eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Parkinson Disease in Young Adults: Treatment & Medication

Author: Stephen T Gancher, MD, Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University
Contributor Information and Disclosures

Updated: Aug 11, 2008

Treatment

Medical Care

• The approach to the medical treatment of Parkinson disease in younger patients is generally similar to that used in older individuals. However, younger patients seem to be at higher risk of developing complications with long-term levodopa treatment, particularly motor fluctuations, choreiform dyskinesias, and painful "off" dystonias. These motor complications are sometimes as disabling as tremor and bradykinesia and may persist despite multiple changes in medications.
• Frequently, one or two target symptoms are the chief concern of younger patients, and control of these specific symptoms should be emphasized. Common problems include micrographia, pain (which can represent either dystonia or underlying bradykinesia), tremor, depression, fatigue, or anxiety. Each of these symptoms may be approached differently; for example, tremor may respond particularly well to anticholinergics, whereas fatigue may represent bradykinesia and may require levodopa or dopamine agonists.
• Of the drugs that are commercially available, selegiline, rasagiline (monoamine oxidase B inhibitors), and dopamine agonists each have been studied for possible disease-altering effects. The early use of selegiline delays the need for levodopa by an average of 13 months in patients with very mild Parkinson disease, but the reasons for this effect are uncertain. Once patients are treated with levodopa, the rate of disease progression is not altered by selegiline, and therefore no convincing body of evidence exists to suggest that selegiline affects disease progression.
  • Rasagiline has also been studied for disease-altering effects in early Parkinson disease by comparing the change in Parkinson disease signs over time in patients treated with either 12 months of rasagiline or 6 months of placebo, followed by 6 months of rasagiline. In this delayed-start study, the subjects receiving rasagiline for the entire study had a slower decline than subjects whose treatment was delayed for 6 months. The magnitude of these changes was quite small, and further studies involving more patients for longer periods are needed.
  • The dopamine agonists pramipexole and ropinirole have also been studied in early Parkinson disease. In comparison to treatment with levodopa, patients treated with the dopamine agonists exhibited a reduced risk of the development of motor fluctuations and dyskinesias and showed greater retention of the uptake of radiolabeled tracer drugs in the basal ganglia over time. However, the uptake of these radiolabels is influenced by treatment with levodopa and dopamine agonists, and the significance of these changes in basal ganglia signal over time and the relationship to disease progression is unclear.
• A number of studies have investigated the use of dopamine agonists as initial treatment. When administered as monotherapy, dopamine agonists have a very low risk of producing motor fluctuations or dyskinesias and may delay the need for administration of levodopa. This has been demonstrated recently in 2 large trials; in one trial, ropinirole was compared with levodopa under blinded conditions, and in the other, pramipexole was studied similarly. In both trials, these drugs were able to control symptoms of Parkinson disease in the majority of mildly affected patients.
• After several years of treatment, the majority of patients may require a combination of both levodopa and a dopamine agonist. Whether the prevalence of motor fluctuations, dyskinesias, or psychiatric complications in patients treated with levodopa first and then given a dopamine agonist is any different after several years of combination treatment than patients who first receive a dopamine agonist has not been established. As the costs of dopamine agonists are considerably higher than the cost of levodopa, this question has significant implications.
• Questions remain as to the effects of these drugs in altering the progression of the underlying pathology of Parkinson disease. Data exist to suggest that levodopa may be toxic in some animal models, but a recent clinical study of low- and high-dose levodopa in newly treated patients found no evidence of any acceleration of disease progression. In some animal models and cell culture experiments, some dopamine agonists appear to have a protective effect, but no clinical data are known to demonstrate this either, and the early use of dopamine agonists to delay disease progression cannot be recommended at the present time.
• Treatment of other symptoms
  • In addition to treatment of the cardinal manifestations of Parkinson disease, a number of other symptoms, such as constipation, dysphagia, urinary retention or frequency, impotence, orthostatic hypotension, imbalance, and falls may require other treatment approaches.
  • Many patients have associated mood and sleep problems and may benefit from antidepressants, anxiolytics, and sedatives. In patients with more severe Parkinson disease, levodopa or dopamine agonists as well as other adjunctive medications may produce agitation, hallucinations, or psychosis. These symptoms should be managed by first discontinuing or reducing antiparkinsonian medications. Some patients improve with the use of donepezil or by using low doses of the atypical antipsychotics clozapine and quetiapine.
  • In young patients with motor fluctuations or dyskinesias that are refractory to medical treatments, stereotaxic neurosurgical treatments may be useful, particularly since younger patients usually do not have dementia or severe imbalance, which are contraindications to these treatments. These are discussed in detail in the article Surgical Treatment of Parkinson Disease.

Surgical Care

Surgical treatment is discussed in Surgical Treatment of Parkinson Disease.

