LOS ANGELES—Physicians who treat patients with Parkinson’s disease have many decisions to make based on therapeutic efficacy and desired outcomes. At the 70th Annual Meeting of the American Academy of Neurology, Melissa J. Nirenberg, MD, PhD, outlined the current landscape of Parkinson’s disease therapeutics, including data about symptom control, timing of treatment, and new therapies.
Initial Therapy: No Benefit to Levodopa Sparing
Levodopa, along with dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, has Level A evidence as initial symptomatic therapy for Parkinson’s disease. “There is no question that levodopa is the most effective treatment for Parkinson’s disease,” said Dr. Nirenberg, Chief Medical Officer of the New York Stem Cell Foundation Research Institute and Adjunct Professor of Neurology at NYU Langone Health in New York City. “However, after people have been taking levodopa for a number of years, its therapeutic effect lasts for shorter periods of time, and patients spend an increasing amount of time in the off state, rather than in the on state.”
In addition to this wearing-off effect, levodopa treatment is associated with dyskinesias. This association and the wearing-off effect have prompted many physicians to adopt levodopa-sparing strategies, such as using dopamine agonists as initial treatment. However, dopamine agonists have other serious side effects, and research shows that in the long run, starting with a dopamine agonist does not improve outcomes.
In one study, data were compared between a large cohort of patients with Parkinson’s disease in Ghana, where levodopa therapy was initiated after a mean of 4.2 years’ disease duration, and patients with Parkinson’s disease in Italy, where levodopa was initiated at a mean of 2.4 years’ disease duration. “Disease duration and medication dosage, rather than the duration of levodopa therapy, affected the likelihood of dyskinesia,” Dr. Nirenberg said. “When you start levodopa late, you miss the honeymoon period,” she said, referring to the period during which patients experience the benefits of levodopa therapy before developing motor complications. “Simply put, levodopa as initial treatment works better [and] has fewer short- and long-term adverse effects [than dopamine agonists].”
Dopamine agonists are highly efficacious as add-on treatment, but they also can have serious adverse effects. “Neurogenic orthostatic hypotension, psychosis, and sleepiness are adverse effects that are worse with dopamine agonists than with levodopa,” Dr. Nirenberg noted. “Another common adverse effect associated with dopamine agonists is impulse control disorders—pathologic gambling, compulsive eating, compulsive shopping, and hypersexuality.”
MAO-B inhibitors are also commonly used, well-tolerated medications that can be administered alone or in combination with levodopa or other medications. Of these drugs, selegiline and rasagiline can be used as monotherapy, Dr. Nirenberg noted, but a newer MAO-B inhibitor, safinamide, is not effective as monotherapy and should only be used as an adjunctive therapy with levodopa.
Extended release (ER) carbidopa–levodopa capsules, which contain immediate-release and ER beads to provide initial and extended levodopa plasma concentrations, have been effective in reducing wearing off between doses of levodopa, but conversion to this formulation from immediate-release levodopa is not straightforward. Rather than using the suggested conversion table in the package insert, neurologists might try the approach suggested by investigators who participated in the original clinical trials, said Dr. Nirenberg. Extended-release “capsules can be twisted open, and the beads poured into applesauce for people who have trouble swallowing,” she added.
Amantadine and anticholinergics are second-line medications that can be used as initial or adjunctive therapy. “They are weaker than the first-line drugs and have unfavorable adverse-effect profiles,” said Dr. Nirenberg. Amantadine, of which a newly approved extended-release formulation is available, can reduce dyskinesias.
New and Investigational Treatments
Deep brain stimulation (DBS) techniques are advancing, said Dr. Nirenberg. With DBS, a device implanted in the chest sends electrical pulses to electrodes inserted into targeted areas of the brain. “Recent studies are looking at closed-loop systems that provide direct feedback from the brain to the pacemaker so that stimulation is adjusted in real time.”
Continuous enteral infusion of carbidopa–levodopa intestinal gel over 16 hours via percutaneous endoscopic gastrojejunostomy is an option for people for whom DBS is being considered, but who have contraindications such as cognitive impairment or psychosis. “This [treatment] should only be prescribed to someone who has a good caregiver, because the pump has to be flushed often, removed before bathing, and checked to make sure there are no hardware problems or infections associated with its use.”
Droxidopa, a synthetic amino acid precursor of noradrenaline, received orphan-product designation for treatment of neurogenic orthostatic hypotension. Its effectiveness was shown in two two-week clinical trials. “It is expensive, costing tens of thousands of dollars per year. Although it is well tolerated, there is evidence of tachyphylaxis, and it may not work for longer than two weeks.”
Pimavanserin, a first-in-class drug approved in 2016 to treat hallucinations and delusions associated with Parkinson’s disease psychosis, is an atypical antipsychotic with a serotonergic mechanism of action. While the prospect of having such a treatment option initially generated excitement in the medical community, there have been recent concerns about adverse events in patients taking pimavanserin, including deaths, falls, insomnia, and nausea, in addition to continued hallucinations.
Focused ultrasound is approved for essential tremor and is investigational for Parkinson’s disease, Dr. Nirenberg noted. During the procedure, which can be performed on an outpatient basis, focused beams of ultrasonic energy are trained on targets deep in the brain to destroy diseased tissue without damaging surrounding normal tissue. Because of the lack of long-term follow-up of these patients, neurologists “do not know where this ultimately will fit in with Parkinson’s disease management,” said Dr. Nirenberg. Focused ultrasound is mainly being investigated as unilateral treatment because of concerns about the safety of bilateral ablative therapy.
To date, research on oral cannabinoids has not shown evidence of benefit for Parkinson’s disease, said Dr. Nirenberg. Neurologists have concerns about potential drug interactions and side effects such as imbalance, falls, cognitive impairment, and psychosis, which are of particular concern in people with Parkinson’s disease.
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(Pt 10):2731-2742.
Tetrud J, Nausieda P, Kreitzman D, et al. Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson’s disease. J Neurol Sci. 2017;373:116-123.