Review: management of Parkinson’s disease

Figures & data

Table 1 Possible disease modifying agents in the treatment of Parkinson’s disease

Substance	Mechanism	Dosage	Adverse events	Special monitoring	Evidence
MAOBinhibitors
Rasagiline	Selective inhibition of MAOB → less metabolization of monoamines including dopamine	1 mg/day	Nausea, dizziness, abdominal pain, dry mouth, vivid dreams, and/or hallucinations, dyskinesias, might improve tremor at the beginning	None required but possibility of inducing serotonin syndrome effect together with SSRI, for example, is feasible (although improbable)	Possibly delays progression in early stages of the disease,^Citation17 but at present insufficient evidence for a role in prevention/delay of PD^Citation28

Abbreviations: MAO_B, monoamine oxidase B; PD, Parkinson’s disease; SSRI, selective serotonin reuptake inhibitor.

Table 2 Management of motor impairments in Parkinson’s disease

Substance	Mechanism	Dosage	Adverse events	Special monitoring	Evidence
Dopaminergic medication
Levodopa together with peripheral aromatic acid decarboxylase inhibitor in a standard formulation	Precursor to dopamine	Depending on patient and the therapeutic effect, up to 1000–1500 mg/day	Hypotension, nausea, disorientation and confusion, insomnia and/or vivid dreams, hallucinations, somnolence	None required	Efficacious for symptomatic monotherapy and for the treatment of motor complications^Citation18,Citation28
levodopa together with peripheral aromatic acid decarboxylase inhibitor in a controlled release formulation	Precursor to dopamine	Depending on patient and the therapeutic effect, up to 1000–1500 mg/day	Hypotension, nausea, disorientation and confusion, insomnia and/or vivid dreams, hallucinations, somnolence	None required	Efficacious for symptomatic monotherapy but insufficient evidence for treatment of motor complications^Citation18,Citation28
Pramipexole	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	3 × 0.35–0.7 mg/day	Leg swelling, somnolence, fatigue, nausea, constipation and edema, impulsive or compulsive behavior	Psychiatric side effects should be taken into consideration and monitored cautiously	Efficacious for symptomatic monotherapy, symptomatic therapy adjunct to levodopa, the prevention/delay and the treatment of motor complications^Citation28
Ropinirole	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	6–24 mg/day	Leg swelling, somnolence, fatigue, nausea, constipation and edema, impulsive or compulsive behavior	Psychiatric side effects should be taken into consideration and monitored cautiously	Efficacious for symptomatic monotherapy, symptomatic therapy adjunct to levodopa, the prevention/ delay and the treatment of motor complications^Citation28
Rotigotine	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	Once-daily transdermal patch 4–16 mg/day	Local skin reactions. leg swelling, somnolence, fatigue, nausea, constipation and edema, impulsive or compulsive behavior	Skin reactions at the application site have to be considered. Psychiatric side effects should be taken into consideration and monitored cautiously	Efficacious for symptomatic monotherapy, symptomatic therapy adjunct to levodopa, the prevention/delay and the treatment of motor complications^Citation28
Piribedil	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	150–250 mg/day	Leg swelling, somnolence, fatigue, nausea, constipation and edema, impulsive or compulsive behavior	Psychiatric side effects should be taken into consideration and monitored cautiously	Efficacious for symptomatic monotherapy, symptomatic therapy adjunct to levodopa^Citation139,Citation28
COMT inhibitors
Entacapone	Reversible inhibition of COMT → less inactivation of levodopa/dopamine	Together with levodopa 300–1200 mg/day	Digestive symptoms such as diarrhea and/or nausea, orthostatic hypotension, urine discoloration	None required	Efficacious as symptomatic adjunct to levodopa in PD patients with motor fluctuations (but not in patients without motor fluctuations) as first-line option^Citation28
Tolcapone	Reversible inhibition of COMT → less inactivation of levodopa/dopamine	Together with levodopa 300–600 mg/day	Hepatotoxicity, digestive symptoms such as diarrhea and/or nausea, orthostatic hypotension, urine discoloration	Regular follow-up and control of liver transaminases required	Efficacious as symptomatic adjunct to levodopa in PD patients with motor fluctuations as second-line option (after entacapone)^Citation28
Selegiline	Selective inhibition of MAOB → less metabolization of monoamines including dopamine	1–2 × 5 mg/day	Nausea, dizziness, abdominal pain, dry mouth, vivid dreams and/or hallucinations, dyskinesias, might improve tremor at the beginning	None required but possibility of inducing serotonin syndrome effect together with SSRI, for example, is feasible (although improbable)	Efficacious for symptomatic monotherapy, symptomatic adjunct to levodopa, treatment of motor complications^Citation28
Rasagiline	Selective inhibition of MAOB → less metabolization of monoamines including dopamine	1 mg/day	Nausea, dizziness, abdominal pain, dry mouth, vivid dreams and/or hallucinations, dyskinesias, might improve tremor at the beginning	None required but possibility of inducing serotonin syndrome effect together with SSRI, for example, is feasible (although improbable)	Efficacious for symptomatic monotherapy, symptomatic adjunct to levodopa, treatment of motor complications^Citation28
Other drugs
Amantadine	Unclear, possibly the interaction of several pharmacological mechanisms	2–3 × 100–200 mg/day	Reversible corneal edema, nervousness, anxiety, agitation, insomnia, exacerbations of preexisting seizure disorders and psychiatric symptoms	None required	Likely efficacious for symptomatic monotherapy, symptomatic adjunct to levodopa, treatment of motor complications^Citation28

