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Non-motor symptoms of Parkinson’s disease: dopaminergic
pathophysiology and treatment
K Ray Chaudhuri, Anthony HV Schapira

Lancet Neurol 2009; 8: 464–74 Several studies, including work from the Parkinson’s disease (PD) non-motor group and others, have established that
National Parkinson Foundation the non-motor symptoms of PD are common, occur across all stages of PD, are under-reported, and are a key
Centre of Excellence, King’s determinant of quality of life. Research suggests that the non-motor symptoms of the disease are frequently
College Hospital and University
unrecognised by clinicians and remain untreated. Even when identified, there is a common perception that many of
Hospital Lewisham, London,
UK (K R Chaudhuri DSc); these symptoms are untreatable. The role of dopaminergic drugs in treating the various non-motor problems of PD,
King’s College and Institute of although clinically recognised, has received little attention. In this Review, we investigate the dopaminergic basis of
Psychiatry, London, UK the range of non-motor symptoms that occur in PD such as depression, apathy, sleep disorders (including rapid-eye
(K R Chaudhuri); University
movement sleep behaviour disorder), and erectile dysfunction. We discuss the evidence that these symptoms are
Department of Clinical
Neurosciences, Institute of treatable, at least in part, with various dopaminergic strategies and, where relevant, we also refer to the use of deep-
Neurology, Queen Square, brain stimulation of appropriate targets in the brain. This Review provides a comprehensive overview of the
University College London, management of this challenging aspect of PD.
London, UK
(A H V Schapira, FMedSci)
Correspondence to:
Introduction misdiagnosis, inappropriate referrals, and delayed
K Ray Chaudhuri, 9th Floor Although the motor symptoms of Parkinson’s disease treatment.13 The occurrence of non-motor symptoms
Ruskin Wing, King’s College (PD) are well defined, the non-motor features of this preceding the motor diagnosis of PD correlates closely
Hospital, Denmark Hill, London disorder are under-recognised and, consequently, under- with the progression of Lewy pathology in PD.14,15
treated. Non-motor symptoms and their management Although this association suggests that Lewy body
have been recognised by the UK National Institute for deposition and neuronal dysfunction (but not death)
Clinical Excellence as an important unmet need in PD.1–3 begin in the olfactory bulb and lower medulla, the motor
Results from a recent international survey show that up features of PD are not apparent until there is loss of
to 62% of non-motor symptoms of PD, such as apathy, dopaminergic neurons in the substantia nigra pars
pain, sexual difficulties, bowel incontinence, and sleep compacta. The axons from the substantia nigra pars
disorders, might remain undeclared to health-care compacta, ventral tegmental area, and hypothalamus—
professionals because patients are either embarrassed or the key dopaminergic areas in the brain—project
unaware that the symptoms are linked to PD.4 This extensively to form four main pathways: the mesocortical,
under-reporting and under-recognition have important mesolimbic, nigrostriatal, and tuberoinfundibular
therapeutic and societal implications as many of these pathways. These pathways mediate several non-motor
non-motor symptoms are treatable and, if left untreated, symptoms such as cognition, sleep, and pain.
can have an adverse effect on quality of life. Additionally, The importance of a dopaminergic contribution to
non-motor symptoms are a frequent cause of non-motor symptoms in PD is highlighted by a recent
hospitalisation and institutionalisation, which can PET study (figure 1), which reported in vivo evidence of
increase the cost of care of patients with PD by four dopamine dysfunction by ¹¹C-raclopride imaging in the
times.1,5–8 hypothalamus of patients with PD.16 This finding
A large range of symptoms comprise the non-motor- suggests at least a dopaminergic contribution to several
symptom complex of PD (table 1) and several reviews non-motor symptoms of PD, such as sleep disorders,
have focused on these symptoms and the efforts made to autonomic dysfunction, and neuro-endocrinal problems.
quantify and manage them.1,9,10 There are specific A recent review has described the role of non-
validated tools available for their assessment, including dopaminergic treatments in clinical trials aimed at
the non-motor questionnaire (NMS Quest), the non- management of some non-motor symptoms of PD such
motor scale (NMS Scale), the revised PD rating scale as depression, psychosis, cognition, excessive daytime
(UPDRS), and the scales for outcomes in PD sleepiness, and urge incontinence.10 However, the fact
(SCOPA).9,11 that non-motor symptoms are not synonymous with a
Non-motor symptoms of PD occur not only in advanced non-dopaminergic cause should be noted. In this Review,
disease but also in early stages, and some symptoms we investigate the potential of available dopaminergic
such as olfactory deficit, constipation, rapid-eye treatments to improve certain aspects of non-motor
movement (REM) sleep behaviour disorder (RBD), and symptoms (table 1). Where relevant, we have also
depression might precede the expression of motor referred to effects of deep-brain stimulation of the
symptoms by more than a decade.1,12 A UK brain bank subthalamic nucleus and internal pallidum. Although
clinicopathological study reported that, in a cohort of deep-brain stimulation is not a specific dopaminergic
433 patients with PD, 91 (21%) initially presented with therapy, it affects dopaminergic modulation within the
non-motor symptoms, which led to frequent nigrostriatal pathway.

