J Neurol Neurosurg Psychiatry 2000;68:685–690 685 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.6.685 on 1 June 2000. Downloaded from EDITORIAL Dopamine agonists: their role in the treatment of Parkinson’s disease Parkinson’s disease is a chronic and disabling illness. There inirole and pramipexole are non-ergoline agonists. is still some uncertainty in its diagnosis, particularly in the Apomorphine, one of the first dopamine agonists shown to early stages, as some other neurological conditions present improve parkinsonian symptoms, is a combined D1 and D2 with similar clinical features. There has been wide variation agonist but has to be administered subcutaneously. Its use in the management of Parkinson’s disease due to a lack of has been well documented and will not be discussed in this consensus on the best approach. Recently, United review.12–14 Kingdom specific guidelines for the management of Parkinson’s disease have been produced1 which provide, where possible, evidence based recommendations and the Rationale for use collective opinion of a Parkinson’s Disease Consensus Dopamine agonists have proved antiparkinsonian activity.15 Working Group, whose members have substantial experi- Initially, they were introduced as an adjunct to levodopa ence in managing patients with the disease. treatment in patients exhibiting fluctuating motor re- Current drug therapy in Parkinson’s disease is sympto- sponses and dyskinesias associated with its chronic use.15–17 matic and primarily aimed at restoring dopaminergic func- Addition of agonists to these patients’ regimes allows tion in the striatum. Levodopa, in combination with a around a 20%-30% reduction in the dose of levodopa in peripheral decarboxylase inhibitor, is still the most eVective practice and leads to improvement in the disabling compli- symptomatic treatment.2 Levodopa enters dopaminergic cations. Dopamine agonists have also been successfully neurons where it is metabolised to dopamine, replacing the used as monotherapy in de novo patients with the intention depleted endogenous neurotransmitter. Along with its of delaying treatment with levodopa and consequently proved eYcacy, levodopa is well tolerated, easy to adminis- deferring the onset of complications.18–21 ter, and relatively inexpensive.3 However, long term use is Dopamine agonists are not metabolised by oxidative http://jnnp.bmj.com/ associated with disabling complications such as fluctuating pathways and so do not lead to the cytotoxic free radical motor responses and dyskinesias4–6 and narrowing of the formation that may be associated with metabolism of therapeutic window.7 In addition, levodopa is toxic in vitro dopamine. By suppressing endogenous dopamine release it to dopaminergic neurons8 and in vivo its use could lead to is also conceivable that they may protect dopaminergic formation of cytotoxic free radicals when exogenous neurons from injury, a theoretical concern if high concen- dopamine is decarboxylated; these would cause damage to trations of exogenous dopamine are present. The reason surviving dopaminergic neurons and potentially exacerbate why motor complications are less often encountered with on September 29, 2021 by guest. Protected copyright. the disease.910 dopamine agonists than with levodopa is not fully In the light of these complications, the United Kingdom understood. It may be related to the longer half life of guidelines suggest that pharmacological intervention dopamine agonists and diVerences in receptor selectivity.22 should be delayed until a diagnosis of Parkinson’s disease Chase (1998) has suggested that pulsatile use of levodopa has been confirmed by a specialist in movement disorders leads to an imbalance of basal ganglia opioid concentra- and the symptoms start to interfere with daily life.1 In tions and resetting of voltage gated channels in N-methyl- addition, the United Kingdom guidelines recommend that D-aspartate (NMDA) receptors.23 The de novo use of treatment with levodopa should be delayed for as long as dopamine agonists may help to avoid these downstream possible providing alternative drugs, such as dopamine pharmacological changes in the striatum and pallidum.24 agonists, can achieve adequate symptom control. Various therapeutic strategies may be adopted when starting treatment of Parkinson’s disease in an attempt to delay and minimise the long term complications associated The role of dopamine agonists with levodopa. One approach is to start treatment with low DEFINITION dose levodopa and, if the eYcacy declines, to add a Dopamine agonists exert their antiparkinsonian eVects by dopamine agonist instead of increasing the levodopa acting directly on dopamine receptors and mimicking the dose.19 Conversely, treatment may be started with a endogenous neurotransmitter.11 There are two subclasses dopamine agonist or alternative symptomatic agent and of dopamine agonists: ergoline and non-ergoline agonists. low dose levodopa added later if required. Finally, it has Both of these subclasses target dopamine D2-type recep- been suggested that treatment should be