Abbreviations: COMT, catechol-O-methyltransferase; MAO_B, monoamine oxidase B; PD, Parkinson’s disease; SSRI, selective serotonin reuptake inhibitor.

Table 3 Treatment of special motor restraints in Parkinson’s disease patients

Symptom/ substance	Mechanism	Dosage	Adverse events	Special monitoring	Evidence
Dyskinesias
Pramipexole	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	3 × 0.35–0.7 mg/day	Leg swelling, somnolence, fatigue, nausea, constipation and edema, impulsive or compulsive behavior	Psychiatric side effects should be taken into consideration and monitored cautiously	Patients treated with pramipexole showed a significantly lower risk of motor complications in dyskinesias especially and wearing off^Citation30,Citation40,Citation140
Ropinirole	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	6–24 mg/day	Leg swelling, somnolence, fatigue, nausea, constipation and edema, impulsive or compulsive behavior	Psychiatric side effects should be taken into consideration and monitored cautiously	Patients treated with ropinirole (also with prolonged release formulation) showed a significantly lower risk of motor complications in dyskinesias especially and wearing off^Citation40,Citation141,Citation142
Amantadine	Unclear, possibly the interaction of several pharmacological mechanisms	2–3 × 100–200 mg/day	Reversible corneal edema, nervousness, anxiety, agitation, insomnia, exacerbations of preexisting seizure disorders and psychiatric symptoms	None required	Clinically useful for treating levodopa-induced dyskinesias^Citation34,Citation35,Citation41,Citation143
Clozapine	Antagonist at the 5-HT2A, dopamine, and several other receptors	25–50 mg/day	Agranulocytosis, cardiac toxicity, hypersalivation, fatigue, weight gain	Regular blood testing is mandatory and regular echocardiograms can be performed	Possibly useful in the treatment of levodopa-induced dyskinesias^Citation144
Tremor^Citation3
Propranolol	Antagonist at adrenoreceptors (sympatholytic)	3 × 80 mg/day	Nausea, diarrhea, bronchospasm, exacerbation of Raynaud’s syndrome, bradycardia, hypotension, hallucinations, erectile dysfunction, sleep disturbances, alteration of glucose metabolism	None required	Possibly useful, particularly when there is postural tremor
Biperiden	Antagonist at muscarinic M1 receptors	3–16 mg/day	Drowsiness, vertigo, agitation, anxiety, delirium, and confusion; additionally, peripheral side effects may be observed (eg, dry mouth, obstipation, and mydriasis)	None required	Efficacious for symptomatic monotherapy and symptomatic adjunct to levodopa for treating tremor^Citation145
Clozapine	Antagonist at the 5-HT2A, dopamine, and several other receptors	12.5–50 mg/day	Agranulocytosis, cardiac toxicity, hypersalivation, fatigue, weight gain	Regular blood testing is mandatory and regular echocardiograms can be performed	Treatment of levodopa-resistant tremor^Citation146

Abbreviation: 5-HT_2A, 5-hydroxytryptamine receptor 2A.

