an external device.
• It is possible to provide the individual with a degree of control of the stimulator.
• The pulse generator has a battery within it which will need to be replaced in a simple surgical procedure every few years.
• The structures in the brain that are targeted when treating Parkinson's disease are either of the following:
• The subthalamic nucleus (STN).
• The globus pallidus interna (GPi).
• The thalamus.
• The National Institute for Health and Clinical Excellence (NICE) has approved the use of STN-DBS and GPi-DBS procedures for people who meet all of the following criteria:
• They have motor complications that are refractory to best medical treatment.
• They are biologically fit with no clinically significant active comorbidity.
• They are levodopa responsive.
• They have no clinically significant active mental health problems, for example depression or dementia.
• NICE has approved thalamic DBS as an option for people with Parkinson's disease who predominantly have severe disabling tremor and where STN stimulation cannot be performed.
• STN-DBS is usually preferred; GPi-DBS and thalamic DBS are rarely performed in the UK.
• Limited evidence suggests that STN-DBS: reduces 'off' time, dyskinesia, and levodopa dose; improves motor impairments and disability; and improves quality of life at the expense of a small but significant risk of permanent neurological disability, and a possible increased risk of depression and suicide.

[National Collaborating Centre for Chronic Conditions, 2006; Pahwa et al, 2006]

The responsibility for undertaking these tests may vary depending on local agreements between primary and secondary care.

• Ergot-derived dopamine agonists (bromocriptine, cabergoline, pergolide) can rarely cause fibrotic reactions, including lung and heart-valve fibrosis, cardiac valve thickening, and reddening of the legs.
• At baseline, erythrocyte sedimentation rate and serum creatinine should be measured and chest radiography obtained.
• During treatment, people taking an ergot-derived dopamine agonist should be monitored for signs and symptoms of pleuro-pulmonary disease (such as shortness of breath, persistent cough, and chest pain) and retroperitoneal disorders. Renal insufficiency or ureteric or abdominal vascular obstruction might occur, with pain in the loin or flank and leg oedema. Abdominal masses or tenderness could suggest retroperitoneal fibrosis.
• Echocardiography should be done before treatment with cabergoline or pergolide to exclude cardiac valvulopathy.
• Echocardiography should also be done within 3–6 months of starting treatment, and subsequently at 6–12 month intervals. Treatment should be stopped if an echocardiogram shows new or worsened valvular regurgitation, valvular restriction, or valve-leaflet thickening [CSM, 2002; CSM, 2003; National Collaborating Centre for Chronic Conditions, 2006; MHRA, 2007; MHRA, 2008].
• Tolcapone has (rarely) caused fulminant hepatic failure. Liver function should be checked before starting treatment with tolcapone and then monitored every 2 weeks for the first year of therapy, every 4 weeks for the next 6 months, and every 8 weeks thereafter [ABPI Medicines Compendium, 2009]. However, such monitoring will not always predict the development of severe hepatic disease [CSM, 1999], and people using tolcapone should be asked to report any signs or symptoms of liver disease (such as yellowing of the skin or eyes).
• Entacapone does not seem to cause hepatic problems, and monitoring of liver function tests is not required.
• Apomorphine's summary of product characteristics states that people using apomorphine with levodopa should have regular haematological monitoring (for example, every 6 months) to detect rare instances of haemolytic anaemia [ABPI Medicines Compendium, 2008a]. There is no need to do this if a person using apomorphine does not use levodopa (even if they are taking other drugs to treat Parkinson's disease) [American Medical Directors Association, 2002; Goetz et al, 2002].

Motor complications include:

• Motor fluctuations — variations or fluctuations in clinical motor response or motor performance.
• Wearing off of the benefit from levodopa usually at the end of the dosing period, before the next dose is due (this is usually predictable).
• On–off phenomenon — rapid and unpredictable fluctuations between 'on' and 'off' periods.
• Dyskinesias — involuntary movements (in response to levodopa or dopamine agonist intake) that may be choreiform (quick, fidgety movements) or dystonic (slow, distorted postures).
• Peak-dose dyskinesia — dyskinesias occurs at peak-dose levels and are typically choreiform, but may involve dystonia or myoclonus.
• Diphasic dyskinesia — dyskinesias occur at the beginning of turning 'on' and/or at the beginning of turning 'off', but they are different, less severe, or absent at the time of peak levodopa effect.
• Off-state dystonia — dystonia when plasma levodopa levels are low.
• Freezing of gait — inability to start or continue walking, characterized by difficulty in stepping forward (at initiation or during walking), inability to lift the foot from the floor, and trembling of the legs.
• Freezing of gait is a common cause of falls, particularly as there is an associated disturbance of balance.
• Freezing of gait occurs during the 'off' phase and, less frequently, in both 'off' and 'on' phases.