464 Vol 8 May 2009

and depression to frank than placebo in 174 patients with PD and depression21 and dementia. ·· colour vision) Sleep-disordered breathing ·· Other symptoms Autonomic symptoms Non-motor fluctuations Yes Bladder disturbances ·· Autonomic symptoms ·· Urgency Yes (detrusor overactivity) Cognitive or psychiatric symptoms ·· Nocturia Yes Sensory symptoms including pain ·· Frequency ·· Fatigue Yes Sweating ·· Orthostatic hypotension ·· Yes?=some anecdotal reports of response to dopaminergic treatment.20 The beneficial effect of dopaminergic suggested that pramipexole has a specific antidepressant therapy in mood disorders and apathy in PD might be effect in PD on the basis of a possible effect of dopamine partly explained by the fact that levodopa is taken up and receptor agonism at limbic dopamine D3 receptors. whereas depression coeruleus and in the limbic system in patients with PD scores rated by the Zung self-rating depression scale and depression compared with those who did not have were significantly decreased in both groups. choking ·· Cognitive dysfunction ·· Reflux.20 An 16 women with PD and mild or moderate depression in vivo imaging study that used ¹¹C-RTI-32 (a ligand that who did not have dementia. depression rating scale (MADRS) scores were decreased reuptake sites). had shown The cognitive and neuropsychiatric non-motor symptoms antidepressant activity similar to fluoxetine and better of PD range from anxiety. multicentre. apathy. randomised study comparing pramipexole early cognitive changes.18 The clinical definition of depression in PD Rektorova and colleagues23 did an 8-month. anxiety Yes Ageusia ·· Anhedonia Yes Dysphagia.17 Depression is an important neuropsychiatric was better than placebo as an add-on therapy to a mood symptom in PD and can affect up to 45% of patients with stabiliser in treatment-resistant bipolar depression. Yes Non-REM sleep-related movement disorders ·· dyskinesias) Excessive daytime somnolence ·· Paraesthesia ·· Vivid dreaming ·· Olfactory disturbance ·· Insomnia ·· Visual dysfunction (contrast sensitivity. which can also However. decarboxylated in serotoninergic neurons. illusions. is complex and comprises features that might indicate prospective. delusions ·· Constipation Yes Dementia ·· Unsatisfactory voiding of bowel Yes Confusion ·· Faecal incontinence Panic attacks Yes (when related to “off” Sensory symptoms period) Pain ·· Sleep disorders Primary pain related to Parkinsons’s Yes Restless legs and periodic limb movements Yes disease (central pain) REM behaviour disorder Yes? Secondary pain ·· REM loss of atonia ·· Fluctuation-related pain (wearing off. Depression used to treat motor symptoms of PD. The Montgomery-Asberg binds to dopamine-reuptake and norepinephrine. Pramipexole. including levodopa and dopamine agonists. and norepinephrinergic on therapy to levodopa treatment in 25 men and pathways in the limbic system has been implicated. apathy.22 the disease. detected decreased binding in the locus significantly in the pramipexole arm. the results indicated that the effect might also convert levodopa to dopamine. which is There have been many attempts to use dopaminergic also an agonist at dopamine D3 receptors. be seen with ergot agonists such as pergolide.19 Dysfunction of a combination to pergolide (an ergot-derived dopamine agonist) as add- of dopaminergic.thelancet. serotoninergic. Review Neuropsychiatric symptoms were small open-label or non-randomised. Some Erectile impotence Yes unmarked symptoms might also respond to treatment. suggesting a therapies. These studies Responsive to dopaminergic treatment Responsive to (Continued from previous column) dopaminergic treatment Gastrointestinal symptoms Neuropsychiatric symptoms Dribbling of saliva Yes? Depression. vomiting ·· Attention deficit ·· Nausea ·· Hallucinations. (Continued in next column) Table 1: The non-motor symptom complex of Parkinson’s disease Vol 8 May 2009 465 .1. for the treatment of depression in PD. The authors depression.