Table 4 Treatment of sleep disorders in Parkinson’s disease patients

Symptom/substance	Mechanism	Dosage	Adverse events	Special monitoring	Evidence
REM sleep behavior disorder
Clonazepam	Benzodiazepine (allosteric modification of GABAA receptor)	0.5–2.0 mg at night	Drowsiness, confusion, irritability and aggression and/or psychomotor agitation, cognitive impairments, hallucinations	None required	Possibly effective, but only case reports and retrospective studies available^Citation147,Citation64
Insomnia
Levodopa together with peripheral aromatic acid decarboxylase inhibitor in a controlled release formulation	Precursor to dopamine	200 mg at night	Hypotension, nausea disorientation and confusion, insomnia and/or vivid dreams hallucinations, somnolence	None required	Possibly effective for increasing sleep time and nocturnal akinesia^Citation148
RLS
Pramipexole	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	3 × 0.35–0.7 mg/day	Fatigue, nausea, constipation and edema, somnolence	Psychiatric side effects should be taken into consideration and monitored cautiously	Efficacious in the treatment of moderate-to-very severe RLS^Citation149^–^Citation151 and especially suited for PD
Ropinirole	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	6–24 mg/day		Psychiatric side effects should be taken into consideration and monitored cautiously	Efficacious in the treatment of moderate- to-very severe RLS^Citation152,Citation153 and especially suited for PD
Rotigotine	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	Once-daily transdermal patch 4–16 mg/ day	Fatigue, nausea, constipation and edema, somnolence	Skin reactions at the application site have to be considered. Psychiatric side effects should be taken into consideration and monitored cautiously	Rotigotine as a transdermal patch is effective in the treatment of moderate- to-severe RLS^Citation154,Citation155 and especially suited for PD
Gabapentin enacarbil	Prodrug of gabapentin (see below)	600–1800 mg/day	Fatigue, dizziness, weight gain, edema, drowsiness	None required	Gabapentin enacarbil is effective in the treatment of moderate- to-severe RLS^Citation156^–^Citation160 but experience is lacking. Second-line option in PD
Levodopa together with peripheral aromatic acid decarboxylase inhibitor in a standard or controlled release formulation	Precursor to dopamine	200–400 mg at night	Hypotension, nausea, disorientation and confusion, insomnia and/or vivid dreams hallucinations somnolence	None required	Levodopa is effective in the treatment of RLS, but carries the risk of augmentation^Citation161
Gabapentin	Possibly inactivates the α2δ-subunit of a voltage gated calcium-channel	600–1800 mg/day	Fatigue, dizziness, weight gain, edema, drowsiness	None required	Gabapentin may be used as it is effective in the treatment of mild- to-moderate RLS^Citation162,Citation163 but is considered second-line option due to possible side effects^Citation66
Opioids	Binding at different opioid receptors in the central and peripheral nervous system	Different agents available	Nausea and vomiting, drowsiness, dry mouth, myosis, constipation	Clinical monitoring of worsening of sleep apnea and potential of abuse	Opioids are effective in the treatment of RLS, especially for patients with RLS that is not relieved by other treatments^Citation66
Pregabalin	Possibly inactivates the α2δ subunit of a voltage-gated calcium channel	50–450 mg/day	Dizziness, drowsiness, increased appetite, euphoria, confusion, vivid dreams, attention changes, tremor, dysarthria, dry mouth, constipation	None required	Pregabalin is effective in the treatment of moderate-to-severe RLS^Citation66

Abbreviations: GABA_A, γ-aminobutyric acid type A; PD, Parkinson’s disease; REM, rapid eye movement; RLS, restless legs syndrome.

Table 5 Treatment of autonomic dysfunctions in Parkinson’s disease patients

Symptom/ substance	Mechanism	Dosage	Adverse events	Special monitoring	Evidence
Orthostatic hypotension
Fludrocortisone	Synthetic corticosteroid	0.05–0.3 mg/day	Edema, water and sodium retention, insomnia, fatigue	None required	Possibly effective,^Citation164 but insufficient evidence for improvement due to methodological concerns^Citation65
Domperidone	Antagonist at dopamine receptors located outside the blood–brain barrier	3 × 10–20 mg/day	Extrapyramidal symptoms, increased levels of prolactin leading to gynecomastia or galactorrhea	None required	Possibly effective,^Citation164 but insufficient evidence for improvement due to methodological concerns^Citation65
Urinary disturbance
Trospium chloride	Muscarinic receptor antagonist	2–3 × 10–20 mg/day	Dry mouth, constipation, nausea, diarrhea, eye or eyesight problems, cognitive impairment	None required	Possibly useful for treatment of urge incontinence but insufficient evidence^Citation65
Oxybutynin	Muscarinic receptor antagonist	2 × 2.5–5 mg/day	Dry mouth, constipation, nausea, diarrhea, eye or eyesight problems, cognitive impairment	None required	Possibly useful for treatment of urge incontinence but insufficient evidence^Citation65
Gastrointestinal motility problems
Macrogol	Polyethylene glycol which works as osmotic laxative	1–3 × 125 mL/day	Abdominal pain, diarrhea	None required	Likely efficacious for treatment of chronic constipation^Citation165
Domperidone	Antagonist at dopamine receptors located outside the blood–brain barrier	3 × 10–20 mg/day	Increased levels of prolactin leading to gynecomastia or galactorrhea, extrapyramidal symptoms	None required	Possibly useful for treatment of nausea/ vomiting due to medication^Citation65
Erectile dysfunction
Sildenafil Tadalafil Vardenafil	Inhibition of cGMP-specific phosphodiesterase type 5	Sildenafil: 50 mg 1 hour before sexual activity. Tadalafil: 10 mg 0.5–12 hours before sexual activity. Vardenafil: 10 mg 0.5–1 hour before sexual activity	Headache, flushing, dyspepsia, nasal congestion, myocardial infarction	None required	Sildenafil is possibly useful for treatment of erectile dysfunction in PD^Citation166

Abbreviations: cGMP, cyclic guanosine monophosphate; PD, Parkinson’s disease.