Consultations

• Generally, patients with Parkinson disease are best treated and monitored by a neurologist, except in the early stage of the disease.
• A urologist is consulted for evaluation and treatment of urinary frequency, urgency, incontinence, or erectile dysfunction.
• A physiatrist, physical therapist, and occupational therapist may be able to improve the patient's ability to perform activities of daily living, reduce pain, and avoid fractures and compression neuropathies from falls. Botulinum injections for limb dystonia can be very helpful and are administered by specially trained physiatrists or neurologists.
• A gastroenterologist and speech therapist may be needed to evaluate dysphagia, a common complication in patients with more advanced Parkinson disease. Excessive sialorrhea can be treated with botulinum toxin injections into the salivary glands, usually administered by otolaryngologists. In some patients, a gastrostomy may be needed to maintain adequate nutrition.
• Psychiatric consultation may be required to control mood disorders and psychiatric symptoms, especially in patients with refractory depression or psychosis.
• Neurosurgical consultation may be appropriate in patients with tremor, dyskinesias, motor fluctuations, or dystonia refractory to medical treatment.

Diet

Few dietary restrictions are needed in most patients with Parkinson disease who are not experiencing significant dysphagia.

• Protein-restricted diets may be useful in patients who are experiencing motor fluctuations with long-term levodopa treatment. As levodopa is transported into the brain by a carrier protein that transports large neutral amino acids found in dietary protein, large protein meals can compete for the transport of levodopa and reduce or eliminate its effects. A protein-restricted diet can therefore improve the response to levodopa and can be useful in patients with otherwise refractory motor fluctuations.
• Two general approaches are used for this diet. In one, the total daily protein requirement is spread more or less equally over the day. The other approach aims at consuming food very low in protein or not containing protein during the day and a high-protein meal in the evening.
• Generally, these diets are difficult to follow; however, in patients with severe, unpredictable motor fluctuations, this approach may be worthwhile.

Medication

A number of different medications are used in the treatment of Parkinson disease. Drugs that improve motor symptoms include dopaminergic drugs—immediate and controlled-release levodopa; catechol-O -methyltransferase (COMT) inhibitors tolcapone and entacapone; and the dopamine agonists bromocriptine, ropinirole, and pramipexole. In addition, nondopaminergic drugs, including anticholinergics, selegiline, and amantadine can help motor symptoms as well.

Patients with Parkinson disease often benefit with treatment of psychological and behavioral symptoms. For depression, any of the standard antidepressants may be used. These include tricyclic antidepressants, such as amitriptyline, nortriptyline, and doxepin, as well as the selective serotonin reuptake inhibitors (SSRIs) paroxetine (Paxil), sertraline (Zoloft), fluoxetine (Prozac), and citalopram (Celexa). Newer antidepressants unrelated to SSRIs or tricyclic antidepressants include bupropion (Wellbutrin), venlafaxine (Effexor), nefazodone (Serzone), and mirtazapine (Remeron). Concern has been expressed about the risk of serotonin syndrome with the concomitant use of selegiline and the SSRIs; however, a survey of Parkinson disease specialists reported that these drugs often are combined with negligible evidence of toxicity.

Insomnia may be especially challenging to treat. Some patients having difficulty with sleep initiation may benefit from a benzodiazepine; however, because tachyphylaxis is very common with drugs in this class, a sedating antidepressant (eg, trazodone, amitriptyline) may be a better long-term choice. Other patients awaken with symptoms of Parkinson disease such as stiffness, dystonia, or tremor; in such patients, a nocturnal dose of levodopa or a dopamine agonist may be effective.

In addition to depression and insomnia, some patients experience psychiatric reactions with levodopa or dopamine agonists. These include visual hallucinations that can evolve into a delusional state in which auditory hallucinations, paranoia, psychosis, and violent behavior can occur. These problems are sometimes so severe that the use of a dopamine agonist is precluded; however, these reactions sometimes can be eliminated or treated effectively with an antipsychotic. Of the available antipsychotics, most agents worsen the symptoms of Parkinson disease and cannot be used; however, quetiapine and clozapine are well tolerated in most patients and may be very effective at low doses.

Catechol-O-methyltransferase (COMT) inhibitors

These agents are used for treatment of motor fluctuations in patients treated with levodopa for long periods. Tolcapone and entacapone are inhibitors of an enzyme, COMT, which converts levodopa into an inactive metabolite, 3-O -methyldopa. Coadministration delays clearance of levodopa from plasma and prolongs the action of individual doses of levodopa. Neither drug has any effect in Parkinson disease symptoms independent of levodopa.

Entacapone (Comtan)

Selective and reversible inhibitor of COMT, used in Parkinson disease as adjunct to levodopa/carbidopa therapy.

