A Golden Anniversary to Celebrate – Levodopa and Parkinson’s disease

Over the past 50 years since it emerged for treating Parkinson’s disease (PD), levodopa has been a mainstay therapy. Also known as L-DOPA, it is the active ingredient of Sinemet® and is available as a generic drug, mixed together with carbidopa. Levodopa continues to amaze patients and physicians alike with its remarkable ability for restoring functionality. The majority of patients experience improvements even from the first doses, and these benefits never are lost. Levodopa is one of the most cost-effective medications ever developed. Even though other options are available for treating symptoms of PD, none has greater impact at improving quality of life for this disorder. Unlike many other medications, levodopa is nothing more than a simple amino acid, present in some foods and normally synthesized in the brain (although, in PD, not in sufficient quantity). The pharmacological concept behind levodopa involves replacing an important signaling chemical in the brain, dopamine, which is necessary for enabling normal movement and for preventing tremors and rigidity. Levodopa is not a cure and is far from perfect as a symptomatic treatment. Nevertheless, it is difficult today to imagine living with PD in the absence of this treatment option.

Although the pharmacological concept of levodopa as a direct precursor of dopamine seems logical, there is actually greater complexity to this drug. Levodopa has additional actions in the nervous system that are means unrelated to the generation of dopamine. Outcomes after chronic therapy with levodopa also can be puzzling, in that some patients start to experience inconsistency of benefits or involuntary movements (dyskinesias or dystonia). Not all patients experience these problems, and the risk factors for acquiring them are still poorly understood. We don’t know how to prevent dyskinesias other than by avoiding the use of levodopa altogether, which would be a bad idea considering all the benefits it can offer. There isn’t sufficient evidence to recommend a plan for holding back on adequate levodopa dosing (that is, less than the amount a patient needs for ideal relief of PD symptoms). Another long-standing controversy pertains to combining levodopa with drugs classified as dopaminergic agonists: pramipexole, ropinirole, or rotigotine. In the past, several inconclusive studies were carried out to determine if combination therapy might help to prevent the development of dyskinesias. It now seems clear that the use of dopaminergic agonists doesn’t seem to confer any improved outcomes, although these drugs can be quite useful when added to levodopa for enhancing its effects. Involuntary movements developing during chronic therapy with levodopa are sometimes more feared than they should be, since they can be quite mild (and only one-third or fewer of chronically-treated patients ever develop them). The use of amantadine can block dyskinesias for some patients, and adjusting levodopa dosing can also lessen problematic dyskinesias if they occur. 

Another concern about when to start levodopa is sometimes encountered by patients trying to learn about the drug: this is the mistaken notion that levodopa has only a limited duration of action before it loses its effectiveness. Often, periods of no more than 5 years have been cited for such an outcome, but there is no evidence for this. Other misinformation about levodopa includes fears that it is potentially toxic and, therefore, should be delayed in its start and dosing minimized. Again, this widely-held but incorrect notion sometimes appears on the Internet or even in advice given by physicians. There is no substantiation for many concerns about the safety of levodopa and, hence, no reason to be fearful of using this important PD therapy. The major fault with levodopa is the short-duration of effect and inconsistency of uptake from oral administration. These problems become evident for some patients within three years after onset of this drug and are associated with frustrating experiences of “off” states, sometimes less than predictably throughout the day. Factors that interfere with regular uptake of levodopa include the influence of meals (and sometimes their protein content). Because of its rapid clearance from the bloodstream after oral dosing – for some patients, as short as 2 ½ hours – a treatment schedule with multiple daily dosings can be necessary. There is no absolute limit to the daily intake of levodopa; in its typical carbidopa-levodopa 25-100 formulation, up to 12 tablets per day might be necessary for optimal symptom control. Ideally, this medication should be adjusted to gaining maximal control of PD symptoms, and for many patients, experimentation with increased dose may be a good idea. Patients should keep in mind that levodopa doesn’t help all of the problems of PD – forward flexed posture, imbalance, “freezing of gait”, and speech impairment are examples of its limitations. Nevertheless, under-medication with levodopa is a common missed opportunity for maximizing benefit with this therapy. Longer-acting formulations of carbidopa-levodopa have been a long-term goal of improving treatment outcomes. Sinemet CR® and Stalevo® were developed for this purpose, but these products often fail to deliver extended relief with levodopa. Another controlled-delivery formulation, Rytary®, was developed to serve this need. Though effective for many patients, it sometimes presents a challenge for finding the optimal crossover from a prior immediate-release carbidopa-levodopa regimen, and the cost of its co-pay with some medication insurance plans can be substantial. Intestinal infusion of carbidopa-levodopa (Duopa®) in liquid form by pump is another option for extremely problematic motor fluctuations. This involves inserting a tube into the stomach through the abdomen, and so is reserved for the most severe problems. Fortunately, the pharmaceutical industry has been active at improving ways that levodopa can be delivered. Currently under development (and in clinical trials at Henry Ford Hospital and other locations) are a long-acting formulation of carbidopa-levodopa (the Accordion Pill) and a subcutaneous infusion of carbidopa-levodopa in a liquid formulation. Also under development is an inhaled version of levodopa that can be rapidly absorbed by inhaling it as a rapid means for recovery from an “off” state. Other research into ways to deal with the irregularity of levodopa effect are ongoing. Of course, we need to understand more about how levodopa works so that the initial ideal experience most patients have with this drug (which generally is without dyskinesias or fluctuations in benefit) could be continued lifelong. 

In summary, levodopa is a naturally-occurring substance that for a half-century has offered PD patients a means for return from the discomforts and disabilities of this disorder. For those not well controlled with this drug in its current forms, new products may make life with PD a little bit easier. Ways to lessen its possible side-effects are also the topic of ongoing research
studies.

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