Table 6 Treatment of concomitant psychiatric symptoms in Parkinson’s disease patients

Symptom/ substance	Mechanism	Dosage	Adverse events	Special monitoring	Evidence
Impulse control disorders, punding, dopamine dysregulation syndrome
Amantadine	Unclear, possibly the interaction of several pharmacological mechanisms	2–3 × 100–200 mg/day	Reversible corneal edema, nervousness, anxiety, agitation, insomnia, exacerbations of preexisting seizure disorders and psychiatric symptoms	None required	Investigational as there is only a small study looking at medication-related impulse dyscontrol and pathologic gambling^Citation84 and only for a few weeks
Quetiapine	Acts as antagonists for many neurotransmitters (at dopamine, serotonin, histamine, and adrenergic receptors)	25–75 mg at night	Somnolence, fatigue, dry mouth, dizziness, constipation, weight gain	None required	Personal experience without any studies available
Psychosis in PD
Clozapine	Antagonist at the 5-HT2A, dopamine, and several other receptors	12.5–50 mg/day	Agranulocytosis, cardiac toxicity, hypersalivation, fatigue, weight gain	Regular blood testing is mandatory and regular echocardiograms can be performed	Good evidence for efficacy in treatment of psychosis in PD^Citation93,Citation94,Citation96
Quetiapine	Acts as antagonists for many neurotransmitters (at dopamine, serotonin, histamine, and adrenergic receptors)	25–75 mg at night	Somnolence, fatigue, dry mouth, dizziness, constipation, weight gain	None required	Possibly useful for treatment of psychosis in PD,^Citation94^–^Citation96,Citation167^–^Citation169 but insufficient evidence due to methodological concerns
Donepezil	Acetylcholinesterase inhibitor	5–10 mg	Nausea, diarrhea, abdominal pain, transient increase of tremor severity	None required	Possibly useful for treatment of psychosis in patients suffering from Lewy body dementia^Citation97
Antidementive therapy in PD
Rivastigmine	Acetylcholinesterase inhibitor	4.6–9.2 mg/day	Diarrhea, bradycardia, nausea, abdominal pain, transient increase of tremor severity	None required	Efficacious in the treatment of dementia in PD^Citation65,Citation100
Memantine	NMDA receptor antagonist	20 mg/day	Confusion, drowsiness, headache, agitation and/or hallucinations	None required	Possibly useful but contradictory results in small studies^Citation65,Citation100^–^Citation102,Citation170
Antidepressive therapy in PD
Pramipexole	Partial or full dopamine receptor agonist with different affinity to the distinct dopamine receptor subtypes^Citation27	3 × 0.35–0.7 mg/day	Fatigue, nausea, constipation and edema, somnolence	Psychiatric side effects should be taken into consideration and monitored cautiously	Efficacious for the treatment of depressive symptoms in PD^Citation141,Citation171,Citation172
Desipramine	Norepinephrine and (to a lesser extent) serotonin reuptake inhibition		Cardiac arrhythmicity, dry mouth, constipation, orthostatic dysregulation, mild blurred vision	Cardiac monitoring	Likely efficacious for the treatment of depression in PD^Citation173
Nortriptyline	Norepinephrine and (to a lesser extent) serotonin reuptake inhibition	75–150 mg/day	Dry mouth, constipation, orthostatic dysregulation, mild blurred vision	None required	Nortriptyline possibly improves depression in PD patients,^Citation174 but insufficient evidence up to now for the treatment of depression in PD^Citation65
SSRIs	Selectively inhibit the serotonin reuptake	Different agents available	Apathy, anhedonia, nausea/vomiting, headache, diarrhea, weight gain, SSRI may induce tremor or worsen parkinsonian symptoms, especially at the beginning	Possibility of inducing serotonin syndrome effect together with MAOB inhibitors, for example, is feasible (although improbable)	No clear evidence yet to be found,^Citation65 but possibly clinically useful as SSRIs have a better safety profile compared to TCAs

Abbreviations: 5-HT_2A, 5-hydroxytryptamine receptor 2A; MAO_B, monoamine oxidase B; NMDA, N-Methyl-D-aspartic acid; PD, Parkinson’s disease; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Figure 1 German guidelines for treatment of PD 2012.

Abbreviations: COMT-1, catechol-O-methyltransferase-Iinhibitor; DA, dopamine agonist; DBS, deep brain stimulation; PD, Parkinson’s disease.

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