Should People with Parkinson’s Delay Starting Medication?

The question of when to start medication is one most people with Parkinson’s disease (PD) will need to consider at some point in the course of their illness. As PD is caused by a degeneration of the cells that produce dopamine in the brain, medications, commonly in the form of levodopa or dopamine agonists, aim to restore a balance of this important neurotransmitter in order to alleviate troublesome symptoms. Despite their efficacy, many people with Parkinson’s may be hesitant to start taking medications. They may worry about bothersome side effects, potential long-term toxicity, and whether or not the medications speed up disease progression or lose effectiveness over time.

Worrying about side effects is the top reason people with Parkinson’s are hesitant to start medication (Mestre et al., 2014). Their fears are not completely unfounded – younger individuals with Parkinson’s are particularly at risk of developing levodopa-induced dyskinesia, a common side effect that is characterized by abnormal, involuntary movements. This is why another class of drugs called dopamine agonists may be the best choice at the beginning of their treatment. While these drugs may provide symptom relief for a long duration of time in those who can tolerate them, dopamine agonists are not ideal for everyone. For a small subset of individuals, they have been associated with the emergence of behavioral changes, such as impulse control disorders (Thanvi et al., 2007).

One unique study looked at motor side effects, such as dyskinesias, as a result of levodopa use. Individuals with Parkinson’s disease from Italy and Ghana were compared. Those from Ghana had experienced symptoms of PD longer before starting levodopa, as economic factors resulted in limited access to medication. When compared to people from Italy, who commenced medications much sooner after the onset of symptoms, both groups developed motor complications, like dyskinesia, from levodopa at similar stages of disease progression. Thus, it appears that how long someone has had Parkinson’s disease, not the timing of starting levodopa, is responsible for the emergence of motor complications. In fact, several studies have shown that motor side effects and dyskinesias first appear approximately six to seven years after symptoms begin, regardless of when levodopa was started. The authors therefore concluded that there was no benefit in delaying levodopa (Cilia et al., 2014).

Despite the risks of dyskinesia, behavioural changes, and other unwanted side effects, there are risks to delaying medication. Uncontrolled motor symptoms of Parkinson’s disease can increase the likelihood of falls, which can lead to fractures, hospitalization, and other adverse health outcomes. While it is completely reasonable to consider the pros and cons of taking medication, it is important to keep in mind that choosing to delay medication comes with its own set of risks and rewards.

Beyond the concerns of side effects, many people with Parkinson’s, as well as researchers, have wondered about levodopa’s long-term safety and whether it is toxic for humans. Some in vitro studies (conducted on cells in laboratories, often grown in petri dishes) have shown that levodopa can possibly degenerate dopamine neurons, but similar findings in humans or animals have not been found (Mytilineou et al., 2003). One reason why levodopa may be toxic to cells in a petri dish, but not to cells within a human brain, is because neurons in the brain are supported by a network of glial cells, which protect and transport nutrients to them. There are far fewer glial cells in in vitro conditions, making those neurons more vulnerable. One researcher notes that in addition to levodopa, oxygen and calcium are also more toxic in vitro (Agid, 1998).

A randomized, double-blind, placebo-controlled study (the gold standard of scientific research) on 361 people with Parkinson’s disease sought to uncover whether levodopa use could accelerate neurodegeneration. Study participants were split into two groups – one receiving levodopa, another receiving a placebo – for 40 weeks. They were not allowed to take any other anti-parkinsonian medication during the study. At the end of the study, participants underwent a two-week “washout” period, which meant they stopped taking the medication to clear it from their system, giving the researchers an ability to see if the medication made a clinical difference in their disease progression. They found no evidence that levodopa made Parkinson’s any worse. In fact, when compared to the group receiving a placebo, the participants in this study taking levodopa actually had less worsening of their PD symptoms, which could possibly suggest levodopa may slow disease progression. However, the researchers cautioned that future research is needed on this topic to conclusively determine if levodopa is protective, harmful, or neither (The Parkinson Study Group, 2004). Another study compared starting levodopa early versus late and found no significant differences in outcome between the groups at the end of the study period (The LEAP Study Group, 2019).

Additionally, some people consider delaying medications in fear that they will lose their efficacy over time. Fortunately, this does not seem to be the case either. As the disease progresses, people with PD will need to take more medication, not because the drugs are losing their effectiveness, but rather because there are less dopaminergic neurons in the brain, and therefore a worsening of symptoms occurs. There also may be misunderstandings about what drugs like levodopa can help with. Non-motor symptoms, such as depression, cognitive problems, and bowel/bladder issues cannot be treated with levodopa and may develop as PD advances. The inability of levodopa to treat these symptoms may lead someone to incorrectly think that it is losing its effectiveness (American Parkinson Disease Association, n.d.).

If, for whatever reason, you choose to delay medication, know that there are alternative options you can try. Exercise has, time and time again, been shown to be one of the most powerful non-pharmacological treatments available for PD. Exercises that incorporate movement, balance, flexibility, and coordination, such as tai chi and yoga, can be especially helpful for motor symptoms. Movement therapies, like the Alexander Technique, may also be beneficial for mobility in people with PD (Hopkins Medicine, n.d.).

If you have any questions about medication, make sure to speak with your doctor or pharmacist.

Sources

Agid, Y. (1998). Levodopa: is toxicity a myth? Neurology, 50(4), 856-853.

American Parkinson Disease Association (n.d.). Levodopa and Parkinson’s Disease. https://www.apdaparkinson.org/article/five-myths-about-levodopa

Cilia, R., Akpalu, A., Sarfo, F. S., Cham, M., Amboni, M., Cereda, E., Fabbri, M., Adjei, P., Akassi, J., Bonetti, A., & Pezzoli, G. (2014). The modern pre-levodopa era of Parkinson’s disease: Insights into motor complications from sub-Saharan Africa, Brain, 137(10), 2731-2742. https://doi.org/10.1093/brain/awu195

Hopkins Medicine (n.d.). 6 Medication-Free Ways to Feel Better with Parkinson's Disease. https://hopkinsmedicine.org/health/conditions-and-diseases/parkinsons-disease/6-medication-free-ways-to-feel-better-with-parkinsons-disease

Mestre, T.A., Teodoro, T., Reginold, W., Graf, J., Kasten, M., Sale, J., Zurowski, M., Miyasaki, J., Ferreira, J. J., & Marras, C. (2014). Reluctance to start medication for Parkinson's disease: A mutual misunderstanding by patients and physicians. Parkinsonism Relat Disord., 20(6), 608-612. DOI: 10.1016/j.parkreldis.2014.03.001

Mytilineou, C., Walker, R. H., JnoBaptiste, R., & Olanow, C. W. (2003). Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress. Journal of Pharmacology and Experimental Therapeutics, 304(2), 792-800. doi: 10.1124/jpet.102.042267

Thanvi, B., Lo, N., & Robinson, T. (2007). Levodopa‐induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment. Postgraduate Medical Journal, 83(980), 384-388. doi: 10.1136/pgmj.2006.054759

The LEAP Study Group (2019). Randomized delayed-start trial of levodopa in Parkinson’s disease. The New England Journal of Medicine, 380, 315-324. DOI: 10.1056/NEJMoa1809983

The Parkinson Study Group (2004). Levodopa and the progression of Parkinson's disease. The New England Journal of Medicine, 351, 2498-2508. DOI: 10.1056/NEJMoa033447

This content was published in the Summer 2023 edition of our quarterly magazine, Viewpoints. The content was accurate as of this publication date.