and 6·0 h) levodopa in the pramipexole group than in the sertraline group treatment. Patients with used. Therefore. although small doses of sertraline were release or controlled-release levodopa. manifested as panic attacks) and would therefore respond to dopaminergic strategies aimed to prevent wearing off. with no difference between immediate- with sertraline. This finding suggests 0·44 that an antidepressant action might also be evident with ropinirole. pramipexole was significant effect and a tendency towards decreased shown to have greater antidepressant effects compared anxiety (p=0·06). immediate-release formulation compared with patients Results from observational studies have suggested that who did not have wearing off (3·6 ± 1·5 vs 5·2 ± 0·8. wider dopamine-mediated class effect in the treatment of Similarly. a randomised but unblinded study also improves with treatment with pramipexole. improved motor scores could also C-raclopride binding potential 0·34 * have confounded interpretation. a conventional antidepressant in patients with respond to dopaminergic therapy. open-label. 3·5. However. anhedonia. anxiety can occur as a with PD. as suggested from PET studies of the human dopamine transporter. double-blind. multicentre. randomised. there was a greater motor benefit with wearing off had a significant reduction in their visual pramipexole than sertraline. (B) Mean hypothalamic ¹¹C-raclopride binding of specific neurobiological or neuropeptide abnormalities potential values and standard deviation in control individuals versus patients associated with PD. which could have contributed analogue scale anxiety scores 3·5 h after taking the to the improvement seen in depression scores. although. an established 11 0·06 antidepressant.30 yellow-red areas indicating decreased binding of ¹¹C-raclopride within the Anxiety disorders usually comprise generalised anxiety. hypothalamic region.32 The rating scale score decreased throughout treatment but a State Trait Anxiety Inventory and a visual analogue scale greater proportion of patients recovered (defined by a for anxiety were used and assessments were made before final Hamilton depression rating scale score of 8 or less) and after (0·5. results of a multicentre. In both groups. crossover study.29 Anxiety Figure 1: Binding of ¹¹C-raclopride within the hypothalamus in individuals with and without PD Anxiety usually coexists with depression and motor (A) Coronal image from PET scan by use of statistical parametric mapping.26 Other antidepressant drugs might also work via dopaminergic pathways. the Hamilton depression PD after overnight withdrawal of PD medications.27 The recent Ropinirole 24-Hour 5 Efficacy and Safety Evaluation in PD (EASE-PD) adjunct 4 study. in some patients. 1·0. the (1·5–4·5 mg/day) or sertraline (50 mg/day) were given to effects of immediate-release or controlled-release 67 patients with PD and major depression but no motor levodopa on anxiety were compared in 14 patients with complications. A 7 placebo-controlled trial of adjunct pramipexole versus 6 placebo in stable levodopa-treated patients with PD and depression was initiated. Review basis of these observations. PD=Parkinson’s disease. 12-week trial that compared pramipexole with independent of dopaminergic state and that might not sertraline. Visual analogue scale scores showed a non- (61% vs 27%. 2·5. by inhibition of dopamine 0·16 reuptake. 2 assessed the antiparkinsonian efficacy of prolonged- release ropinirole. 5·0. and social phobia and might be the result individuals (statistical parametric mapping results from the comparison between PD and controls). 2·0.31 Clinically. randomised. a multicentre.26 On the showed a significant improvement in anxiety after deep- 466 www.31 PD and depression. with fluctuations and can respond to dopaminergic therapy. another D2/D3 dopamine agonist. at least in part.16 with permission dopamine-dependent event as part of “wearing off” (often from Academic Press. assessor. depression-related anxiety might also respond depression in PD.thelancet. anxiety can remain a constant underlying problem that is blinded. which showed a significant effect with prolonged-release ropinirole B compared with placebo (p<0·02). 0·25 Buproprion is an antidepressant drug used in PD and is thought to act. Reprinted from Politis and co-workers. double-blind. randomised. As 1 a secondary outcome measure. p=0·006).com/neurology Vol 8 May 2009 . *p=0·0005.28 Sertraline. Additionally. Barone and co-workers24 reported the to dopaminergic treatment. although.25 Either open-label pramipexole In a double-blind. in patients with PD compared with healthy control panic attacks. regarded as a core symptom of depression p=0·02). is a selective serotonin-reuptake inhibitor with an additional stimulant action due to dopamine- Control individuals Patients with PD reuptake inhibition. mood was assessed by 0 use of the Beck depression inventory. a phase III. 3 placebo-controlled study in advanced cases of PD.

