Addressing Levodopa-Resistant Parkinson Disease

Degeneration of a neuron
Degeneration of a neuron
In later stages of the condition, it is possible that the nerves become incapable of storing dopamine consistently, rendering levodopa practically useless, even if it is administered more regularly.

Parkinson disease (PD) has a wide range of symptoms, including slow movement, lack of dexterity, tremors, rigidity, freezing gait, and a host of other motor and cognitive degenerations. Although there is no cure for PD, the most common method used to control symptoms is the administration of levodopa — a natural dopamine precursor. However, unlike dopamine, it can easily pass into the brain and be used for neural signalling.

Levodopa has very mild side effects and, according to Giuseppe Frazzitta, head of the PD and neurorehabilitation department at Moriggia-Pelascini Hospital in Italy, it is “the best drug for rigidity and bradykinesia in PD.” However, the drug is not effective for parkinsonism (progressive supranuclear palsy, multiple system atrophy) — the symptoms of tremors and slowness of movement. “While levodopa is effective in the early stages of the disease, as the condition progresses and the symptoms of postural and gait dysfunction arise, the drug becomes ineffective.” In rare cases, levodopa may even exaggerate these symptoms and cause worsening of the patient’s cognitive function.

Why Does Levodopa Resistance Occur?

Although levodopa resistance can happen at any time, resistance develops in the majority of people at later stages of disease progression, or when they have been living with the condition for a long time.1 Levodopa is absorbed in the intestines and has a relatively short half-life of approximately 1.5 hours; therefore, after administration of the drug, patients experience a short, intense peak of the chemical in the blood stream.2 Some levodopa is broken down into dopamine in the intestines by the catechol-O-methyltransferase (COMT) enzyme and the rest is converted into dopamine by neurons in the brain.3

In the early stages of PD, dopaminergic neurons in the adrenal medulla can produce and store the dopamine, allowing the beneficial effects of levodopa to persevere over an extended period. However, as the disease progresses and the cells in the brain continue to deteriorate, their capability to store dopamine becomes greatly impaired. Subsequently, the beneficial effects of levodopa become increasingly short lived. In later stages of the condition, it is possible that the nerves become incapable of storing dopamine consistently, rendering levodopa practically useless, even if it is administered more regularly.2

Treatment Options

According to Mayo Clinical neurologist Angela Deutschlaender, MD, PhD, “levodopa drugs with differential half-lives as well as different methods of application, such as nasal or intramuscular delivery, may provide help in some levodopa-resistant patients with typical parkinsonism. Nasal delivery avoids the drug not being absorbed in the intestines — by inhaling the drug, it can be absorbed into the blood stream and access the brain quicker. Another possibility is the well-known intramuscular apomorphine injection (administered to the area of the abdomen or legs). Apomorphine has a short half-life and acts fast.”

Other treatment options include COMT blockers, drug pumps, prescription medications, and in severe cases, deep brain stimulation.

COMT Blockers

Resistance to levodopa manifests as motor response fluctuations, or “wearing off,” which essentially means that the effect of the drug is shortened and the patient’s symptoms will return before their next scheduled dose. If this occurs, the first course of action is the administration of COMT blockers alongside the levodopa. By blocking COMT, the levodopa is not metabolized into dopamine in the intestines, and therefore can reach the brain. Any levodopa converted to dopamine outside of the brain cannot be used for neural signalling because dopamine cannot cross the blood-brain barrier. COMT blockers can also be useful if patients show signs of levodopa resistance at earlier stages of the disease when peripheral metabolism of the drug can appear to cause a reduced sensitivity to it.4

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Drug Pump

Another method to improve the administration of levodopa is to use a “drug pump,” which administers a levodopa gel constantly. Use of a drug pump means that levodopa levels never drop and the neurons don’t have to store dopamine; they can produce it as needed. The downside to this method is that surgery is required to install the pump, which can cause complications such as infection where the tube enters the body or a blockage in the tube.2,5

Prescription Medications

If the patient is (or is becoming) resistant to levodopa and prolonged administration does not improve symptoms, there are other drugs that can be used to treat the condition. Dopamine agonists and monoamine oxidise-B (MAO-B) inhibitors are the 2 most common classes of drugs used. Dopamine agonists, such as pramipexole and ropinirole, act as an artificial dopamine and allow the nerve cells to signal and better regulate body movement,5 whereas MAO-B inhibitors such as rasagiline and selegiline stop dopamine from breaking down,6 allowing the dopamine to exist longer in the brain so that it can continue to act as a messenger for the brain.

Dopamine agonists can be used over a longer duration than levodopa because they have fewer long-term side effects and can be taken in addition to or instead of levodopa. This makes it especially useful for managing symptoms as levodopa resistance develops in a patient.5 MAO-B inhibitors are often used in conjunction with levodopa, but they are also used to treat early stage PD.6

The problem with alternatives to levodopa, however, is that they all have more common and severe side effects.3

Deep Brain Stimulation (DBS)

If a patient has become unresponsive to all medical therapies, or if the side effects of the drugs are too severe, DBS can be offered as a method to manage symptoms.7 This treatment has been found to control symptoms effectively and improve quality of life in the majority of patients who undergo the procedure. However, it is not successful for all patients and in some cases may even have a detrimental effect on cognitive function. This is a highly invasive surgery and should not be used as a first line of treatment.

By using one or a combination of these treatments, symptoms can usually be managed effectively and people with PD can enjoy an improved quality of life and increased longevity, even if they have resistance to levodopa. It is ultimately the responsibility of the healthcare provider to weigh the pros and cons of each treatment option, with the final decision being highly dependent on the individual patient, the severity of the symptoms, and the side effects the patient experiences from each treatment.


  1. Nonnekes J, Timmer MH, de Vries NM, Rascol O, Helmich RC, Bloem BR. Unmasking levodopa resistance in Parkinson’s disease. Mov Disord. 2016;31(11):1602-1609.
  2. Thankvi BR, Lo TC. Long term motor complications of levodopa: clinical features, mechanisms, and managements strategies. Postgrad Med J. 2004;80:452-458.
  3. Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014;13(2):141-149.
  4. Parkinson’s Disease Clinic and Research Center. Catechol-O-methyl Transferase (COMT) Inhibitors. University of California, San Francisco School of Medicine. Accessed October 17, 2018.
  5. Parkinson’s UK. Dopamine agonists. Updated August 2015. Accessed October 17, 2018.
  6. Parkinson’s UK (2015). MOA B inhibitors. Updated August 2015. Accessed October 17, 2018.
  7. Pham T, Bronstein JM. Neuropsychological outcomes from deep brain stimulation – stimulation versus micro-lesion. Ann Transl Med. 2017;5(10):217.