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Review |

Pharmacological Treatment of Parkinson Disease:  A Review

Barbara S. Connolly, MD1; Anthony E. Lang, MD2,3
[+] Author Affiliations
1Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
2Morton and Gloria Shulman Movement Disorders Center and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, Ontario, Canada
3Division of Neurology, Department of Medicine, University of Toronto, Ontario, Canada
JAMA. 2014;311(16):1670-1683. doi:10.1001/jama.2014.3654.
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Published online

Importance  Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life.

Objective  To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea.

Evidence Review  References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic.

Results  Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies.

Conclusions and Relevance  Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.

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Figure 1.
Schematic Illustration of Neurologic Pathways Affected in Parkinson Disease and Sites of Action of Medications for the Treatment of Motor Symptoms

Available medications to treat the motor symptoms of Parkinson disease act on complex neurologic interactions in the striatum that affect motor activity. Dopaminergic afferents from the substantia nigra, glutamatergic afferents from the cerebral cortex and thalamus, and cholinergic striatal interneurons all converge to influence the activity of the main efferent neurons of the striatum, the medium spiny GABAergic neurons. Levodopa is transported from the peripheral circulation across the blood-brain barrier and is converted centrally to dopamine, replacing the neurotransmitter deficient in Parkinson disease. Outside the blood-brain barrier, in the peripheral circulation, dopamine decarboxylase inhibitors (DDCIs) block the conversion of levodopa to dopamine, and catechol-O-methyltransferase inhibitors (COMTIs) block its degradation to 3-0-methyldopa (3-0MD). In the striatum, levodopa, dopamine agonists, and monoamine oxidase type B inhibitors (MAOBIs) all have dopaminergic effects. Anticholinergic drugs and amantadine act on postsynaptic receptors for other neurotransmitters in the striatum. These neurotransmitters bind to and activate multiple different subtypes of receptors present on the various presynaptic afferents in the striatum, as well as on postsynaptic efferent medium spiny neurons. NMDA indicates N-methyl-d-aspartate.aTolcapone, unlike entacapone, is able to cross the blood-brain barrier and block degradation of levodopa and dopamine.bAmantadine has dopamine releasing effects in addition to affecting NMDA glutamate receptors.

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Figure 2.
Algorithm for the Treatment of Parkinson Disease With Tremor-Dominant Motor Symptoms

aAnticholinergic use is anecdotal and not supported by randomized clinical trials.bIf the patient experiences inadequate symptom control while on current therapy and there was more than 1 treatment option in the previous step, go back to previous step and try an alternate treatment option. If all options in the previous step fail to provide adequate symptom control, move to the next step in the algorithm.cSuboptimal benefit is defined as improvement in parkinsonian symptoms following initiation of therapy, but the patient still experiences a bothersome or disabling degree of symptoms either continuously or intermittently. In these cases, increase the dose of current medication if the patient is not receiving a maximal dose or add another medication. If benefit is absent, stop the current medication and try another.dSurgery for refractory tremor includes deep brain stimulation or neuroablative lesion surgery (eg, thalamotomy).

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Figure 3.
Algorithm for the Treatment of Parkinson Disease With Predominant Bradykinesia and Impaired Dexterity

aSuboptimal benefit is defined as improvement in parkinsonian symptoms following initiation of therapy, but the patient still experiences a bothersome or disabling degree of symptoms either continuously or intermittently. In these cases, increase the dose of current medication if the patient is not receiving a maximal dose or add another medication. If benefit is absent, stop the current medication and try another.bIf the patient experiences inadequate symptom control while on current therapy and there was more than 1 treatment option in the previous step, go back to previous step and try an alternate treatment option. If all options in the previous step fail to provide adequate symptom control, move to the next step in the algorithm.

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Figure 4.
Algorithm for the Treatment of Parkinson Disease With Predominant Postural Instability and Gait Impairment

aSuboptimal benefit is defined as improvement in parkinsonian symptoms following initiation of therapy, but the patient still experiences a bothersome or disabling degree of symptoms either continuously or intermittently. In these cases, increase the dose of current medication if the patient is not receiving a maximal dose or add another medication. If benefit is absent, stop the current medication and try another.bIf the patient experiences inadequate symptom control while on current therapy and there was more than 1 treatment option in the previous step, go back to previous step and try an alternate treatment option. If all options in the previous step fail to provide adequate symptom control, move to the next step in the algorithm.cPersistent ambulatory problems including freezing, postural instability, and falls despite optimal dopaminergic therapy are generally refractory to other treatments. Trials of amantadine or a cholinesterase inhibitor, added to ongoing dopaminergic therapy for other symptoms of Parkinson disease, can be considered.dConsider deep brain stimulation if motor fluctuations are refractory to medical therapy and postural instability and/or gait impairment remains responsive to levodopa.

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