33 In an observational study by motor function in PD. patients with early PD found that 72 of 126 (57%) had mild cognitive impairment at baseline with a cutoff of more than 1·0 SD below the normal levels for age. The authors suggested that such as assembling and disassembling objects or dopamine deficiency.46 The method of delivery of Wijtas and Vol 8 May 2009 467 .41 (possibly activating daytime sleepiness Abnormalities of dopamine uptake and brain D2 autoreceptors) metabolism in cortical targets of striatal dopaminergic High-dose effect Decreased Decreased Increased: insomnia fibres have been reported.38 Patients with PD can also have *On dopaminergic drug withdrawal. This Panel 1: Non-motor symptoms potentially exacerbated by finding could suggest that aspects of anxiety in PD might dopaminergic treatment in Parkinsons’s disease also be improved by the motor benefits seen after deep- brain stimulation of the subthalamic nucleus or by a Antiparkinson drug related possible limbic effect of subthalamic nucleus Autonomic stimulation. collecting household objects) can cause apathy and be reversed by dopaminergic • Impulse control disorders treatment.44.34 fluctuation-related anxiety was dopamine could be important.42. • Pleuropulmonary In a recent study. A dopaminergic basis is possible.45 Early reports suggest that agonists on wakefulness and somnolence safinamide (a drug with multiple mechanisms of action. cognitive dysfunction can • Ankle swelling occur in the early stages of PD and can present as a • Blurred vision frontal dysexecutive syndrome. the notion of mild cognitive impairment in sleep PD is contentious. improved substantially. mechanical tasks.thelancet.40 Slow-wave REM sleep Wakefulness However. with dementia affecting up to 80% of patients with Non-parkinsonian drug related late-stage disease. which might manifest • Weight gain as difficulty in maintaining an adaptive response against • Diarrhoea competing alternatives. • Cardiac as seen in anxiety disorders. • Parkinson hyperpyrexia syndrome or neuroleptic malignant syndrome* Apathy • Serotonin syndrome† Apathy is a specific symptom of PD that can occur with • Malignant parkinsonism* or without depression. tricyclic antidepressants. and performance of.36 • Excessive daytime sleepiness whereas an observational study indicated that levodopa treatment reversed apathy in the “on” state compared Gatrointestinal with the “off” state. apathy might also • Orthostatic hypotension coexist with anxiety disorder and mask itself as Fibrotic complications depression. †Interaction of or reaction to monoamine oxidase visuospatial or visuoperceptual deficits.19 However. The early cognitive changes of PD Low-dose effect Increased Increased Reduced: excessive might involve the caudate and corticostriatal pathways. There are anecdotal reports of dopamine Sleep related agonists improving apathy in some patients with PD. and mood as rated by the MADRS scale with.43 (via D1 receptors) There is evidence that at least a component of the REM=rapid-eye movement. possibly involving the limbic areas. although.37 • Nausea • Diarrhoea (related to intake of catechol-O-methyl Cognitive dysfunction transferase inhibitors) Cognitive impairment is a common feature of advanced PD. cognitive dysfunction associated with PD can be improved Table 2: The variable effects of dopaminergic drugs and dopamine with dopaminergic therapy. and selective serotonin-reuptake inhibitors commonly implicated. Czernecki and co-workers35 reported that eight patients with PD who had not received Behavioural and neuropsychiatric dopaminergic treatment. showed a notable • Delusions improvement 6 weeks after treatment with ropinirole. www. Therefore. with a gradual rise in reported to be significantly lowered after deep-brain stimulation of subthalamic nucleus in advanced PD. and who developed apathy after • Hallucinations subthalamic nucleus stimulation. repetitive. • Dopamine dysregulation syndrome Improvement in apathy as rated by the apathy scale and • Punding (activity characterised by compulsive fascination apathy inventory.39 A study of B inhibitors. apathy can be unresponsive • Retroperitoneal to dopaminergic therapy. Review brain stimulation of the subthalamic nucleus compared including inhibition of monoamine oxidase B and with conventional and best medical treatment at antiglutamatergic activity) can improve cognitive and 6 months of follow-up.