Tolcapone (Tasmar)

Mechanism of action unknown, but possibly related to ability to inhibit COMT and alter plasma pharmacokinetics of levodopa. When given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. Sustained plasma levels of levodopa may result in more constant dopaminergic stimulation in brain, which may lead to greater effects on signs and symptoms of Parkinson disease as well as increased levodopa adverse effects, sometimes requiring decrease in dose of levodopa. Tolcapone enters CNS to minimal extent but has been shown to inhibit central COMT activity in animals. Should always be used as adjunct to levodopa/carbidopa therapy.

Anti-Parkinson agents

These agents comprise the dopaminergic agents, which stimulate dopaminergic receptors in basal ganglia; the MAO-B oxidase inhibitors, which prevent inactivation of dopamine by MAO-B and possibly the conversion of compounds into neurotoxic types; and the dopamine agonists (see separate Drug Category below).

Levodopa and carbidopa (Sinemet)

Available in US in combination with carbidopa, an inhibitor of dopa decarboxylase in GI mucosa. In Europe, levodopa sold in combination with benzaseride, another dopa decarboxylase inhibitor.
Used in patients with established Parkinson disease; most effective in relieving bradykinesia and rigidity; it is less consistently effective in relieving tremor and usually ineffective in relieving postural flexion, severe imbalance, freezing gait, dysarthria, and dysphagia.
In elderly patients, lower doses of levodopa should be used to initiate treatment. In patients on long-term levodopa therapy, higher doses usually are administered
Although no absolute dose limit, for patients to require more than 1.5 g/d is very unusual.

Selegiline (Eldepryl)

MAO-B oxidase inhibitor, FDA approved as adjunct to levodopa/carbidopa in patients who exhibit deterioration in response to that therapy. For patients who experience motor fluctuations on levodopa/carbidopa, addition of selegiline reduces "off" time, improves motor function, and allows levodopa dose reductions. If patient experiences increase in troublesome dyskinesia, reduce levodopa dose.
Irreversible inhibitor of MAO, acts as "suicide" substrate for enzyme such that MAO converts it to an active moiety that combines irreversibly with active site or enzyme's essential FAD cofactor. Blocks breakdown of dopamine and extends duration of action of each dose of L-dopa. Often allows L-dopa dose reduction that is needed for optimal effect.
Has greater affinity for type B than for type A active sites, thus serves as selective inhibitor of MAO type B at recommended dose. However, doses higher than 10 mg/d may significantly inhibit MAO-A sites. May inhibit dopamine reuptake. Metabolites, amphetamine and methamphetamine, may inhibit dopamine reuptake and enhance dopamine release.
Rapidly absorbed and has 73% bioavailability. Metabolized in liver to N-desmethylselegiline, L-amphetamine, and L-methamphetamine
Half-life approximately 10 h; metabolites excreted in urine.
Inhibition of MAO-B irreversible, thus loss of new protein synthesis activity, if it occurs, may last for several months
After 2-3 d of treatment, attempt to reduce dose of levodopa/carbidopa. A 10-30% reduction is typical. Further reductions of levodopa/carbidopa may be possible during continued selegiline therapy.

Amantadine (Symmetrel)

Inhibits N -methyl-D-aspartic acid (NMDA) receptor-mediated stimulation of acetylcholine release in rat striatum. May enhance dopamine release, inhibit dopamine reuptake, stimulate postsynaptic dopamine receptors, or enhance dopamine receptor sensitivity.
Has efficacy as monotherapy and as adjunct to levodopa/carbidopa (or levodopa/benserazide in Europe) in treating Parkinson disease. Provides some benefit in tremor, rigidity, and bradykinesia.
Half-life is approximately 9-37 h and prolonged in renal insufficiency; 90% is excreted unchanged in urine

Rasagiline (Azilect)

Irreversible MAO-B inhibitor that blocks dopamine degradation. Not metabolized to amphetamine derivatives. Main metabolite, aminoindan, has some activity and has been shown to improve motor and cognitive functions in experimental models. Indicated for Parkinson disease as initial monotherapy or as adjunctive therapy with levodopa.

Dopamine agonists

These agents may be used either as monotherapy in patients not yet taking levodopa or as adjunctive therapy in patients taking levodopa who are experiencing motor fluctuations or dyskinesias.

In patients not yet taking levodopa, dopamine agonists may relieve signs and symptoms of Parkinson disease but are somewhat less effective than levodopa; use of this class of medications is most appropriate in patients with mild disease not affecting gait or balance.

This class of medications may allow introduction of levodopa to be delayed, thus reducing the risk of developing troublesome fluctuations and dyskinesias.

