Adverse effects
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By K K Jain MD

Levodopa infusion may improve some aspects of motor performance while worsening others. Different components of the motor cortico-striato-pallido-thalamo-cortical loop and related pathways may underlie motor improvement and adverse motor effects of levodopa therapy for Parkinson disease. Clinically, levodopa improves the symptoms of the disease and delays its progression, but neuroimaging data indicate that levodopa either accelerates the loss of nigrostriatal dopamine nerve terminals or modifies the dopamine transporter (Fahn et al 2004). However, a study of nigral neuronal count and Lewy body density in Parkinson disease showed that use of levodopa during lifetime did not enhance progression of Parkinson disease pathology (Parkkinen et el 2011). Neurologic complications are considered to be due to the nonphysiological replacement of dopamine. Various complications of levodopa therapy are discussed in the following paragraphs.

Movement disorders. The following types of movement disorders have been reported (Jain 2010):

  • Choreoathetosis. This is the most common.
  • Dystonia. This occurs in 20% to 30% of patients.
  • Akathisia. This occurs in 26% of patients, may precede treatment.
  • Ballism. This can be severe.
  • Stereotyped movements. This involves stepping or kicking movements of legs.
  • Myoclonus. This is rare. It is usually in association with dementia.
  • Tremor. Often present before treatment and difficult to evaluate.
  • Dyskinesias. There are various types of dyskinesias associated with levodopa therapy. Peak dose or "on" dyskinesia is the most frequent type. Diphasic dyskinesia occurs when levodopa begins to take effect, and as the drug effect wanes with minimal manifestations during the peak dose. Movement disorders associated with chronic levodopa therapy are also referred to as tardive dyskinesias and need to be differentiated from the tardive dyskinesias due to antipsychotics.

Continuous levodopa infusion with steady plasma levels of the drug is associated with reduced motor complications compared with the standard oral formulation of the drug that is associated with fluctuation of plasma levels, particularly low levels, in patients with advanced Parkinson disease (Stocchi et al 2005). Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to a number of individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations (Nyholm et al 2005). A retrospective, long-term follow-up analysis of the clinical experience with application of levodopa/carbidopa-gel suspension directly in the duodenum showed that a continuous delivery by a portable pump resulted in smoother plasma concentrations of levodopa, whereas the daily dose of levodopa decreased by 5% (Odin et al 2008). Continuous jejunal levodopa infusion is an effective and feasible alternative treatment option for patients with advanced Parkinson disease, although there may be technical problems with the device (Eggert et al 2008). Modified preparations of levodopa such as controlled release preparations and liquid levodopa, catecholamine-O-methyltransferase inhibitors, dopamine agonists, and amantadine have been used in the prevention and treatment of motor complications. Other medications that are currently being studied to treat established levodopa-induced dyskinesias include antiepileptics and serotonergic medications. Deep brain stimulation of the subthalamic nucleus is effective in treating levodopa-induced dyskinesias (Zesiewicz et al 2007). Repetitive transcranial magnetic stimulation over the cerebellum as continuous theta burst stimulation has an antidyskinetic effect in Parkinson disease patients with levodopa-induced dyskinesia (Koch et al 2009).

Findings of PET studies suggest that dissociation between cerebral blood flow and cerebral metabolism is a distinctive feature of levodopa treatment and may be especially pronounced in patients with levodopa-induced dyskinesia (Hirano et al 2008).

Peripheral side effects. These include nausea, vomiting, and postural hypotension.

Central side effects. These include visual hallucinations, psychoses, and disturbed sleep with vivid dreams. The rare complication of disordered respiration is described as a levodopa-induced dyskinesia, but levodopa might affect the central control of respiration to produce irregular breathing patterns (Rice et al 2002).

Levodopa withdrawal. A neuroleptic malignant-like syndrome (fever, akinetic crisis, rigidity, autonomic disturbances) has been reported following withdrawal of levodopa.

Wearing-off. This is a complication of long-term levodopa therapy and is defined as re-emergence of symptoms of Parkinson disease before the next scheduled levodopa dose. It may require modification of the levodopa dose, switching to another levodopa formulation, and adjunct therapies, such as catechol-O-methyltransferase inhibitors and monoamine oxidase-B inhibitors (Pahwa and Lyons 2009).

Long-term dopa syndrome. This is the term used for motor, autonomic, and psychiatric symptoms occurring in Parkinson disease patients after some years of levodopa therapy.

Progression of neurodegeneration in Parkinson disease. There is a suspicion that long-term use of levodopa may accelerate neurodegeneration in Parkinson disease. There is no conclusive evidence for neurotoxicity of levodopa. It is generally accepted that deterioration in Parkinson disease patients is due to natural progression of the disease, and not due to levodopa. This deterioration correlates with degeneration in nonlevodopa circuits in the brain.

See also the Physician's Desk Reference.

Management of adverse effects. Levodopa-induced dyskinesias are problematic. To prevent peak dose dyskinesias, levodopa concentrations should be maintained in the therapeutic range, but below the dyskinesia threshold. Drugs such as amantadine, buspirone, fluoxetine, mirtazapine, propranolol, and riluzole may be used. A metaanalysis of randomized, placebo-controlled clinical trials confirms the short-term benefits of amantadine therapy in the treatment of dyskinesia (Elahi et al 2012). According to the finding of an exploratory trial, levodopa in doses slowly titrated to 1000 mg/day could be useful in improving levodopa-induced dyskinesias (Stathis et al 2011). A metaanalysis of various studies has shown that adjuvant therapy such as dopamine agonists reduces off-time and levodopa dose and improves United Parkinson Disease Rating Scale scores in patients who develop motor complications on levodopa therapy, but this may be at the expense of increased dyskinesia and numerous other side effects (Stowe et al 2010). Those who do not respond are treated surgically by pallidotomy or thalamic deep brain stimulation. Levodopa-induced psychoses may be treated with clozapine.

In This Article

Historical note and nomenclature
Clinical trials
Goals and duration of treatment
Precautions and use in special groups
Adverse effects
References cited