significant improvements in the overall PD sleep scale at high doses. expression. rotigotine in advanced-stage PD. EASE-PD=Ropinirole 24-Hour Efficacy and Safety Evaluation in PD.47. cabergoline was more beneficial than shorter-acting drugs. difficulty in falling asleep) and PDSS (cm) –2 p=0·0196 1 sleep-maintenance insomnia (ie. double-dummy.45–47 Dopaminergic Vol 8 May 2009 . but not levodopa treatment. but not placebo. however. number of awakenings. in 40 patients with pedunculopontine nucleus (implicated in the PD. which mediates a precise sleep-wake cycle. and reversal of sleep p=0·0006 patterns). The ventral tegmental area levodopa. placebo-controlled trial in elderly patients with PD. which contribute to sleep-maintenance 4·3 ± 21·1 1 Placebo insomnia by causing frequent awakenings at night. and the extended amygdala.47. sleep-related problems might be dopamine awake (which was significantly decreased from 2·13 to sensitive. Morning ratings of motor UPDRS and the receives projections from hypocretin neurons (key King’s College Hospital PD rating scale scores were hypothalamic peptides that mediate wakefulness and are significantly improved (p<0·05) after cabergoline typically almost absent in narcolepsy). does scores compared with controls. randomised controlled trial autonomic regulatory centre and is central to the that compared the efficacy of pramipexole and transdermal proposed “sleep switch”. Another role of A B 6 dopaminergic drugs is reversal of nocturnal “off“ state- Ropinirole (24 h) Pramipexole 2 1·3 ± 4·1 Placebo 5 4·9 ± 19·3 Rotigotine related symptoms. Projections from the ventral tegmental area link The role of sustained dopaminergic stimulation thalamocortical arousal via the thalamus and the limbic throughout the night was further investigated in a recent system. general sleep satisfaction were not improved. Review highest maintenance dose is reached. and dopaminergic cell PD and disruptive nocturnal symptoms.55 In this study. difficulty in maintain- –3 ing sleep for periods of time) are common in PD. however. 67% to 93% and improve early-morning walking.48 comparative. Similar results were somnolence reported during the titration phase of some reported with extended-release ropinirole in the EASE-PD dopamine agonists seems to be diminished after the adjunct study (figure 2). whereas. which mediate dopamine agonist. nocturnal akinesia (ability to turn in bed) and total time and.48 Clinical experience suggests that were also noted in sleep akinesia. hours slept. and placebo (CLEOPATRA study). Improvements induce wakefulness. the treatment. they reduce slow-wave and REM sleep and scores compared with placebo (figure 2). a long-acting ergot the midbrain (the ventral tegmental area).48 The hypothalamus is a key sleep and double-blind.54 The use of a groups in the rat ventral periaqueductal grey matter seem targeted nocturnal dopamine agonist for nocturnal to be selectively active during wakefulness.47 Dopamine shares structural similarity with 0·67 h in a 12-month.thelancet. although the number of have the potential to worsen cognitive function.50. and both drugs promote slow-wave and REM sleep and induce pramipexole and rotigotine patch resulted in small but somnolence (possibly via the D2 autoreceptors).52 Stocchi PDSS=Parkinson’s disease sleep scale. All active strategies.49 Dopaminergic drugs.26 468 www. these measured by use of the validated PD sleep scale. in PD. suggesting that the long duration of action of pathogenesis of RBD). sleep latency. At low doses. led to an improvement in overall PDSS improve sleep quality (as measured subjectively and by score (higher scores denote improvement).50 n=201 4 0 PDSS (cm) 3 Insomnia –1 n=201 n=204 n=190 2 Sleep-onset insomnia (ie.48 severe sleep disruption caused by nocturnal motor An analogous scenario is seen in dopamine neurons of symptoms. Another study reported that sustained-release levodopa and Sleep dysfunction benserazide combination tablets substantially improved Dopamine has a complex role in the sleep-wake cycle.51 In a double-blind. sleep-maintenance insomnia –2 could be due to a range of problems such as nocturnal –3 –2·8 ± 21·6 akinesia and “off” state-related motor and non-motor –4 symptoms (eg. open-label trial of 15 patients with several wake-promoting drugs. with Fos akinesia was first investigated in an open-label. (B) Pramipexole versus rotigotine transdermal patch. –3·3 ± 4·2 0 –4 Although sleep-onset insomnia is associated with PD –1 p=0·2 n=101 itself and its effect on sleep. restless legs syndrome and p=0·0129 periodic limb movements. levodopa and carbidopa Figure 2: Effect of dopamine agonists on the PDSS total score combination tablets given at bedtime were reported to (A) Extended-release ropinirole versus placebo (EASE-PD study). cabergoline. or particularly in patients with advanced disease (panel 1). was compared with controlled-release arousal and wakefulness. nocturia. and co-workers53 reported that treatment with slow-release levodopa and carbidopa combination tablets led to a concentrations having the greatest effect on working significant improvement in mean nocturnal akinesia memory.56 Sleep parameters were have variable effects on sleep (table 2).26.56 CLEOPATRA=Clinical Efficacy of Pramipexole and Transdermal measurement of spontaneous movements in bed) from Rotigotine in Advanced Parkinson’s Disease. observational study in patients with PD with Lesions of this area led to 20% increased sleep in rats.