In patients already taking levodopa, dopamine agonists are useful as adjunctive therapy; these medications may prolong the duration of action of individual doses of levodopa, reduce the severity of motor fluctuations such as "off" bradykinesia and dystonia, allow the doses of levodopa to be lowered, and improve dyskinesias.

All drugs in this class should be initiated at low doses and the doses increased very slowly. The first few days are usually the most troublesome, but tolerance develops rapidly to many of the peripheral adverse effects such as nausea. Because of this, all of these drugs, except bromocriptine, are available at very small initial doses.

Pergolide (Permax)

Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

Dopamine agonist believed to exert therapeutic effect by directly stimulating postsynaptic dopamine receptors in nigrostriatal system. Usually administered in divided doses tid. During dosage titration, dosage of concurrent levodopa/carbidopa may be decreased cautiously.

Ropinirole (Requip)

Non-ergot dopamine agonist that has high relative in vitro specificity and full intrinsic activity at D2 subfamily of dopamine receptors, binding with higher affinity to D3- than to D2- or D4-receptor subtypes.
Has moderate affinity for opioid receptors. Metabolites have negligible affinity for dopamine D1, 5-HT1, 5-HT2, benzodiazepine, GABA, and muscarinic receptors and alpha1-, alpha2-, and beta-adrenoreceptors.
Precise mechanism of action in Parkinson disease unknown. However, possibly related to stimulation of dopamine receptors in striatum.
Discontinue gradually over 7-d period. Decrease frequency of administration from tid to bid for 4 d. For remaining 3 d, decrease frequency to once daily prior to complete withdrawal.
When administered as adjunct therapy to levodopa, concurrent dose of levodopa may be decreased gradually as tolerated.

Pramipexole (Mirapex)

Nonergot dopamine agonist with specificity of D2 dopamine receptor, but also has been shown to bind to D3 and D4 receptors and may stimulate dopamine activity on nerves of striatum and substantia nigra.

Apomorphine (Apokyn)

Elicits dopamine agonist effect. Indicated to treat acute immobility episodes (hypomobility or "off-periods") in Parkinson Disease. These episodes consist of inability to rise from a chair, speak, or walk and may occur toward the end of the dose interval or may be spontaneous and unpredictable in onset. Approximately 10 percent of individuals with stage IV Parkinson Disease who do not respond to standard medications for acute immobility may respond to apomorphine.

Bromocriptine (Parlodel)

Semisynthetic, ergot alkaloid derivative; strong dopamine D2-receptor agonist; partial dopamine D1-receptor agonist; FDA approved as adjunct to levodopa/carbidopa, but less effective than other dopamine agonists.
May relieve akinesia, rigidity, and tremor associated with Parkinson disease. Stimulates dopamine receptors in corpus striatum.
Approximately 28% absorbed from GI tract and metabolized in liver. Approximate elimination half-life is 50 h with 85% excreted in feces and 3-6% eliminated in urine. Initiate at low dosage; slowly increase dosage to individualize therapy. Maintain dosage during introductory period. Assess dosage titration every 2 wk. Gradually reduce dose in 2.5-mg decrements if severe adverse reactions occur.

Rotigotine (Neupro)

April 2008: A recall was issued for Neupro patch in the United States because of crystal formation in the patch resulting in decreased dopamine absorption transdermally. As of August 1, 2008, the patch is still unavailable, although the manufacturer is working to correct the defect and hopefully return it to the market. For more information see Medscape News.
Dopamine agonist stimulating D3, D2, and D1 receptors. Improvement in Parkinson-related symptoms thought to be its ability to stimulate D2 receptors within the caudate putamen in the brain. Available as transdermal patch that provides continuous delivery for 24 h (2 mg/24 h [10 cm²], 4 mg/24 h [20 cm²], or 6 mg/24 h [30 cm²]). Indicated for symptoms of early Parkinson disease.

Anticholinergics

These agents are used in the treatment of tremor and dystonia (painful or painless involuntary muscular contractions); they are most useful in patients with tremor. They can be administered as monotherapy or in combination with other drugs and usually are administered tid/qid; they may be effective in relieving dystonia in patients with motor fluctuations. Parenteral benztropine and diphenhydramine produce sedation, therefore, patients should not drive after receiving these medications.

Benztropine (Cogentin)

By blocking striatal cholinergic receptors, may help in balancing cholinergic and dopaminergic activity in striatum.
Available in tablets and parenteral formulation, 1 mg/mL.

Diphenhydramine (Benadryl, Benylin)

Has strong anticholinergic and sedative properties. In patient with severe tremor, IV diphenhydramine can be used as adjunct for minor surgery or to facilitate detailed examination.

Trihexyphenidyl (Artane)

Centrally acting anticholinergic that tends to diminish muscle spasms.

Procyclidine (Kemadrin)

May block excess acetylcholine at cerebral synapses.

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