[Horstink et al, 2006; Chou, 2008; Dewey, 2008; Okuma and Yanagisawa, 2008]

Wearing off

There is insufficient evidence to conclude that any one drug is superior to another in reducing off-time. The following strategies may be used, either alone or in combination:

• Adjustment of levodopa dosing:
• This may be useful during early disease when motor fluctuations are just becoming apparent.
• Usually an increase from three to six smaller daily doses (whilst maintaining the total daily dosage) is used.
• Oral adjuvant therapy:
• Oral catechol-O-methyl transferase inhibitors (COMT) inhibitors and monoamine oxidase-B inhibitors:
• Reduce off-time by 1–1.5 hours per day.
• Are likely to be equivalent in effectiveness.
• Oral dopamine agonists:
• Reduce off-time.
• There is no evidence to guide choice of dopamine agonist, but ergot agonists are not recommended first-line because of the risks of fibrotic reactions.
• Amantadine may be used if other strategies fail.
• Other strategies:
• Deep brain stimulation (DBS) of the subthalamic nucleus (STN).
• Subcutaneous apomorphine.
• Switch from standard to modified-release levodopa (but this can lead to an increase in off-time).
• Switch from standard to modified-release or transdermal dopamine agonist.
• Oral dispersible levodopa (co-beneldopa).
• Levodopa gel via jejunostomy.

On-off phenomenon

There is insufficient evidence for any specific strategies or treatments for the on-off phenomenon, although the strategies for wearing off and dyskinesia may be considered.

[Horstink et al, 2006; National Collaborating Centre for Chronic Conditions, 2006; Pahwa et al, 2006]

Peak-dose dyskinesia

• Add amantadine:
• The benefit may be limited to 8 months' duration.
• Reduce the individual levodopa dose, whilst increasing the dose frequency to compensate for the risk of increased 'off' time. The total daily dosage should remain the same as before.
• Discontinue or reduce the dose of catechol-O-methyl transferase (COMT) inhibitor or monoamine oxidase-B (MAO-B) inhibitor (at the risk of worsening the effects of wearing off).
• Use an apomorphine continuous subcutaneous infusion, which allows reduction of levodopa dosing.
• Perform deep brain stimulation (DBS) of the subthalamic nucleus (STN).
• Add an atypical antipsychotic (such as clozapine or quetiapine), although adverse effects and monitoring limit their use, particularly for clozapine.

Diphasic (biphasic) dyskinesia

This type of dyskinesia can be very difficult to treat.

• Strategies for peak-dose dyskinesia may be employed.
• Increasing the size and frequency of the levodopa dose may be used (but this risks inducing or increasing peak-dose dyskinesia).
• Larger, less frequent levodopa doses may be considered.

Off-state dystonia

• Change the levodopa dosing schedule.
• Add an oral dopamine agonist, a COMT inhibitor, or a MAO-B inhibitor.

[Horstink et al, 2006; National Collaborating Centre for Chronic Conditions, 2006; Pahwa et al, 2006; Chou, 2008]

'Off' freezing

• Treatment for wearing off (see Managing motor fluctuations), such as dispersible levodopa, may be used.
• The use of visual or auditory cues may be useful.

'On' freezing

• May respond to a reduction in dopaminergic therapy, but this may result in worsening symptoms of wearing off.

[Lim et al, 2005; Horstink et al, 2006]

• The National Institute for Health and Clinical Excellence (NICE) recommends that people with Parkinson's disease should have regular access to the following, which may be provided by a Parkinson's disease nurse specialist:
• Clinical monitoring and medication adjustment.
• A continuing point of contact for support, including home visits when appropriate.
• A reliable source of information about clinical and social matters of concern to people with Parkinson's disease and their carers [NICE, 2006].
• There are areas without a Parkinson's disease nurse specialist, but these areas may be providing an equivalent service in other ways [Bell, 2003; National Collaborating Centre for Chronic Conditions, 2006; Thomas et al, 2006].