65. Although the pathological subthalamic nucleus has a beneficial effect on bladder basis of RBD are unclear.60 Akathisia is common in advanced-stage PD with akinetic rigid phenotype and can overlap with Autonomic symptoms symptoms of restless legs syndrome. Studies in cats suggest that brainstem areas such as the laterodorsal tegmental Nocturia nucleus. with dopamine agonists being the drugs of Levodopa has also been effective in open-label studies. sensory motor integration and improvement of higher- which have connections with the dopaminergic ventral order processing of afferent activity.63 In this study.68 In a recent study. Changes in Urinary bladder mesocortical dopamine pathways have been implicated.81 spinal interneurons has been associated with the In an open-label. clinically translated to the complaint of urinary urgency. peri-locus caeruleus region.52 Akathisia can difficulty. international. the disorder seems to be function in PD by improving bladder capacity and reflex associated with degeneration of lower brainstem nuclei. patients with PD have difficulty with voiding. This study pontine micturition centre. had usually are atonic.70 although this syndrome are closely linked and are sensitive to finding has not been investigated in a controlled study. The beneficial effect of pramipexole in the Both periodic limb movements and restless legs treatment of RBD has been reported. decreased human beings. Levodopa can worsen or improve urgency part of wearing off. restless legs syndrome. a non.65.66 Structures such as the 54 patients.61 examined 18 patients with PD during “off” and “on” phases with urodynamic studies before treatment and RBD about 1 h after receiving levodopa 100 Vol 8 May 2009 469 .75.62 An open-label study of 15 patients D1 activity with possible exacerbation by D2 stimulation. dopamine. although there were increased numbers of or an abnormal sphincter action caused by bradykinesia. switched from bromocriptine to pergolide. D1 and D2 receptors seem to nightmares are associated with a paradoxical simple or have different effects on bladder control: pergolide. and periodic limb melatonin have also been used effectively in some movements is another frequent cause of sleep cases. awakenings and stage shifts.80 tegmental area in the midbrain. a significant beneficial effect of rotigotine www.74 Detrusor overactivity is common in PD and is resulted in significantly reduced nocturnal discomfort. Review Periodic limb movements. and data from animal studies indicate agonists in patients with PD and restless legs syndrome that the dopamine receptors have different effects on the apart from a small placebo-controlled study. up to 62% of patients complained magnocellularis. Deep-brain stimulation of the without signs of parkinsonism.66 In combination of increased urine output at night. cabergoline reported reduced periodic limb movements which can be the result of a disorder of bladder contractility in sleep.71.66 Symptoms of RBD can predate the beneficial effects in animals. whereas the D2 receptors activate ergot dopamine agonist.77 whereas a study noted diagnosis of PD and a latent period of 12·7±7·3 years after improvement in nocturia in three patients who were the onset of RBD has been reported.73. the striatal D1 receptors inhibit reported that continuous apomorphine infusion.59. and improved pain and spasm which can be caused by a combination of under-active scores in six patients.67. decreased leg movements.61 Dopaminergic pathways affect urinary bladder-related There are no controlled trials of the use of dopamine symptoms in PD. These unchanged or aggravated. a complex movement during REM sleep when muscles dopamine agonist with possible D1 agonist activity. although gabapentin and of restless legs syndrome in PD. volume. the micturition reflex. nucleus reticularis In the NMS Quest study. given subcutaneously overnight it. Uchiyama and co-workers75 drugs such as clozapine. this effect is possibly secondary to improved such as the pedunculopontine and peri-ceruleal nucleus. degeneration of the sublaterodorsal bladder capacity.65.67. levodopa also which seems to be reversible by apomorphine injection. which might have occurred because of a and the pedunculopontine nucleus are involved. and substantia nigra are also linked to REM and non-REM akathisia sleep circuits.76 decreased the frequency of periodic limb movements An “on” state is usually associated with reduced voiding from 43 per night to 28–33 per night.72 choice for initial treatment of these disorders.78 However. Postuma and colleagues69 estimated the 5-year risk of pergolide is no longer recommended for use in PD as neurodegenerative disease to be 17·7% and the 10-year there is a considerable risk of development of cardiac risk to be 40·6% after RBD was diagnosed in patients valvular fibrosis. although the results of dopaminergic treatment respond to dopaminergic treatment when it presents as are conflicting.57. but might need specific therapy with and detrusor overactivity. and the ventrolateral reticulospinal tracts of nocturia.66 disruption.thelancet. with PD and periodic limb movements who received Additionally. multicentre study of pathophysiology of RBD. Symptoms RBD was first reported by Schenck and co-workers64 and is improved in all patients who had voiding difficulty. and possible impairment of sleep due to nucleus with its direct and indirect projections to the nocturnal akinesia.79. a well known parasomnia typically characterised by vivid although urinary urgency and urge incontinence was and usually frightening dreams or nightmares.58 Several Clonazepam is probably the most effective treatment for studies have reported a two-fold increase in the prevalence RBD in patients with PD.

