This article is focused on the management of Parkinson's disease (PD). Further discussion of PD can be found in the separate related article Parkinsonism and Parkinson's Disease.

Management

Treatment, as always, should be tailored to the needs of the individual. Patients should be helped to make informed decisions about their care, and try to involve the carers as much as the patient will allow.

Drug treatments

There is no universal first-choice drug - this depends on the patient's age, clinical symptoms, lifestyle and personal preferences.

Initial drug treatments

• Levodopa is the most effective drug in the treatment of Parkinson's disease (PD). Virtually all patients respond to it and treatment is associated with reduced morbidity.
  • It is given with a peripheral dopa-decarboxylase inhibitor, which prevents destruction in the bloodstream. Sinemet® and Madopar® are the main preparations.
  • Use the lowest effective dose that maintains good function:⁴ e.g. Sinemet® 62.5 mg tds (at mealtimes) increased to 125 mg after 2 weeks.
  • It is usually well tolerated and adverse effects (nausea and dizziness) are quite rare and mild.
  • There is no evidence that using modified-release levodopa initially delays onset of motor complications.⁴
  • Clinicians should be aware that prolonged levodopa use may be associated with weight loss.⁶
• Dopamine agonists:
  • They are effective in treating motor features of PD and can be used in early disease. In the long term they are associated with fewer dyskinesia and motor fluctuations compared with levodopa and may therefore be more appropriate for use in younger patients.
  • Acute adverse effects are similar to levodopa but more common and severe and are associated with increased treatment withdrawal and poorer motor scores. These occur at the start of treatment and abate over several days to weeks.
  • They are less effective than levodopa, and levodopa is eventually required.
  • Prolonged monotherapy (longer than 1 year) is not always successful because of side-effects.
  • In people with response fluctuations to levodopa, adjuvant dopamine agonists reduce 'off' time, improve motor impairment and activities of daily living and reduce levodopa dose but increase dopaminergic adverse effects and dyskinesias.⁷
  • Non-ergot-derived agonists are preferred (pramipexole and ropinirole); the ergot-derived drugs (bromocriptine, cabergoline, lisuride and pergolide) need renal function, ESR and CXR before treatment, and repeated annually (see individual drug monographs).² Apomorphine is not used first-line and is considered in the section 'Adjuvant therapy for more advanced Parkinson's disease', below.
• Monoamine-oxidase-B inhibitors (MAO-BIs):
  • Random controlled trials confirmed improvement of symptoms and a delay in the need for levodopa.⁸
  • Early research suggesting that selegiline had a neuroprotective effect has been disproved.^9,10
  • There has also been concern that selegiline may be associated with excess mortality in some people also taking levodopa,¹¹ but, again, there is no convincing evidence for this.¹²
  • One study suggested that addition of selegiline to a levodopa/decarboxylase inhibitor combination was more effective when introduced at 5 years than 10 years from the onset of the disease.¹³
  • An orally disintegrating formulation increases bioavailability and can be administered at lower doses than conventional selegiline, with similar clinical effect. It also leads to less variable blood concentrations and produces significantly fewer methamfetamine metabolites. It may be especially useful for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.¹⁴
  • Rasagiline is a new MAO-BI. Studies suggest it has a protective effect against neurodegeneration and may exert more disease-modifying effects.¹⁵

Common management problems^16,17,18

Long-term levodopa treatment is associated with adverse motor effects that limit its use. These are motor fluctuations (on-off phenomena, wearing off, dose failures and freezing) and dyskinesias (peak-dose dyskinesias, diphasic dyskinesia and dystonia). They are best managed by a specialist.

• 'Wearing off' phenomenon - several strategies are available:
  • Add in or adjust dose of dopamine agonist.
  • Smaller, more frequent doses of levodopa.
  • Prolonged-release levodopa preparations (ideally taken at bedtime). Taking both sorts early in the morning may be effective in 'jump starting' the system.
  • Severe fluctuations may be helped by a liquid carbidopa.
  • Adding selegiline or a dopamine agonist may help.
  • Dietary adjustments: take levodopa 30 minutes before food.
  • Catechol-O-methyltransferase (COMT) inhibitors (e.g. entacapone) can be used to prolong the action of levodopa and increase the 'on-time', reduce the levodopa dose and modestly improve motor impairment and disability.¹⁶
• 'On-off' fluctuations (patients may switch from severe dyskinesia to immobility in a few minutes):
  • Combine levodopa with a dopamine agonist. Cabergoline can be used to reduce the levodopa dose and modestly improve motor impairment and disability¹⁹.
  • Fewer doses of levodopa with intermittent injections or subcutaneous infusion of apomorphine.
  • Liquid forms of levodopa (enable more close titration of the dose).
  • Diet: small snacks and one large evening meal.
• Dyskinesias (may occur either at the beginning or end of a dose, or sometimes at its peak):
  • At peak dose (usually choreic):
    • Reduce each dose of levodopa but make it more frequent so that the total daily dose remains the same.
    • Add a long-acting dopamine agonist.
    • Frequent dyskinesias may respond to slow-release or liquid levodopa.
    • Surgery may be indicated.
  • At the beginning or end of a dose:
    • Try soluble levodopa before meals.
    • Add a COMT inhibitor.