initiated with a tors. The ergoline dopamine agonists include bromocrip- combination of low doses of levodopa and a dopamine tine, pergolide, lisuride, and cabergoline, whereas rop- agonist.25 686 Brooks J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.6.685 on 1 June 2000. Downloaded from Summary of key characteristics for dopamine agonists (data adapted from Utti and Ahlskog)15 BPeLCRPr Receptor activity: agonist (antagonist) D2 (D1)D2,D1 D2 (D1)D2 D2 D2,D1 Pharmacological properties Ergot Ergot Ergot Long acting ergot Non-ergot Non-ergot Plasma half life (hours) 3–8 16 1–7 65 6 7–9 Time to peak plasma concentration (hours) 1–2 1.5 1 0.5–4 1.5 2 Administration (max dosage, UK, ABPI data) Oral (10–40 mg/daily) Oral (<5 mg/day)* Oral, subcutaneous Oral (20 mg/day) Oral (<24 mg/day) NA (<5 mg/day) B=bromocriptine; Pe=pergolide; L=lisuride; C=cabergoline; R=ropinirole; Pr=pramipexole; NA=not available. *Some clinics exceed this; the highest daily dose prescribed for several patients with refractory Parkinson’s disease has exceeded 30 mg. In the absence of clear evidence that any particular agent Lisuride has an advantage in slowing or preventing progression of Lisuride, like bromocriptine, stimulates D2-like dopamine Parkinson’s disease, the United Kingdom guidelines receptors. Lisuride is as eVective and well tolerated as bro- recommended that the choice of first line symptomatic mocriptine when used in combination with levodopa in therapy be made on an individual patient basis. Various patients with advanced Parkinson’s disease experiencing a interrelated factors should be borne in mind, including deteriorating response to levodopa and motor age, severity of disease, cognitive impairment, and fluctuations.36 In an open non-randomised study, combina- intercurrent illness.26 For advanced Parkinson’s disease, tion therapy with lisuride and levodopa, over 10 years, has and in elderly patients, levodopa was thought to be the been shown to decrease and delay the development of agent of choice because of its clinical potency and conven- motor fluctuations and dyskinesias in patients with early ience. However, in younger patients with mild to moderate disease compared with therapy with levodopa alone while symptoms, de novo use of dopamine agonists was maintaining an equivalent therapeutic response.37 Trials suggested to be a more appropriate first line option,1 as have also shown that lisuride provides eVective mono- they seem to be as eVective as levodopa in early disease and therapy and, when used in conjunction with levodopa, per- delay its use,21 22 27 thus minimising the long term problems mits reduction of levodopa dose.37 38 associated with levodopa. A summary of the key character- istics of dopamine agonists is shown in the table. Cabergoline Cabergoline is a long acting ergoline dopamine agonist ERGOT-DERIVED DOPAMINE AGONISTS with selective aYnity for D2-like dopamine receptors and a 3 The early oral dopamine agonists were ergot derivatives long plasma half life of 65 hours. Once daily cabergoline has been shown to be eVective as monotherapy in de novo acting primarily on the D2-like (D2,D3 and D4) dopamine receptors (although pergolide has weak D agonist activity patients, reducing the Unified Parkinson’s Disease Rating 1 Scale (UPDRS) motor score by up to 30% and the time in and bromocriptine has D1 antagonist activity). Examples of this type of dopamine agonist are bromocriptine, pergolide, “oV” by up to 60%. It is also eVective as adjunct therapy to 27 lisuride, and the long acting ergoline, cabergoline. levodopa in patients with advanced Parkinson’s disease. Cabergoline monotherapy for up to 1 year has been shown to be only slightly less eVective than levodopa treatment. Bromocriptine Rinne et al found that more than 60% of de novo patients Bromocriptine has been in regular use as adjunct therapy could be managed on cabergoline alone for at least a period in patients receiving levodopa to allow lower doses of levo- of 1 year.3 Recent reports have also confirmed the eYcacy http://jnnp.bmj.com/ dopa to be used and to improve “end of dose” motor of cabergoline in delaying motor complications.25 39 28 fluctuations. Use of bromocriptine as monotherapy in de The eYcacy of cabergoline as adjunct therapy to novo patients has been shown to delay the need for levodopa in patients with advanced Parkinson’s disease and levodopa treatment and the occurrence of motor motor complications has been investigated in studies total- 19 complications. Generally a three times daily regime has ling more than 1500 patients.39 Cabergoline treatment been employed. allowed the levodopa dose to be significantly reduced when compared with placebo (18% v 3%). The activities of daily Pergolide living (ADL) score was also improved by cabergoline treat- on September 29, 2021 by guest. Protected copyright. Pergolide has similarly been shown to improve symptoms ment (23%) compared with placebo (4%). Comparisons of of Parkinson’s disease both when used as monotherapy and cabergoline with bromocriptine have shown cabergoline to in combination with levodopa.