99 Additionally. 10=best) defaecographic abnormalities were normalised in one of Improvement 6 three patients and all five individuals who underwent repeated anorectal manometry showed substantial 4 improvements in manometric parameters. 1·5 Apomorphine injections have been used for erectile 1·0 dysfunction in individuals without PD.98 penile erection after deep-brain stimulation of the There have been various classifications for categorising thalamus. apomorphine has been reported to cause penile 0·5 Vol 8 May 2009 . open-label observational study that used intrajejunal Figure 3: Data from two open-label studies showing improvement in infusion of duodopa in patients with advanced-stage PD nocturia after treatment with rotigotine transdermal patch suggest an improvement in constipation and other bowel (A) Improvement in nocturia counts (p=0·0001). The authors concluded that apomorphine can correct anorectal 2 dysfunction in PD and suggested that abnormalities of defaecation and anorectal function occur as a consequence.84 These symptoms might in part be had an average intensity of 60 mm of 100 mm on a visual related to neuronal degeneration affecting central analogue scale and was twice that reported in the control sympathetic neurons and postganglionic fibres. periaqueductal grey. After apomorphine treatment. and a substantial proportion of pain in this There are no clinical trials investigating the specific disorder is caused by motor fluctuations and dyskinesias effects of dopaminergic drugs for the treatment of erectile secondary to dopaminergic treatment. Review arousal and increased libido are recognised side-effects A of such drugs. thalamus. nervous system. the DOPAMIP (Douleur et maladie de as yet. Parkinson en Midi-Pyrénées) survey in southwest France.82.85 Studies patients after adjusting for co-morbidity. examined the occurrence of chronic pain in 450 patients Sexual dysfunction with PD compared with age-matched and sex-matched Sexual dysfunction is common in patients with PD. Data from a multi-centre.94 the Parkinson’s disease sleep scale.91 Therefore. and patients who had other chronic disorders. 0 at least in part. and cingulate transdermal patch for nocturia in patients with PD was cortex. The plot in B shows nocturia mean scores and confidence intervals at baseline and after 5· 6 months of rotigotine transdermal patch (Wilcoxon signed rank test Sensory symptoms p=0·0001).95.92 Edwards and co-workers93 studied 10 eight patients with PD by use of defaecography and Parkinson’s disease sleep scale scores anorectal manometrics. (B) Improvement in item 8 of symptoms in addition to other non-motor symptoms. the NMS Quest of 30 patients (figure 3). Lines within box plots indicates mean value. stimulation of the dorsal putamen and anterior region of which noted that. loss of libido.1. 62% of patients presentations include erectile dysfunction. 0 Baseline (n=45) End of observational Gastrointestinal symptoms period (n=45) Constipation is a common non-motor feature of PD and B studies suggest a severe loss of both central and colonic dopaminergic neurons.88 In a recent study. limb 470 www.83 There are no controlled trials study reported pain in 29% (158 of 545) of patients. of dopamine deficiency secondary to the Before rotigotine After rotigotine (n=30) (n=30) pathological changes of PD. which was supported by a single-centre study the non-motor symptom complex of PD. pain dysfunction or loss of libido in PD. Data Dopamine can modulate pain at several levels within the compiled from references 82 and 83. 8 (item 8. 70% of the population studied internal capsule induced erections. 0=bad.90.97 The pain or hypersexuality. oro-facial pain. including levodopa. which specifically refers to nocturia.89 Nocturias (counts per night) 2·0 Hypersexuality has also been reported after various other dopaminergic therapies.81 A that have investigated nocturia and dopaminergic therapy recent study. Others have reported had pain.96 Unexplained pains are a major component of reported. basal ganglia. including the spinal cord.thelancet. apomorphine could be investigated for erectile dysfunction in PD. even though sexual in PD might present as central pain. in PD. with PD had at least one form of chronic pain. overall.87 pain in PD. Rotigotine was used as adjunctive treatment with other stable Pain antiparkinsonian treatment. 14 of 15 men taking 2·5 adjunctive dopamine agonists developed hypersexuality Improvement within 8 months of receiving the dopamine agonist. Similar figures by Robinson and Mishkin86 in monkeys showed that were reported in a recent Italian case-control survey.