Complications

Depression and anxiety

Depression and anxiety are common in patients with Parkinson's disease (PD). It is very important to detect and differentiate from dementia and to treat. Either tricyclics or selective serotonin reuptake inhibitors (SSRIs) can be used.

• Use tricyclic antidepressants if the sleep pattern is disturbed. Nortriptyline has the lowest anticholinergic effects and so may have the fewest side-effects.
• SSRIs can be helpful if apathy is a predominant feature (but should not be used with selegiline).
• Psychotherapy and support groups are helpful (both for the patient and carers).

Compulsive behaviours

• Dopamine agonists have been linked to the development of compulsive or disinhibited behaviours, including pathological gambling, hypersexuality, and compulsive eating and shopping, which can have a major impact on the lives of those affected. In rare cases, this may also be observed in some patients on levodopa.²⁰
• Patients and their families/carers should be made aware of this potential side-effect and significant behavioural changes should be monitored.
• A patient's drug regime should be reviewed by a Parkinson's disease specialist if compulsive behaviour is observed.

Hallucinations and psychosis

• May be related to dopaminergic therapy, PD dementia or due to a confusional state (e.g. infection, malnutrition, dehydration or sudden withdrawal of a dopaminergic drug). Consider gradual withdrawal of PD drugs - which may have triggered the psychosis.
• Confusion and hallucinations imply a bad prognosis with high mortality within 1-2 years. Management is very difficult and admission to a nursing home is often required.
• Always consider other causes; it is not always due to PD or drugs.
• Mild symptoms may not need any treatment but atypical antipsychotics should be used rather than typical ones.
• Clozapine (selective D4 antagonist) may be used on occasions (only by specialists). It reduces hallucinations without aggravating the motor disability of PD.

Adjuvant therapy for more advanced Parkinson's disease

• First-choice adjuvant drugs in later Parkinson's disease (PD) are dopamine agonists, MAO-BIs, or COMT inhibitors.⁴
• Catechol-O-methyltransferase (COMT) inhibitors:
  • Reversibly inhibit the peripheral breakdown of levodopa by the COMT enzyme, increasing the amount available for conversion to dopamine in the brain and reducing fluctuations in plasma levels.
  • Produce clinical benefits in people with levodopa motor fluctuations and in those with stable responses to levodopa.
  • Entacapone should ideally be offered as a combination drug (levodopa carbidopa entacapone) because of poor patient compliance. One study found that early addition of entacapone to combined therapy produced more benefit than if it were introduced at a later stage (after 5 years). Tolcapone should only be used if entacapone fails (needs 2-weekly LFTs for the first year).⁴
• Antimuscarinic drugs (orphenadrine, procyclidine and trihexyphenidyl) - evidence for efficacy is poor⁴:
  • May be effective in improving motor function but neuropsychiatric and cognitive adverse events occur frequently and are a more common reason for withdrawal than lack of efficacy.
  • May have beneficial effects on tremor in some people. They are useful in reducing sialorrhoea.
  • Adverse effects include confusion, hallucinations and memory impairment (particularly common in the elderly but may also occur in younger individuals).
  • Reduce the symptoms of drug-induced Parkinsonism. They have no beneficial effect on tardive dyskinesia, however, and may make it worse.
• Amantadine can be used as monotherapy in early PD (for tremor or bradykinesia) but has a weak and short-lived benefit - and evidence for efficacy is poor.⁴ It can be used as an adjuvant in later PD for reducing dyskinesia but other drugs are usually considered better.
• Apomorphine is given subcutaneously. It can be used as a rescue agent in advanced disease to provide rapid but short-lived benefit for sudden, severe 'off' episodes - use intermittent injections to reduce 'off-time' and continuous infusion to reduce 'off-time' and dyskinesias.²¹
• Modified-release levodopa can also help with symptom control in later stages.
• A whole host of drugs is currently being explored for the treatment of cognitive decline in PD, of which entacapone and amantadine are but two examples.²²

Surgical^23,24

The surgical treatment of PD was developed in the mid-twentieth century before the advent of effective medical therapy. It still has a place in treatment and recently enjoyed a resurgence, as various procedures are required to deliver advances in scientific therapy:

• Pallidotomy: indicated for unilateral dyskinesia, severe 'on-off' fluctuations and drug failure. One systematic review found that unilateral pallidotomy improved motor examination and activities of daily living compared with medical treatment but there is a high incidence of adverse effects. Procedure is only performed on one side, as bilateral pallidotomy may cause speech and memory disorders.
• Thalamic surgery: an effective method of controlling tremor but it has no effect on bradykinesia. There are no randomised trials comparing this with medical treatment.
• Subthalamic surgery: can improve tremor, bradykinesia and rigidity but may provoke dyskinesias and hemiballismus.
• Deep brain stimulation: electrodes are placed in the basal ganglia and attached to an internal stimulator, which is placed subcutaneously below the clavicle. May be used to provide unilateral or bilateral stimulation. The subthalamus is the preferred target for stimulation. It may reverse akinesia, rigidity and tremor. Complications include intracerebral haemorrhage and confusion. The National Institute for Health and Clinical Excellence (NICE) has recommended that patients receiving this treatment should be carefully counselled about the risks and benefits and that it should only be considered after drug treatment has failed.
• Recent scientific advances - e.g. gene therapy, nanotechnology and neural transplantation - require surgical techniques for their application and hold much promise.²⁵

Document references

1. Aragon A, Ramaswamy B, Ferguson J et al; The Professional’s Guide to Parkinson's Disease, Parkinson's UK, 2009
2. Diagnosis and pharmacological management of Parkinson’s disease, Scottish Intercollegiate Guidelines Network (SIGN), January 2010
3. Newman EJ, Breen K, Patterson J, et al; Accuracy of Parkinson's disease diagnosis in 610 general practice patients in the Mov Disord. 2009 Nov 4. [abstract]
4. Parkinson's disease: diagnosis and management in primary and secondary care, NICE (2006)
5. Meara J, Bhowmick BK, Hobson P; Accuracy of diagnosis in patients with presumed Parkinson's disease.; Age Ageing. 1999 Mar;28(2):99-102. [abstract]
6. Bachmann CG, Zapf A, Brunner E, et al; Dopaminergic treatment is associated with decreased body weight in patients with Eur J Neurol. 2009 Aug;16(8):895-901. Epub 2009 Apr 3. [abstract]
7. Unified Parkinson's Disease Rating Scale; MD Virtual University
8. Tetrud JW, Langston JW; The effect of deprenyl (selegiline) on the natural history of Parkinson's disease.; Science. 1989 Aug 4;245(4917):519-22. [abstract]
9. Larsen JP, Boas J; The effects of early selegiline therapy on long-term levodopa treatment and parkinsonian disability: an interim analysis of a Norwegian--Danish 5-year study. Norwegian-Danish Study Group.; Mov Disord. 1997 Mar;12(2):175-82. [abstract]
10. Larsen JP, Boas J, Erdal JE; Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study. The Norwegian-Danish Study Group.; Eur J Neurol. 1999 Sep;6(5):539-47. [abstract]
11. No authors listed; Selegiline: a second look. Six years later: too risky in Parkinson's disease.; Prescrire Int. 2002 Aug;11(60):108-11. [abstract]
12. Donnan PT, Steinke DT, Stubbings C, et al; Selegiline and mortality in subjects with Parkinson's disease: a longitudinal community study.; Neurology. 2000 Dec 26;55(12):1785-9. [abstract]
13. Mizuno Y, Kondo T, Kuno S, et al; Early Addition of Selegiline to L-Dopa Treatment is Beneficial for Patients With Clin Neuropharmacol. 2009 Nov 21. [abstract]
14. Lohle M, Storch A; Orally disintegrating selegiline for the treatment of Parkinson's disease. Expert Opin Pharmacother. 2008 Nov;9(16):2881-91. [abstract]
15. Olanow CW, Rascol O, Hauser R, et al; A double-blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med. 2009 Sep 24;361(13):1268-78. [abstract]
16. Marsh L, Berk A. Neuropsychiatric Aspects of Parkinson's Disease: Recent Advances Current Psychiatry Reports 2003;5:68-76
17. Parkinson's UK
18. Molho ES, Factor SA; Parkinson's disease: the treatment of drug-induced hallucinations and psychosis.; Curr Neurol Neurosci Rep. 2001 Jul;1(4):320-8. [abstract]
19. Clarke CE, Deane KH; Cabergoline for levodopa-induced complications in Parkinson's disease. Cochrane Database Syst Rev. 2001;(1):CD001518. [abstract]
20. McKeon A, Josephs KA, Klos KJ, et al; Unusual compulsive behaviors primarily related to dopamine agonist therapy in Parkinsonism Relat Disord. 2007 Dec;13(8):516-9. Epub 2007 Jun 4. [abstract]
21. Gage H, Storey L; Rehabilitation for Parkinson's disease: a systematic review of available evidence.; Clin Rehabil. 2004 Aug;18(5):463-82. [abstract]
22. Vale S; Current management of the cognitive dysfunction in Parkinson's disease: how far Exp Biol Med (Maywood). 2008 Aug;233(8):941-51. Epub 2008 Jun 5. [abstract]
23. Hallett M et al; American Academy of Neurology; Evaluation of surgery for Parkinson's Disease (1999)
24. Deep Brain Stimulation for Parkinson's Disease; Deep brain stimulation for Parkinson's disease, NICE Interventional Procedure Guideline (Nov 2003)
25. Pereira EA, Aziz TZ; Surgical insights into Parkinson's disease. J R Soc Med. 2006 May;99(5):238-44. [abstract]

Acknowledgements