retinal dopamine concentration is decreased compared cognitive and psychiatric. Visual function Visual impairment affecting colour and contrast Non-motor fluctuations. • “Off” period generalised pain Another study investigated the pathophysiology of primary • Nocturnal pain (usually dopaminergic therapy responsive) central pain (no obvious cause) in nine patients with PD • Pain related to restless legs syndrome or periodic limb and primary central pain. might cause greater discomfort than motor Innervation around the fovea is largely dopaminergic and. along with central pain. although a study of six patients with cortex can lead to defective visual processing. the same authors112 reported www. These abnormalities were improved by • Oro-facial pain treatment with levodopa 100 mg. implicating the visual system in the genesis of stop “off” state-related non-motor pain effectively by use PD.104. with similar pathogenesis to motor account for retinal dysfunction in PD and have been fluctuations. PD as apomorphine or duodopa overnight infusion. might • Central pain respond to dopaminergic treatment. pulsatile.107. autopsy studies show that motor fluctuations into three subtypes: dysautonomic. and nine controls. compared with individuals without pain.62 “Off” period-associated pain diencephalic/mesencephalic-pineal axis is primarily improved after deep-brain stimulation of the subthalamic involved in PD and leads to dopamine-melatonin nucleus and after treatment with therapies that aimed to imbalance.thelancet.108 At a higher level. In another study. and sensory or pain. deficiency of PD could lead to a primary visual dysfunction. and discrimination has been suggested as a possible pre-motor continuous dopaminergic stimulation marker for PD. Individuals who had PD and • Nocturnal akinesia-linked pain primary central pain showed hyperalgesia and absence of • Coat-hanger pain (pain around the shoulder area. Motor fluctuation and dyskinesia-related pain. are Panel 2: A proposed classification of pain in Parkinson’s probably associated with PD so can be described as PD disease pain. Brefel-Courbon and • Fluctuation-related pain (dopaminergic therapy colleagues100 reported that the pain threshold to cold is responsive) substantially lower in patients with PD who were • Dyskinetic pain withdrawn from treatment compared with controls.105 Willis has suggested that the retino- apomorphine infusion. rare in habituation of sympathetic sudomotor response to Parkinsons’s disease and linked to postural hypotension) repetitive pain. or musculo-skeletal pain. Djaldetti and co-workers102 reported that • Peripheral limb or abdominal pain the threshold of heat pain was lower in patients with PD • Drug induced and pain. orofacial pain.104. Nocturnal pain and orofacial pain might also be alleviated by dopaminergic therapy. There are no specific studies of pain and dopaminergic reduced metabolism and hypoperfusion in the occipital therapy in PD.105 There is evidence that dopaminergic Non-motor fluctuations can commonly occur in PD and. nine patients with PD without movement pain. in whom dopamine subtypes are thought to occur secondary to pulsatile concentrations return to normal. in some cases. There might be some overlap between categories.110 Dopaminergic strategies aimed to overcome wearing off would help these visual symptoms.34 Loher patients describe blurred vision. These with in patients with treated PD.106 These changes can dopaminergic therapy. whereas other forms of pain are secondary and not • Musculoskeletal pain directly related to PD so can be described as non-PD pain • Parkinsons’s disease-related chronic pain (might respond (panel 2). a secondary pain. typically at lower and colleagues103 reported a notable reduction in “off” luminosity during “off” periods and this is likely to be state-related pain after bilateral pallidal stimulation in related to foveal retinal dopaminergic neuronal advanced-stage PD. whereas nocturnal pain and restless legs syndrome showed patients with RBD can have defective colour marked improvement of pain after overnight discrimination. such deficit and the effect of dopaminergic treatment. fluctuations. • Lower bowel pain associated with retroperitoneal This finding suggests that endogenous pain in PD is fibrosis associated with increased sensitivity to some specific painful stimuli.109 There are few specific studies focusing on visual of the continuous dopaminergic stimulation idea. and more so on the affected side where PD is • Peripheral oedema-linked pain most apparent. Central pain in PD • Visceral pain might be dopamine mediated. which regulate autonomic function and inhibitory responsive) control of pain. Witjas and co-workers111 have classified non- in patients with untreated Vol 8 May 2009 471 . dysfunction. Review pain. to dopaminergic therapy) for instance. and • “Off” period dystonia-related pain that the threshold normalised after levodopa therapy. confirmed by electroretinography.101 The authors suggested • Temporo-mandibular joint pain that the origin of primary central pain in PD is based on • Bruxism-related pain dysfunction of dopaminergic-dependent autonomic • Burning mouth syndrome (might be levodopa centres.

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